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Journal of Drug Delivery Science and Technology 78 (2022) 103936
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Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst
Review article
Sustained and targeted delivery of hydrophilic drug compounds: A review

of existing and novel technologies from bench to bedside
Daniel Hawthorne a, *, Ananth Pannala b, Susan Sandeman c, Andrew Lloyd d
a
Centre for Regenerative Medicine and Devices, School of Applied Sciences, University of Brighton, Brighton, BN2 4GJ, UK
b
Biomaterials and Drug Delivery Research and Enterprise Group, School of Applied Sciences, University of Brighton, Brighton, BN2 4GJ, UK
c
Centre for Regenerative Medicine and Devices, University of Brighton, Brighton, BN2 4GJ, UK
d
School of Applied Sciences, University of Brighton, Brighton, BN2 4GJ, UK
A B S T R A C T
The sustained and/or targeted delivery of hydrophilic drugs is an important field within drug delivery, presenting unique challenges when compared to that of
hydrophobic drugs. Yet relatively few comprehensive reviews specific to hydrophilic drug delivery have been published recently. In this review, therefore, we seek to
establish the recent trends in the delivery of hydrophilic drugs in particular, and recent developments including electrospun core-shell nanofibrous materials, stimuli-
responsive hydrogel carriers, amphiphilic drug-drug conjugates (ADDCs), and nanomaterials including polymer nanoparticles (PNPs), solid lipid nanoparticles
(SLNs), micelles, liposomes, and mesoporous silica nanoparticles (MSNs). A recurring trend in the field has been the relatively slow translation of novel technologies
into viable pharmaceutical products, with few reaching clinical trial phase. Furthermore, we consider the bench-to-bedside potential of these novel technologies,
taking into account the capabilities of these concepts to overcome the technical, legislative, and commercial requirements that must be met in order for a viable
device to be adopted in the real world.
1. Introduction biomolecule ligands for use in targeting pathologies which overexpress

certain biomolecules, for example [5,6], while those to improve mem
Whilst the objectives of using novel technologies in both hydrophilic brane permeation have included lipid conjugated and encapsulation in
and hydrophobic drug delivery are by and large very similar – i.e., lipid vesicles [7,8]. Improved drug lifetime, for example, by instilling a
predictable and constant sustained release, triggered and/or targeted resistance to drainage, has been achieved by conjugating, entrapping or
release, and increased membrane permeation and bioavailability [1] – otherwise embedding the drug within mucoadhesive polymers, and
the methods used to reach these goals can be very distinct due to the nanoparticles of the same [9,10].
opposing natures of these two classes of drugs [2]. In many cases, the There are, undeniably, technologies which can be used to improve
aqueous solubility of hydrophobic drugs must be modified to improve its the sustained and targeted delivery of both hydrophilic and lipophilic
initial dissolution into the aqueous fluids. On the other hand, aqueous compounds. Indeed, co-delivery systems for the simultaneous targeted
solubility is an inherent property of hydrophilic drugs. While this en and sustained release of hydrophilic and hydrophobic drugs together
hances initial mobility within the body fluids, the drugs are susceptible have become more commonplace; these have included amphiphilic
to rapid elimination, and are also unable to cross lipid barriers (e.g. the drug-drug conjugates (ADDCs) and amphiphilic vehicles such as poly
blood-brain barrier), leading to reductions in drug lifetime, bioavail mersomes and polymer nanoparticles [11–14]. However, while many
ability, and productive absorption [3]. review articles have detailed various approaches to specific diseases,
Therefore, common approaches used both historically and contem drugs, classes of drug delivering device, and their applications, rela
porarily in hydrophilic drug delivery technologies have included tively few have been dedicated to the sustained and targeted delivery of
encapsulation within nanocapsules, microemulsions, or nanoparticles, hydrophilic compounds specifically [3,11].
conjugation to hydrophobic moieties such as lipids and polymers using Another important aspect which will be considered in this critical
labile bonds, and immobilisation within macromolecules and three- review is the feasibility of the bench-to-bedside conversion and com
dimensional structures such as hydrogels [1–4]. Innovations to mercial viability for these technologies and devices. The so-called
improve site-specific targeting have included conjugation to ‘translational medicine’ approach will be considered in this review
* Corresponding author.
E-mail address: [email protected] (D. Hawthorne).
https://doi.org/10.1016/j.jddst.2022.103936
Received 28 February 2022; Received in revised form 21 October 2022; Accepted 30 October 2022
Available online 4 November 2022
1773-2247/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
D. Hawthorne et al. Journal of Drug Delivery Science and Technology 78 (2022) 103936
[15]. For a technology in the stages following laboratory inception to coaxial electrospinning experiment is shown in Fig. 1.
complete the translation into clinical trial and commercial adaptation, Coaxial electrospinning provides a rapid way to produce core-shell
there are numerous regulatory requirements and physicochemical pre fibres in a single step, reducing processing time. Moreover, coaxial
requisites that must be met and demonstrated [16,17]. Some of these electrospinning reduces the burst release profile of weakly surface-
relate to shelf life, processing and suitability for scale-up, and – bound hydrophilic drug molecules from the fibre, when compared to
crucially, in particular, for implant-based technologies – the ability of singly electrospun fibres [22]. This can otherwise be achieved by
the device to withstand aggressive sterilisation conditions [18]. These post-treatment including cross-linking or coating the formed fibres in a
considerations are, in many research articles, inadequately explored or second processing step, though both of these options have disadvantages
not considered at all, since many publications for devices at the primary such as increasing cellular toxicity [22]. Fibres can be further processed
research stage are initial, proof-of-concept investigations. into mats or membranes [23–25], from which the rate of release of a
We therefore aim to provide a unique perspective in recent trends in drug is typically diffusion controlled and dependent on the wettability of
the drug delivery review literature; one which focuses primarily on the fibrous matrix [23]. As aqueous channels form through the pre
systems for the sustained and targeted delivery of hydrophilic drugs, and dominantly hydrophobic material slowly, the drug is able to diffuse
one which emphasises the long-term uptake of these systems and drugs. outwardly only at a rate dependent on the permeation of water through
The systems will also be contextualised in terms of applicability to in it. Thus, a plot of drug release over time is theoretically very similar in
dustrial processing and sterilisation requirements, and viability for up shape to the plot of hydration or swelling over time. In turn, the
take as medical devices. wettability of the fibres is affected by their physical properties such as
their hydrophilicity.
2. Electrospun nanofibers and nanofibrous materials
Electrospinning allows facile fabrication of polymer-based devices 2.1. Recent advances in electrospun delivery devices for hydrophilic drugs
with desirable properties including nanometric dimensions, high surface
area to volume ratio, and high porosity, leading to excellent drug Both synthetic and natural polymers have been used successfully in
encapsulation and release [19–21]. In electrospinning, polymer solu the synthesis of electrospun nanofibers. A selection of recent publica
tions are driven through an electrically charged tip, or spinneret, using a tions detailing these devices is presented in Table 1. Formulations of
syringe pump. The application of a high voltage to the droplets exiting electrospun fibre systems have been optimised to encapsulate drugs in a
the tip results in the stretching of the droplet, forming a charged liquid variety of materials, including synthetic and natural polymers. The
jet which accelerates towards an oppositely charged collector. Charge polyesters poly(caprolactam) (PCL), poly(lactide) (PLA), poly(glycolide)
repulsion within the fibre itself, as it accelerates in flight, leads to the (PGA), poly(lactide-co-glycolide) (PLGA), and their copolymers feature
formation of fibres of a reproducible size. Parameters which can be in many published articles; they are well-known biocompatible and
adjusted to influence the structure of the deposited fibres include the biodegradable polymers, with biologically compatible degradation
tip/collector voltage, the solution flow rate(s), collector/tip distance, products [26–28]. PCL fibres formed the basis of several recently pub
polymer solution concentration, and the solvent volatility [19]. lished articles [22,23,29], and fibres composed of PCL and other poly
Recently (within the last 15–20 years), coaxial electrospinning has mers have been used to encapsulate hydrophilic drugs including
been increasingly important in the synthesis of core-shell-type fibres ampicillin, tetracycline and doxorubicin hydrochloride [24,30–32].
with tuneable properties [19–21], allowing hydrophilic drugs to be Sultanova et al. produced coaxially electrospun fibres of the hydro
encapsulated in a hydrophilic or hydrophobic matrix, within a pre philic antibiotic, ampicillin, in PCL, achieving near zero-order release
dominantly hydrophobic outer sheath layer. To achieve this, a second for >72 h [22]. The core was spun from a 10% w/v solution of PCL
polymer solution is introduced to the electrospinning spinneret at a containing 2% w/ampicillin, and the shell was made of a 4% w/v PCL
perpendicular angle to the first solution. When the two polymer solu only. Shell thickness was modulated by modifying the flow rate of the
tions have differing properties, this results in a core-shell fibrous shell solution relative to that of the core solution. In a core-only fibre,
structure of the deposited fibre. Additional secondary interactions, such almost 80% of the drug was released in 4 h; by comparison, a core-shell
as hydrogen bonding, can improve the compatibility of the hydrophilic fibre released just 15% of drug in the first 4 h, with 90% release even
drug core with the hydrophobic shell [19–21]. A typical setup for a tually reached after 72 h. Further experiments showed that increased
shell thickness led to a decrease in rate of drug delivery, supporting the
Fig. 1. Apparatus configured for the coaxial electrospinning of core/sheath fibres from two polymer solutions.
2
Table 1 The mechanism of hydrophilic drug delivery from hydrophobic fi

Electrospun nanofibres and nanofibrous materials used in the delivery of hy bres was studied in more detail recently by Zupančič et al. [23]. Here,
drophilic drugs in the recent literature. nanofibrous mats were produced by monoaxial electrospinning of PCL
Ref Drug compound Description of Release characteristic solution containing metronidazole (MET) and/or ciprofloxacin hydro
electrospunfibre system chloride (CIP), intended for sustained delivery to the periodontium. By
[22] Ampicillin Drug-loaded core/shell Pseudo-zero order electrospinning onto a rotating drum which also moved back and forth
PCLa fibres produced kinetics over 72 h with along its axis, nanofibrous mats of reproducible, varying thicknesses
through coaxial shell, cf. << 24 h could be deposited, controlled by the length of experiment. The material
electrospinning burst release in core
properties found to affect release profile most were the thickness of the
only fibre
[23] Metronidazole Periodontal antibiotic MTZ release nanofibrous mat, its surface area, and the temperature of the release
(MTZ); ciprofloxacin delivery; Electrospun dependent on mat medium. For MET release, mat thickness was found to be of high sig
(CIP) PCL nanofibre mats thickness; CIP release nificance (release rate was inversely proportional to mat thickness),
dependent on while for CIP, drug release rate was independent of mat thickness.
wettability. Maximum
lifetime for MTZ =
Varying surface area was found to be far less significant in release of
200 h; for CIP = 30 h MET from the thickest mat tested. Increasing temperature from 22 ◦ C to
[33] Ampicillin Amyloid-like bovine Sustained release for 37 ◦ C had the effect of increasing the maximum amount of drug released
serum albumen fibres up to 150 h, Fickian from 60% to 100% over an 8 day period, for the thickest mat tested.
produced by diffusion at ≤ 10% w/
Contact angle measurements showed no difference in wettability be
electrospinning w ampicillin/BSA
[34] Tamoxifen citrate Colonic delivery; pH- 6% release in 2 h at tween drug-loaded and drug-free mats, implying that the properties of
sensitive coaxially stomach pH of 2.0. the bulk polymer, and not the drug, are the major influence in wetta
electrosprayed Triggered release at bility and drug release in nanofibre and nanofibrous mat drug delivery
hydrophilic poly(vinyl pH 7.4100% in 5 min. devices.
pyrrolidone) (PVP)-drug
Copolymer and mixed polymer solutions are also commonly used for
core/shellac shell
nanocomposite particles the adjustment of material properties when compared to single-polymer
[29] Tetracycline Alginate/soy protein Initial burst release of fibre components, allowing fine-tuning of the drug release profile ac
isolate core-PCL sheath 49% in 6 h, followed cording to the properties of the carrier system. For example, while PCL is
scaffold constructed via by slow release for a
by far the most used polymer due to its low price and biological
coaxial electrospinning ≥14 days.
[12] Doxurubicin HCl Electrospun nanofibre Ca. 70% release over 8 compatibility, both synthetic and natural polymers such as PLGA [30],
mats composed of h PEG [32] and chitosan [24] have all been used to modify physico
regenerated silk fibroin chemical properties of the spun fibres. In a recent example [30], elec
[35] Diclofenac sodium Electrospun cellulose Linear release for trospun PCL/PLGA fibres were developed as sustained delivery devices
acetate nanofibrous initial 10 h (20%);
for various hydrophilic antiretrovirals, with the ratio of PCL to PLGA
mats then sustained release
up to 100% for 48 h. having significant effect on the release of the drugs. For example, the
[30] Tenofivir, Electrospun PCL-PLGA Sustained release for release of tenofovir from PCL-only fibres was complete within 48 h
azidothymidine, fibres up to 240 h, dependent (100% of encapsulated drug); on the other hand, fibres comprising a
maraviroc, on loading and ratio of
40:60 ratio of PCL:PLGA released ca. 70% of encapsulated drug in 240 h.
raltegravir PCL:PLGA
[31] Naproxen Layered double Sustained release for
The difference in the relative flexibilities of the two polymers control the
hydroxide particle- up to 66 days with no diffusivity of the material; PLGA’s rigidity inhibits mobility of the drug,
loaded electrospun PLA burst phase; dependent while the contrasting flexibility of PCL encourages diffusion of drug
fibres on thickness of outward from the fibres.
hydrophobic PLA
Similarly, mixtures of hydrophilic and hydrophobic polymers at
layers
[32] Doxicycline hyclate Coaxially electrospun Burst phase of 40% in different ratios have been used to adjust the release rate of drugs from
PCL/poly(ethylene 1 h, followed by 60% electrospun fibres. Eskitoros-Togay et al. [32] encapsulated the anti
glycol) (PEG) core-shell in 8 h microbial agent, doxycycline hyclate (DCH) in mixed PEG/PCL fibres.
nanofibres
The ratio of hydrophobic PCL to hydrophilic PEG was optimised to give
[24] Metformin PCL/chitosan 50% released within
electrospun nanofibrous initial 24 h, followed
fibres of desirable smoothness and release properties; a fibre with a 3:1
membranes by lag phase (90% in ratio of PCL/PEG with 3.2% drug loading was found to be the optimal
24 days) formulation for sustaining drug release, with 80% release over 6 h; other
[36] Rosmarinic acid Electrosprayed Sustained release for fibres with different drug loading typically released the majority of their
nanoparticles of PLGA up to 96 h
payload within 2 h.
Biopolymers, such as chitosan (which are already widely used in
conclusion that drug release was controlled by the permeability of the drug delivery and as tissue/bone scaffolds [38–40]) have also been used
hydrophilic drug through the hydrophobic core. Ampicillin was also the in mixed material fibres, for example with PCL in the recent work of Zhu
target drug in a study [33] in which electrospun nanofibrous mats of and co-workers for the encapsulation and sustained release of metformin
amyloid protein-like bovine serum albumin were used as a biopolymer [24]. Here, the electrospun fibres not only acted as a drug delivery de
encapsulating agent for the drug. A concentration of 10% w/v ampicillin vice, but also formed membranes to guide localised bone regeneration.
sodium in these protein fibres was found to sustain release of 81.5% of In vitro studies performed on fibres of ratio 7:3 PCL: chitosan revealed a
the encapsulated drug over 96 h. A follow-up study [37] compared the release rate of 95.8% over a period of 24 days, albeit with initial burst
drug release properties of monoaxial electrospun fibres to fibres of release of 50% within 1 day. Other biologically derived material fibres
amyloid-like BSA spun coaxially, from a drug-containing core and a have recently included a dual-drug delivering electrospun nanofibre of
drug-free shell. In these studies, flow rate ratio of drug-free to silk fibroin [12], encapsulating doxorubicin hydrochloride (hydrophil
drug-containing solutions was 0:1, 2:1 and 3:1. It was found that the ic), and curcumin (hydrophobic), with sustaining their release for over
core-shell structured fibres slowed the release of the drug significantly, 12 h.
as expected due to the increased thickness of the relatively hydrophobic Nanofibre mats of another plant-derived polymer, cellulose acetate,
sheath. were studied by Adepu and co-workers [35], for the transdermal de
livery of diclofenac sodium (a hydrophilic non-steroidal
3
anti-inflammatory drug). In this work, the deposition of the hydrophilic, receive regulatory approval to enter clinical trials, manufacturers must
drug-containing polymer onto the surface through a mesh of 100 μm demonstrate capability to produce sufficient volumes of material as
produced micropatterned mats with favourable drug release properties. appropriate for the number of participants in the trial and its duration
This was due to the introduction of air pockets in the mat, reducing (typically in the region of 10–100 participants over 18 months for a
wettability of the micropatterned mats when compared to the hydro Phase I trial) [45,46], while adhering to current good manufacturing
philic, non-patterned mats. Thus, the micropatterned mat sustained a practices (cGMP). For electrospun nanofibres, the rate of production in
near-zero order transdermal release profile for over 20 h (80%), with lag laboratory settings is typically in the region of less than 1 g per hour
phase up to 48 h; for the non-patterned mat, transdermal detection was [47]; managing scale-up is therefore a significant early barrier for many
much more rapid, with >75% encapsulated drug released in 12 h. novel investigational medical products, and especially nano
Stimulus-responsive fibres have also been synthesised using poly pharmaceuticals/nanofibres [45,46]. However, more recent methods
mers with temperature or pH-responsive properties to ensure drug have enabled outputs of several hundreds of grams per hour [47]. Other
release occurs only under physiological conditions. The main advan important barriers for clinical acceptance of nanofibres include their
tages of these ‘triggered release’ systems come in their specificity and stability with respect to the amorphous-to-crystalline transition of the
enhanced stability in storage. In a recent example [41], a drug and polymer (since the improved bioavailability of
temperature-sensitive electrospun fibrous system comprising fibre-encapsulated drug is due to it existing in an amorphous state [47]),
temperature-sensitive poly(N-vinylcaprolactam) (PNVCL), with poly and the dosage, since most drug-loaded nanofiber systems can only
(methacrylic acid), was used to encapsulate a hydrophilic drug, capto incorporate <10% drug by weight. Thus, for drugs of a higher threshold
pril, and a hydrophobic drug, ketoprofen. PNVCL has a lower critical therapeutic range, the physical size of tablets would have to be un
solution temperature (LCST; the temperature above which the polymer comfortably large, creating a patient compliance issue [47].
is insoluble in water) of 33 ◦ C. The release of both drugs in PBS at 20 ◦ C Finally, for any medical device which is to be inserted into the
and 40 ◦ C was monitored; at 20 ◦ C, the maximum concentration of human body, it is critical that the product is sterile. However, selection
released drug was reached rapidly (<250 s), indicating uninhibited of a suitable sterilisation technique is heavily dependent on the material;
release. However, at 40 ◦ C, the maximum concentration was not reached for example, the majority of the electrospun fibres reviewed here are
until after 24 h. Mechanistic studies revealed Fickian diffusion domi based on biologically compatible polyesters such as PCL, which have
nates below the LCST, and non-Fickian anomalous diffusion above it; relatively low melting points (50–60 ◦ C for PCL and some PCL/PLGA
drug absorbed close to the surface is released rapidly, while drug deep blends [48]), making them unsuitable for certain procedures in down
within the hydrophobic form of the fibres diffuses outward slowly. stream processing required for use as medical devices (e.g. steam steri
Release is therefore dependent both on the drug and the morphology of lisation). Even when steam sterilisation can be avoided, other
the polymer. Differences between observed total dissolved concentra commercial sterilisation techniques such as hydrogen peroxide plasma
tions of ketoprofen and captopril in the release study were explained by and ethylene oxide were shown to modify the physicochemical prop
the tendency of hydrophobic ketoprofen to aggregate in water (rather erties of PCL fibres undesirably. UV sterilisation was effective in steri
than dissolve), compared to the rapid dissolution of captopril. Such lising the surface, but is poorly penetrating and unlikely to be effective
responsive systems, while promising in laboratory settings, suffer from in sterilising thicker mats or fibres [49]. Hydrophilic polyesters (e.g.
poor long-term stability and would have to be carefully stored to avoid PGA) are also typically unstable with respect to hydrolysis in extended
undesired triggered release, especially in warm climates. periods of storage in humid conditions or aqueous solutions [50].
In summary, electrospinning is a versatile and effective tool for the Moreover, since the drug delivery profile of nanofibrous devices is based
encapsulation of hydrophilic drugs within a predominantly hydrophobic on wettability, storage in a humid environment for an extended period
matrix, providing a readily tuneable release profile controlled by would result in the gradual loss of drug compound from the fibres, hence
machining parameters and polymer blends (with polymers and co specialised packaging may be required to extend the shelf life of the
polymers which contrast in hydrophilicity/hydrophobicity, or flexi material.
bility/rigidity). Other approaches have included micropatterning, to The future of nanofibres, nanofibrous mats and implants in bench-to-
introduce of air pockets within fibrous mats [35], and the use of bedside translation will be dictated by advances in polymer chemistry
temperature-sensitive polymers for physiologically-triggered drug (with desired tuneable properties in drug loading, hydrolytic degrada
release [41]. In any case, the attributes of critical clinical importance tion, and biological compatibility), and also in improved understanding
include mechanical properties, surface structure, morphology, and of cellular toxicity long term. The final obstacle will be in development
porosity, which are controllable through varying processing parameters of efficient, high yielding, and standardised method for scale-up in their
(including solvent composition, polymer/copolymer composition and manufacture [51], though some organisations have already developed
concentration, flow rate, spinneret voltage, and annealing time) regulatorily compliant manufacturing protocols and facilities for elec
[19–21]. Mechanical properties are most important where drug-eluting trospinning of nanofibrous materials, and some promising clinical trial
electrospun nanofibres are used in scaffolds for tissue regeneration; for results have been obtained (e.g. Afyx’s Rivelin®
example, tensile strength must be sufficient to withstand strain exerted corticosteroid-delivering nanofibrous oral patch) [52].
e.g. during suturing [42]. Stiffness also plays a crucial role in the ability Our second field of consideration focusses on different polymer
of scaffolds to mimic the extracellular matrix that they seek to imitate; systems; those based on hydrogels and the range of drug delivery ap
Nam et al. showed that even if the chemical composition is identical, proaches that have been developed using these materials.
differing elastic moduli of electrospun scaffolds resulted in differentia
tion of stem cells into either chrondrocytes or osteocytes [43]. Encour 3. Hydrogel systems for hydrophilic drug delivery
aging cell adhesion is also crucial in drug-eluting scaffolds for the
scaffolds to be successful in tissue regeneration; cell attachment is Hydrogels are insoluble, yet hydrophilic, cross-linked polymer sys
initially driven by electrostatic interaction, which can be controlled in tems which readily absorb water and become swollen, to the degree that
the initial stages by incorporating charged polymers into the feed the gel’s composition is more water than polymer, and the gel charac
polymer solution, or by applying a positive or negative voltage to the teristics are consequently dictated more so by water than by the polymer
spinneret (thus influencing orientation of dipoles within the polymer [53,54]. This physical stability is a product of their three-dimensional
fibre and resulting in a net surface charge) [44]. structure and cross-linking of polymer chains due to either physical in
Whilst electrospinning presents a simple, rapid way of producing teractions (ionic, dispersion, polar, hydrogen bonding) or chemical
such sustained delivery devices with desirable properties in vitro, their (covalent) cross-linking [55]. Aside from the nature of their
practicability as clinical devices remains to be assessed. In order to cross-linking, hydrogels are commonly categorised in terms of their
4
origin: synthetic or natural [56]. Synthetic hydrogels are, by and large, Table 2
more mechanically robust and resistant to degradation, as well as having Recent publications detailing hydrogel devices used in the sustained and tar
tuneable properties (e.g. controlled by degree of cross-linking agent, or geted delivery of hydrophilic drugs.
derivatisation of pendant groups). Naturally-derived hydrogels are me Ref Drug compound Description of hydrogel system Release
chanically less stable, but are inherently biologically compatible due to characteristic
being formed from degradable polysaccharides or proteins, and thus [57] Levofloxacin Chitosan/acryloylphenylalanine Release
(unlike many synthetic polymers) do not require post-modification such physically cross-linked hydrogel sustained for
as PEGylation to enhance their biological compatibility [53–56]. ca. 60 h
[58] Naltrexone HCl Temperature-sensitive, PLGA-PEG- Systemic
The high water content and low-leakage properties of hydrogels
(NTX), PLGA in-situ gel lifetimes for
make them suitable polymeric vehicles for hydrophilic drug delivery; polypeptide LXT- LXT-101 and
dissolved drugs can be entrapped in the aqueous nodes of the swollen 101 NTX increased
cross-linked polymer matrix [53–55]. However, the relative free by a factor of
movement of small, hydrophilic compounds through the swollen gel 10x and 4x,
respectively.
network facilitates rapid diffusion of drug into the aqueous surround [59] Ornidazole Mucoadhesive hydrogel composed Controlled
ings, resulting in an undesirable burst release [55]. The so-called ‘second of drug embedded in quaternised release for
generation’ of stimuli-responsive hydrogels were able to combat this by dextran-graft-poly ≥200 h
reversibly collapsing into insoluble, densely cross-linked polymeric gels (dimethylaminoethylmethacylate)
[60] Levofloxacin Self-healing hydrogel formed from Biphasic
from a dissolved polymer solution, in response to changes in their sur
L-lysine crosslinked guar gum/poly release profile;
rounding environment. Thus, these systems reversibly entrap or release (acrylic acid) copolymer 50% release in
drug molecules within the gel by a change in conformation [53], which 24 h, 90%
may be ionotropic, thermotropic, or pH-dependent in nature. Fig. 2 release at 110
depicts the reversible collapsing and swelling of a polymeric hydrogel, h
[61] Rivastigmine Intranasal delivery; In-situ gel of Burst release
resulting in drug entrapment/release.
hydrogen tartrate Poloxamer 407 hydrogel- of ≥25% in « 1
The most useful systems in sustained release of hydrophilic drugs, embedded PLGA nanoparticles h; sustained
then, are those which undergo this sol-gel transition under physiological prepared by nanoprecipitation release up to
conditions of pH or temperature [55,56]. In-situ gels are easily handled 60% up to 8 h
[62] Selegiline HCl Nasal delivery; Thermosensitive in- Release
polymer solutions delivered in topical drops or injectable formulations;
situ gels of Pluronic F-127 sustained for 8
gelation under physiological conditions increases viscosity and thus h
slows the rate of elimination of the dissolved drug and polymer by [63] Acetamidophenol Temperature-and pH-responsive in- <5% dermal
transfer in aqueous fluids [55]. Polymers with the opposite behaviour situ forming gel formed from permeation
have also been used in formulations with targeted delivery properties - chitosan and poly(N-vinyl after 24 h at
caprolactam) 32 ◦ C. 30%
for example, oral formulations which must withstand the acidity of the
release after
stomach to deliver drugs in the more alkaline intestinal tract. In these 24 h at 39 ◦ C at
cases, the drug remains immobilised and entrapped in the cross-linked pH 7.4.
polymer network until exposed to the desired physiological condi [64] Fluorescein Silicone hydrogels containing PVP, Sustained
isothiocyanate poly(hydroxyethylmethacrylate) release for
tions, at which point the polymer matrix will dissolve and the drug is
(PHEMA) and ethylene glycol over 24 at
released rapidly [55]. dimethacrylate neutral and
A selection of recent publications detailing hydrogel based materials, alkaline pH;
including those responsive to various stimuli and with self-healing rapid release
properties, is displayed in Table 2. Subcategories of some of the novel in « 10 h in
acidic media
hydrogel systems which have been recently developed in the field of
[65] Rhodamine B Ocular delivery; PLGA-PEG-PLGA Dye retained
hydrophilic drug delivery are summarised and examined in the sub thermosensitive in-situ forming gel for up to 4
sections below. weeks in in
vivo testing
[66] Doxycycline HCl Temperature-triggered phase Sustained
transforming lyotropic liquid release of drug
crystal capsules of glycerol for 24 h, (burst
monooleate and Gelucire® release of 30%
surfactant in first 2 h,
near linear
release until
80% at 24 h)
[67] Bimatoprost Solid lipid nanoparticles prepared Pseudo-first
from glycerol monostearate, soya order release
lecithin, and Tween 80 embedded (>99% over
in a pH-sensitive gel of Acrypol 941 19 h)
[68] Benzydamine HCl Mucoadhesive, thermoresponsive Sustained
polymer gels of poloxamer, PVP, release for at
and chitosan least 3 h
(49%).
[69] Acetylsalicylic Double networks of responsive Release
acid polymer gels, of poly(butyl sustained for 7
acrylate)/poly(acrylic acid) (pH- h.
responsive) and poly(N-
isopropylacrylamide) (PNIPAM)
(thermoresponsive).
[70] Mitomycin Thermoresponsive gels synthesised Sustained
from methylcellulose and oxidised release of drug
Fig. 2. The reversible entrapment of drug molecules in a polymer hydrogel
(continued on next page)
solution, which gels (becomes cross-linked) or de-gels in response to an envi
ronmental stimulus.
5
Table 2 (continued ) oral delivery of benzydamine hydrochloride (BZD), a drug used in the
Ref Drug compound Description of hydrogel system Release treatment of mucositis [68]. Gelation temperatures in the useful range of
characteristic 30 and 34 ◦ C were achieved through variation of concentrations of PPG,
carboxyl nanocellulose, conjugated for up to 14
PF-127, and drug, in the pre-gel solution [62], granting slow release of
to drug. days SEL for up to 8 h in PBS (pH 7.4). Drug lifetime in mucosal tissues such as
[71] Methadone HCl Drug-loaded PCL microspheres Linear release the nasal passage can be enhanced by using mucoadhesive drug delivery
embedded in a PEG and profile up to vehicles [9]. Therefore, in the work of Pagano et al. [68], the authors
pentaerythritol-based hydrogels 50% release in
blended PF-127 with polyelectrolytes including poly(acrylic acid) and
67 h
[72] 5-fluorouracil Colonic delivery; pH-sensitive core- 35% maximal chitosan, to give the polymers mucoadhesive properties by ion pairing
shell structured polyelectrolyte release at pH interactions. The drug/polymer solutions could be sprayed onto the
complex microparticles synthesised = 1; burst affected area and would gel in-situ due to increased temperature, be
from alginate, Pluronic F127 (core) release for 30 retained on the negatively charged mucosa, and provide sustained
and Eudragit RS 100 min followed
by sustained
release of BZD for at least 3 h.
release to As well as the ratio of hydrophilic/hydrophobic blocks, the degree of
100% after 3 h cross-linking in a thermogel also controls the release rate of drug mol
at pH = 6.8 ecules, as was investigated by Kang Derwent and Mieler [74]. In their
[73] Procaine Poly(styrene maleic anhydride)-b- Maximal 10%
mechanistic study, the ratio of cross linker PEG-diacrylate in a PNIPAM
PNIPAM temperature-sensitive in- released over
situ forming micelles 700 min at 25 thermogel was varied, and the release of large molecular weight com
◦
C; ca. 50% pounds such as proteins to the ocular surface was measured. The initial
release at 200 release was rapid and driven by shrinking of the swollen polymer as
min at 37 ◦ C gelation occurred; the contraction in volume led to the ejection of the
large drug. The second, slow phase was limited by diffusion of the
3.1. Stimuli-responsive hydrogels relatively large proteins as they travelled through the densely
cross-linked polymer matrix. As such, high cross-linking density was
The thermotropic gelation of polymeric hydrogels has been explored associated with a slower second phase release, but a more rapid and
and exploited for many years in the field of drug delivery, especially in dramatic initial burst release.
topical, transdermal, and injectable applications [55,56]. Since the Another ocular in-situ gelling polymer was developed by Prasannan,
human body has a core temperature which is typically significantly Tsai and Hsiue for the sustained delivery of epinephrine to the anterior
higher than the temperature of the surrounding environment, hydrogels eye in order to alleviate intraocular pressure (IOP) in conditions such as
which collapse upon surpassing a temperature of 32–37 ◦ C are partic glaucoma [76]. Their system comprised cross-linked drug-loaded
ularly useful in in-situ gel formulations [55,74]. Such behaviour is nanogel particles, themselves entrapped within a graft copolymer of
observed in polymers such as poly(N-isopropyl acrylamide) (PNIPAM), poly acrylic acid and pNIPAM. Applied as an eyedrop, the in-situ gel
which have the property of lower critical solution temperature (LCST). formed as a thin film over the ocular surface, providing extended release
Below the LCST, hydrogen bonding between the polymer and water is of epinephrine for approximately 2 days in PBS. Animal models revealed
favourable, thus the polymer is solvated fully by water. Above the LCST, reduction in IOP for 36 h, as opposed to 8 h for an epinephrine eyedrop
however, the inter- and intra-chain interactions become more favour containing no polymer vehicle. Such in-situ gel formulations are also
able than those with solvent molecules, thus the polymers collapse and suitable not just for direct encapsulation of drugs, but also for secondary
form gels. This is complicated by changes in behaviour resulting from encapsulation of polymeric or nanoparticulate drug delivery vehicles.
tonicity – for example, the LCST of hydroxypropyl cellulose (HPC) is For example, rivastigmine hydrogen tartrate (RHT), a hydrophilic salt of
known to decrease with increasing salinity [75]. the cholinesterase inhibitor used in treatment of Alzheimer’s and Par
Triblock copolymers of PEG-PLGA-PEG exhibit temperature sensi kinson’s diseases, was encapsulated in PLGA nanoparticles which were
tivity and gel at temperatures which increase according to the ratio of subsequently embedded in a thermoresponsive hydrogel of poloxamer
lactic:glycolic acid in the hydrophobic portions. These systems have 407 [61]. This composite nanomaterial sustained the release of RHT for
been used in the delivery of hydrophilic agents including drugs and up to 8 h (60%), following an initial burst release of ca. 25% in 2 h.
proteins [58,65]. In the work of Zhang et al. [58], an injectable, ther Though rarer, there are recent examples of gels which behave in the
moresponsive in-situ PEG-PLGA-PEG gel was shown to sustain release of opposite manner to those described above, and instead dissolve at
high molecular weight compound LXT-101 (a gonadotropin-releasing higher temperatures and precipitating at lower temperatures. Poly(N-
hormone) tenfold, and low molecular weight naltrexone hydrochloride acryloyl glycinamide) (PNAGA), has a tuneable upper critical solution
(a hydrophilic opioid antagonist) four-fold, when compared to the free temperature (UCST) of between 38 and 94 ◦ C, influenced both by Mw of
drugs alone. In their 2019 article, Chan et al. [65] describe a topical drop the polymer and its concentration in solution [77]. Boustta et al. pub
containing PEG-PLGA-PEG for topical delivery of hydrophilic drugs to lished work which showed that an injectable PNAGA solution would gel
the ocular surface; thermogelation at ca. 30 ◦ C was useful in increasing at human body temperature as it cooled, and would sustain the release of
the viscosity of the drug-containing polymer matrix at the ocular sur methylene blue, a hydrophilic dye, for up to 300 h at body temperature
face, so that the gel was able to resist elimination via nasolacrimal [77]. However, the size and shape of the gel could not be controlled in
drainage. The delivery of model hydrophilic dye, Rhodamine B, was of vivo. Many other gels with UCST in useful range of 32–34 ◦ C tend to be
zero order type in a release medium of PBS at 34 ◦ C, releasing ca. 90% of synthetic ureido group-containing polymer derivatives [78]. In general,
the encapsulated hydrophilic compound over 20 days. it should be noted that UCST behaviour in (clinically) useful tempera
Another family of triblock copolymer systems are the Pluronics®/ ture ranges is uncommon, and useful drug delivery systems using UCST
Poloxamers comprising hydrophilic PEG units with a hydrophobic behaviour are few and far between when compared to LCST polymers.
polymer, poly(propylene glycol), PPG, which exhibit thermoresponsive Polymers with ionisable functional groups (e.g. amine or carboxyl
gelation. Pluronic® F-127 (PF-127) in particular, with a ratio of 1:0.65:1 moieties) can reversibly form pH-responsive gels as result of proton
PEG:PPG:PEG, has been consistently identified as a candidate for ther ation/deprotonation [53–56]. Increased charge density of a poly
moresponsive gel hydrophilic drug delivery systems. Recently, PF127 electrolyte results in inter-chain repulsion, allowing water to solvate the
has been employed in the nasal delivery of selegiline hydrochloride
(SEL), a drug used in the treatment of Parkinson’s disease [62], and the
6
polymer chain. Removal of charge facilitates agglomeration and activation), have applications in medical technology applications
precipitation due to inter-and intra-chain interactions such as including wound healing, scaffolds, and drug delivery [91,92]. The
hydrogen bonding. Chitosan, a naturally ubiquitous glucosamine/N- self-repair process typically occurs rapidly (<1 h [57,60]), via attrac
acetylglucosamine copolymer, has ionisable amine groups which tions between the two edges as a result of secondary interactions,
become protonated in acidic conditions, thus making it one of very few eventually reforming the solidified material. This process is illustrated in
naturally occurring polycations. Its availability, biocompatibility, and Fig. 3.
interesting properties in pH-sensitivity and enzyme degradability have Embedding antimicrobial drugs into self-healing scaffolds and
made it one of the most heavily cited natural biopolymers in the drug dressings offers a facile method to support the body’s natural repair
delivery literature [39,79,80]. Applications for pH-sensitive hydrogels mechanisms and simultaneously offer sustained protection from infec
in drug delivery have included ocular in-situ gels which collapse at the tion. Two self-healing hydrogels designed for the release of the hydro
neutral pH of the tear film [81–83], and hydrogels with the opposite philic antimicrobial, levofloxacin, were described by Sharma and co-
behaviour which swell in the neutral pH of the intestines after remaining workers recently [57,60]. In the first, the self-healing material was
collapsed to entrap drug in the acidic gastric tract [72]. However, as the chitosan/acryloylphenylalanine/methylenebisacrylamide, synthesised
polymer is produced from the deacetylation of natural chitin (extracted through template polymerisation [57]. Even when the hydrogel film is
from fungi, arthropods and crustaceans [84]), chitosan of known purity, cracked completely by razor blade scission, the gel reforms within 30
molecular weight, degree of deacetylation, and uniformity of frequency min with no visible deformity. In one example, a self-healing hydrogel
of deacetylation, is difficult to produce; these issues in synthetic repro soaked in lexofloxacin sustained the release of the drug over 60 h in
ducibility are a major issue in the approval of chitosan-based pharma aqueous buffer solution (PBS, pH 7.4). The same authors later published
ceuticals by regulatory bodies [85,86]. another system for the release of levofloxacin with improved properties,
Dual and multi-responsive gels provide additional specificity in synthesised from self-healing guar gum/acrylic acid hydrogels [60]. The
terms of environmental trigger, thus improving control over drug de in-situ polymerisation of acrylic acid in the presence of guar gum created
livery by increasing the specificity of the conditions required to initiate an entangled hydrogel, cross-linked by hydrogen bonding of the hy
drug release. For example, pH-responsive chitosan was grafted to droxyl groups in guar gum with the carboxylic acid groups of acrylic
temperature-sensitive poly(N-vinyl caprolactam) to form a dual- acid. In comparison to their previous system, this self-healing hydrogel
responsive, on-demand topical pain relief system for transdermal de exhibited excellent elasticity even after one cracking and healing cycle,
livery of hydrophilic acetamidophenol and hydrophobic etoricoxib in and favourable drug release profile of nearly 98% in 120 h, after an
recent work by Indulekha et al. [63]. The hydrogel had an LCST of 35 ◦ C, initial burst phase of ca. 55% in the initial 24 h.
and chitosan’s pKa is ca. 6.5. Therefore, application of the device to the In both cases, the impressive drug release profiles, coupled with
skin (of pH typically <5 [87] and temperature typically in the range of excellent elasticity and self-repair properties, offer clear advantages
33.5–36.9 ◦ C [88]) results in the most rapid rate of drug delivery. At over currently existing antimicrobial wound dressings. Existing hydro
temperatures below the LCST and pH above the pKa of chitosan, the gel wound dressings, made from materials such as alginate [93], are
release rate is slowest. The effect of temperature was much more sig prone to fail mechanically by tearing, cracking or ripping on movement
nificant than that of pH; less than 20% of hydrophilic acetamidophenol of the patient, and thus require regular replacement and re-dressings
was released at 25–32 ◦ C at either pH 5.5 or 7.4. On the other hand, at [94]. Furthermore, these drug releasing dressings offer advantages
39 ◦ C, 100% drug release was achieved in 90 min at pH 5.5, while 100% over traditional, non-drug releasing dressings, in that the wound does
release took 180 min at pH 7.4.
Dual-responsive hydrogels sensitive to both pH and glucose con
centration have recently been developed for the triggered delivery of
insulin to the open wound area of diabetic foot ulcer sufferers [89],
employing a system comprising a phenylboronate ester of chitosan,
polyvinyl alcohol, and end-capped PEG-dibenzaldehyde. The reaction of
chitosan with the benzaldehyde groups crosslinks the chitosan, while
the electrostatic interaction of PVA with the boronic acid moieties
cross-links forms the 3-dimensional network. Boronic acid preferentially
binds to glucose over PVA, thus granting sensitivity to the glucose, while
the pH-sensitive Schiff base grants sensitivity towards acidic media.
Thus, release of insulin from the hydrogel proceeds slowly at typical
physiological pH of 7.4 and in the absence of glucose, but is rapid at pH
6.5 and more so in the presence of glucose. In terms of real wound
healing activity, wound area was reduced by 50% in ca. 3 days with the
hydrogel dressing, compared to 6 days for a PBS control, and was nearly
0% in 18 days cf. >15% in the same period for the PBS control. By
combining environmental and biological stimuli, this work provides an
example of a truly intelligent material which is specific and selective to
the disease it seeks to target.
3.2. Self-healing and miscellaneous hydrogels
Self-healing hydrogels have received considerable attention in the

recent literature, approaching the forefront of hydrogels in engineering
applications in the last 20 years [90], especially as biomaterials [91].
These materials, upon mechanical damage such as tearing or cracking,
will repair themselves through interactions of compatible moieties
constituting the material’s fractured edges. These so-called autonomous Fig. 3. The self-healing of an electrostatically cross-linked hydrogel, as sec
self-healing hydrogels, self-repairing via hydrogen bonding and elec ondary interactions rapidly form between oppositely charged components of
trostatic interactions (without requirement for energy input or chemical the fractured edges, repairing the gel macrostructure.
7
not need to be exposed for repeat dosing of antimicrobial agents, thereby impact of the nanoparticle impregnation of the hydrogel contact lens on
increasing risk of infection. These properties therefore make these its visual clarity was not assessed, nor oxygen permeability or user
self-healing, drug-releasing hydrogels excellent candidates for use in comfort – each examples of additional considerations in translational
home, hospital, and emergency settings. therapeutics not commonly addressed in the literature [104]. In sum
mary, with tuneable multi stimulus-responsive behaviour and enhanced
3.3. Hydrogel soft contact lenses biocompatibility due to the nature of the materials used and their high
water content, hydrogel reservoirs for drugs and drug-encapsulating
Since the patent was filed for their invention in the late 1960s, soft nanoparticles are versatile and can be used in topical, injectable and
contact lenses (CLs) constructed from hydrogel-forming synthetic oral applications, as we have seen. Their disadvantages include low
polymers such as pHEMA have been envisioned as drug delivery devices mechanical strength, poor physical stability, and the
for ophthalmic pharmaceuticals [95–98]. Most common, commercially non-biodegradability of certain synthetic hydrogel polymers [55].
available ophthalmic medications are available to the consumer as Indeed, the mechanical properties of hydrogels are highly variable, and
topical eyedrops, yet drugs delivered by aqueous eyedrops suffer from tuneable depending on the materials used, and their desired purpose.
premature precorneal elimination and thus poor bioavailability For example, injectable hydrogels must have the necessary fluidity to be
[95–98]. This results in a need to re-administer the drugs often (and injected, yet must also possess the rigidity required to remain in place
sometimes even overnight), commonly resulting in poor patient once injected. For these applications, shear-thinning polymers and
compliance [95–98]. Frequent re-administration can also lead to unde non-covalent gelation are the most common forms of forming a hydrogel
sired systemic side effects, if sufficient concentrations of drug enter the in-situ. Examples of noncovalent gels used in clinical and commercial
bloodstream after absorption by the conjunctiva [99]. CLs, as polymeric successes include carboxymethylcellulose (e.g. Osteogenic protein 1
platforms, can effectively act as removable implants and reservoirs for (OP-1®) implant, OP-1® Putty (Stryker Biotech)), hyaluronic acid (e.g.
absorbed drugs. However, unmodified CLs alone are typically unable to EUFLEXXA® (Ferring Pharmaceuticals Inc.) and alginic acid (e.g. Algi
significantly sustain drug release for hydrophilic drugs, due to the ten syl-LVR® Hydrogel Implant (LoneStar Heart, Inc.)) [105].
dency of these compounds to elute relatively unencumbered from the On the other hand, covalently cross-linked hydrogels, made from
hydrated CL [100], as the mesh voids (typically <10 nm [101]) are (commonly) acrylate-based polymers, have more easily tuneable prop
significantly larger than even large pharmaceutical compounds. Thus, erties including porosity, water content, and mechanical strength.
the unmodified CL is a poor diffusion barrier. However, their drawbacks are that due to their nature and method of
Nonetheless, the nature of CLs allows drug delivery devices to be formation, they are not injectable. and that these hydrogels must un
constructed to be a part of the hydrogel itself. Methods used to achieve dergo careful post-processing to remove any toxic unreacted initiators
this have included the polymerisation of the CL around a template of and monomers. Therefore, any loaded drug must be retained during
drug molecules (i.e. molecular imprinting), as in the work of Chu et al., these wash stages, but remain releasable at the target tissue for the
who embedded dexamethasone sodium phosphate (DSP) into molecu required lifetime of the drug. Examples of covalently cross-linked, syn
larly imprinted CLs, considerably improving the drug loading efficiency, thetic polymers used in clinically and commercially successful products
and extending the drug release lifetime from several min to >2 h [102]. include PHEMA (e.g. Vantas® (Endo Pharmaceuticals)), and poly
Incorporation of photonic crystals allowed the CL to self-report drug (acrylamide) (Bulkamid® hydrogel (Searchlight Pharma)) [105]. More
release progression, as the refractive index of the CL changes with recently, as we have seen, hybrid materials have been becoming
swelling. As an alternative to loading or imprinting the drug molecule by increasingly common; grafting of a biologically compatible co-polymer,
polymerising the CL monomers around a template of the drug, the such as PEG or a biopolymer, to an otherwise poorly tolerated synthetic
anchoring or coating of drug delivery devices onto the preformed CL can polymer backbone can give linear polymers and hydrogels with the
be performed instead. For example, a study by Mehta et al. [103] used a desired mechanical strength and biological compatibility.
novel template device to coat exclusively the outer perimeter of a sili By far the most common synthetic hydrogels already used as medical
cone CL with nanofibers of timolol maleate-containing mixed fibres of devices worldwide are CLs, for vision correction [105]. However,
poly(N-isopropylacrylamide) (PNIPAM) and poly(vinylpyrrolidone) despite a wealth of scientific literature indicating they may be suitable
(PVP). Thus, the central portion of the contact lens was transparent and for use as drug delivering systems, no drug-eluting CLs are available
retained its desired vision-correcting properties. The delivery profile in commercially today [98]. The main barriers preventing their main
aqueous buffer comprised a biphasic release, whereby 50–75% encap stream adoption have been the significant alteration of material prop
sulated drug was released over 6 h, followed by up to 65% release over erties as drug load in the CL changes during drug release, issues with
24 h. As is common for these nanofibre systems, the total % of drug sufficiently extended wear, which increases the risk of developing ocular
released, and the rate of drug release, was inversely proportional to the diseases such as microbial infection, corneal hypoxia, and dry eye dis
thickness of the fibre. While the authors ensured that the centre of the ease [98].
lens remained transparent and uncoated to maintain visual correction Challenges for any drug-eluting hydrogel to be clinically and
efficacy, the smoothness and comfort of the lens were not assessed. Its commercially successful are manifold – firstly, as with all preclinical
true viability as a wearable implant for the delivery of ophthalmic drugs investigational medicine products, simply scaling up the manufacturing
therefore remains to be fully established. operation in line with cGMP and producing a sufficiently robust process
Another common method for embedding drug delivery systems into is often difficult, especially when working with materials of natural
CLs is through entrapment of the durg in nanoparticles which are then origin whose characteristics may themselves vary from batch to batch of
secondarily embedded into a CL. Maulvi et al. described such a system, raw material. Pharmacologically, the fates of each component (polymer
where pH-sensitive, drug-loaded nanoparticles of Eudragit® S100 were (s), drug(s), cross-linker(s)), must be understood and demonstrably
incorporated into a CL during curing [82]. The CLs were stored at a pH reproducible, with predictable behaviour and stability both in vivo-eye
of <6.5 and, when exposed to simulated tear fluid at a pH of around 7.4, and under storage conditions. This may be difficult to achieve depending
released cyclosporine for up to 156 h. A shelf-life study showed that drug on the manufacturing methods used, especially given the sheer number
loss to bulk solution in the 90 days following autoclave sterilisation was of variables required for synthesis of the hydrogel, loading with drug,
reduced by a factor of 16, in comparison to a lens soaked in a solution of and packaging/storing the drug-loaded hydrogel. For CLs specifically,
drug rather than a NP suspension. The sizes of NPs measured were clinical uptake may be hindered by a limited willingness of physicians to
45–61 nm. Maulvi’s is one of fairly few studies in the recent literature prescribe (and for patients to accept prescription of) drug-eluting CLs
which studies the feasibility of these particles in a real-world setting, i.e. products, due to psychological reasons such as predicted discomfort, or
by including shelf-life and autoclave stability studies. However, the simply a technical inability to insert CLs safely and efficiently [98].
8
Sterilisation of hydrogels is relatively simple, as most are compatible

with the commonly used steam sterilisation process. However, there is
evidence that drug release from drug-eluting hydrogels following steam,
γ-radiation or ozone sterilisation result in a decrease in the amount of
drug delivered, with γ-radiation and ozone both resulting in the chem
ical degradation of the embedded drug itself [106]. Numerous hydrogel
materials have entered the clinical trial phase in recent years,
evidencing the bench-to-bedside applicability of these materials [107].
Overall, while many hydrogels are now entering clinical trials, the final
limitation is simply one of resources; it can take up to 10 years and $800
million for a product to translate from the preclinical to commercial
stage [105].
The library of hydrogel materials is constantly evolving, and the
focus on commercialisation expanding. Remaining challenges include
the balancing of costing, shelf life, and differences in patient-to-patient
interactions between synthetic and living tissues, as well as the current Fig. 4. Comparison between lipid core of SLN and NLC particles and the
lack of any standardised testing procedures for monitoring the efficacy consequent effects on drug loading capability and encapsulation efficiency.
of the devices, and their fate in the body [107]. The current landscape in
the literature is one of a sustained interest (from researchers, clinicians there is a requirement for a certain degree of imperfection in the
and investors alike), in biologically compatible hydrogels. Thus, these structure [113]. Typically, therefore, SLNs are associated with lower
materials are likely to remain among the strongest candidates for drug encapsulation and a less desirable, burst release profile, when
approval in biomedical applications, including tissue scaffolds and drug compared to NLCs [114].
delivery. NLCs, on the other hand, use mixtures of lipids with high and low
An alternative approach is to use encapsulated micro- and nano melting points to give a nanoparticle comprising both solid and liquid
particulate carriers. The next section explores this expanding field of core character, permitting encapsulation of much more drug per volume
nanomedicine and its potential application for the delivery of hydro (since the prerequisite for crystalline imperfections is met inherently).
philic compounds. Thus, the drug may be entrapped within liquid nano-compartments
dispersed throughout the particle, within imperfections in the particle
4. Micro- and nanoparticulate carriers semi-crystalline structure, or dispersed relatively more homogeneously
within an amorphous particle matrix [114]. This leads to higher drug
Nanomedicine is arguably one of the most widely used approaches in loading efficiency and a more favourable diffusion- or
contemporary drug delivery, due to the ability of nanoparticles to erosion-controlled release.
encapsulate drugs in vehicles with desired properties of biological In both cases, the entrapment of hydrophilic drugs within a hydro
compatibility, targeting, and size [4,108,109]. These properties differ phobic lipid core is understandably more complicated than the entrap
significantly at the nanoscale in comparison to the bulk material [110]. ment of lipophilic drugs. There are two methods commonly used to
Furthermore, the small size range of these particles enables particles of synthesise lipid particles in the nano scale. For example, the double
an appropriate size to interact with, and enter, cells and release drugs emulsion solvent evaporation technique, in which the water soluble
directly into the cytoplasm, via endocytosis [111]. Drug release from drug is dissolved in water and emulsified in an oily phase, which is then
these particles can either be driven mechanistically by diffusion through further emulsified in an aqueous phase; the solvent is then removed to
the nanoparticle matrix, erosion of the particle, or a combination of the form the particulates [115,116]. Alternatively, a single emulsion
two [109]. Self-assembling liposomal formulations have already proven method is used in which a drug-lipid dispersion is formed by adding the
successful in enhancing the delivery of poorly soluble, hydrophobic hydrophilic drug to a molten lipid phase, which is then added to a
cancer drugs, and are used today in real-world healthcare applications surfactant-containing aqueous phase and homogenised [67,117–121].
[4]. Table 3 contains a list of recent work in which hydrophilic drugs have
In the delivery of hydrophilic compounds specifically, then, the re been encapsulated in nanoparticulate lipid carriers.
quirements are the reverse of those for hydrophobic compounds; NLCs and SLNs have been used to modulate the solubility and
aqueous solubility must be reduced instead of increased, thus modu bioavailability of hydrophilic drugs, making them useful in delivery
lating of the drug’s lifetime in the body and ability to penetrate lipo vehicles for the brain [115,117,119] and ocular surface [67], for
philic barriers (e.g. the blood-brain barrier, BBB). This has been example. Furthermore, surface modification of the particles can be used
achieved by encapsulation into an amphiphilic or hydrophobic partic to induce site-specific targeting (e.g. conjugate of biomolecules for
ulates, including lipid carriers (solid lipid nanoparticles and nano recognition by cancerous tissues [116]) or enhanced cellular/mucosal
structured lipid carriers), polymeric matrix nanoparticles and capsules, adhesion [117]. In each example, maximal entrapment of the hydro
functionalised porous silica nanoparticles, and self-assembling struc philic drug in a hydrophobic lipid matrix is accomplished by optimising
tures such as micelles and liposomes. Recent advances in these tech blends of different solid and liquid lipids, at differing ratios, and with
nologies are explored below. different surfactants. Details of the individual formulations in terms of
lipids and surfactants used in various recent articles can be found listed
4.1. Lipid carriers in Table 3. Some of the novel and innovative modifications, which have
increased specificity by conjugation of targeting moieties to the particle
The two main types of lipid carrier used in contemporary drug de surface, for example, are explored in more detail below.
livery are solid lipid nanoparticles (SLN) and nanostructured lipid car SLNs with biological targeting for the specific treatment of breast
riers (NLC). While similar, the two differ in that the SLN particles have a cancer were the subject of work by Radhakrishnan and co-workers
solid lipid core at room and body temperature, often being prepared [116], in which the targeting moiety, bombesin, was conjugated to
from a solution of molten lipid at a raised temperature. Upon cooling, the outer surface of lipid particles containing the drug epigallocatechin
drug molecules are entrapped between fatty acid chains, between lipid gallate. Bombesin, a short chain peptide, has a high affinity for gastrin
layers, or within imperfections in the particulate crystal structure (as releasing peptide receptors which are overexpressed in breast cancer.
illustrated in Fig. 4) [112]. Thus, for reasonable entrapment efficiency,
9
Table 3 viscosity of the formulation and reducing premature elimination of the

Recent publications detailing SLN/NLCs used in the sustained and targeted de lipid particles from the tear fluid.
livery of hydrophilic drugs. The main benefits of SLNs and NLCs are in their ability to entrap and
Ref Drug compound Description of lipid Release characteristic sustain the release of both hydrophilic and hydrophobic drugs in
nanocarrier system aqueous media and stabilise otherwise unstable drugs for periods of
[117] Almotriptan Brain delivery; Chitosan- Final drug brain months or more, due to protection from oxidative and hydrolytic
coated nanostructured concentration over 7 x degradation when in the lipid surroundings [112,123]. However, these
lipid carriers composed greater for the lipid lipid matrix nanoparticles gradually undergo a transition from an
of Compritol, Labrafil, carrier than the free
imperfect crystalline structure containing amorphous regions to a highly
Tween 80 and drug
lauroglycol ordered lipid crystal structure. Given that the drug is encapsulated in
[115] Baclofen Brain delivery; Sustained delivery of these amorphous regions, the restructuring of the lipid crystal phase
Nanostructured lipid 74.6% encapsulated results in the expulsion of drug molecules [112,113]. Typical high
carriers based on soy drug over 28 h. Typical pressure steam sterilisation of these particles at 121 ◦ C is likely to result
lethicin and glyceryl, brain permeation ca. 2 x
mono-, di-, and that of the free drug
in the loss of efficacy due to the melting of the lipids, and flocculation of
tristearates stabilised by solution polymer stabilisers [112,124]. Aseptic preparation and pre-filtering
Tween 80 therefore remain the most common form of sterile manufacture of
[118] Sulforhodamine Solid lipid nanoparticles No release data. SLNs, though little research has been made into the effects of γ-radiation
101 of stearic and capric acid Encapsulation
sterilisation on the formulations and their pharmacology as a whole
stabilised by lecithin and efficiency of 63%
polysorbate [125], other than in specific, recent examples [121,126]. In the latter
[67] Bimatoprost Solid lipid nanoparticles Pseudo-zero order example, γ-radiation was effective in sterilising the particles, but nearly
prepared from glycerol release (>99% over 19 halved the total amount of drug released [126].
monostearate, soya h)
lecithin, and Tween 80
embedded in a pH-
4.2. Polymer nanoparticles, spheres and beads
sensitive gel of Acrypol
941 Polymer nanoparticles (PNPs), as an umbrella term, can relate to any
[116] Epigallocatechin Targeted release to Tumour growth sub-micron sized structure which is formed from polymer materials, but
gallate tumour cells; solid lipid inhibited over 30 days
is most used to refer to polymer nanospheres and nanocapsules. Unlike
nanoparticles of stearic in-vivo.
acid, glycerol self-assembling nanocapsules and SLNs/NLCs, PNPs are formed of
monostearate, and polymers and are therefore constructed from a covalent, drug entrap
lecithin, conjugated to ping network rather than less stable secondary interactions. They can be
bombesin synthesised from a ‘top-down’ or ‘bottom-up’ approach; i.e. from pre-
[119] Rasagiline Poloxamer 407-stabilised Initial burst release
Mesylate stearic acid SLN (30%, 2 h); sustained
made polymers which are manipulated through solvent control to
release for 24 h form nanoparticles, or from monomers which are polymerised to form
[120] Valacyclovir Ocular delivery: SLNs Burst release 20–40% in nanoparticles, respectively [127]. These methods include
formed from stearic acid 90 min; 80% release in emulsion-diffusion or solvent evaporation methods, coacervation, and
and tristearin, stabilised 12 h
nanoprecipitation, as well as emulsion and interface polymerisation for
by surfactants Poloxamer
188 and sodium the bottom-up methods.
taurocholate Particle size control is achieved by optimising parameters including
[115] Baclofen Brain delivery; Sustained delivery of solution concentration, surfactants concentration, polymer molecular
Nanostructured lipid 74.6% encapsulated weight, homogenisation technique, and characteristics of the solvent
carriers based on soy drug over 28 h. Typical
lethicin and glyceryl, brain permeation ca. 2 x
and solvent environment. Loading of hydrophilic drugs into predomi
mono-, di-, and that of the free drug nantly hydrophobic polymers is typically achieved either through dou
tristearates stabilised by solution ble emulsion solvent evaporation polymerisation [128,129], complex
Tween 80 coacervation [130,131], or nanoprecipitation [132]. These nanoparticle
[121] Alendronate Glyceryl monostearate 93.2% drug release (of
synthesis techniques are illustrated in Fig. 5.
sodium and Tween 80 SLN the optimised
carrier, emulsified in formulation) over a Many different polymers have been used in the fabrication of
drug-containing aqueous period of 102 h. nanoparticles, but in drug delivery applications, most are typically based
phase containing either on biologically compatible acrylate polymers, alkylene oxides
Poloxamer 127 such as PEG, or, more recently, biodegradable polyesters such as PLA,
[122] Berberine Poly(glycerol sebacate) Biphasic release; 15%
gel macrostructures drug released over 62
PLGA, and PCL [127,133]. pH-sensitivity and biorecognition can be
days. instilled to the particles through construction using pH-responsive ma
terials or through conjugation to targeting moieties [134,135]. Other
modifications, such as PEGylation, are necessary since hydrophobic
Over a 30 day period in tumour-implanted mice, the particles are recognised as foreign by the body and are eliminated by the
bombesin-conjugated SLN system was found to inhibit tumour growth reticuloendothelial system [111]. Table 4 summarises recent publica
while maintaining body weight, indicative of specificity for the tumour tions in which polymer nanoparticles have been used in the sustained
environment. release of hydrophilic drugs.
In another example of targeting, bimatoprost-containing SLNs were An uncommon, novel system for the on-demand topical delivery of
recently embedded in a pH-sensitive hydrogel of poly(acrylic acid) by drugs from a nanoparticulate preparation was detailed by Rajama
Wadetwar et al. [67]. In comparison to SLN-only formulations (i.e. those nickcam et al. [129]. In this device, compressible silicone elastomer
not encapsulated in a hydrogel matrix), the pH-sensitive hydrogel was microparticles were impregnated with the model hydrophilic dye, so
found to sustain release of the drug with near zero-order kinetics, dium fluorescein. Upon application of mechanical stress to the elas
releasing 99.7% of the drug in ca. 19 h (cf. 10 h for the NP-only tomer, compression of these particulate-containing void spaces resulted
formulation) due to the additional diffusion barrier provided by the in the release of drugs from the particulates. By embedding these par
cross-linked matrix. This formulation was designed for use in ticles in a thin film of PDMS, an applicable, thin film device could be
ophthalmic therapeutics, thus the hydrogel was useful in increasing the fabricated, which releases the drug when force is applied. Release
10
Fig. 5. Schematic representing the processes behind (a) double emulsion solvent evaporation, (b) polyelectrolyte complex coacervation, and (c) nanoprecipitation, in
the formation of hydrophilic drug-loaded nanoparticles.
studies on this device conducted in PBS showed that release of drug was compounds, both hydrophilic and hydrophobic [111]. PLA nano
proportional to the amount of pressure applied to the film, and a particles have been used for dual drug delivery applications (for hy
maximum of 5% encapsulated sodium fluorescein was released in the drophilic theophylline and hydrophobic budenoside) [140], which were
absence of an externally applied force. Such a technology has potential found to sustain the delivery of theophylline for ≥24 h in diffusion cell
for the on-demand elution of e.g. painkillers and antibiotics from studies. PEG-PLA nanoparticles were synthesised by Surwase et al.
compressible wound-healing dressings. [139], for the sustained delivery of gemcitabine. These particles were
As an alternative to aqueous core, or matrix nanoparticles, novel, prepared using the double emulsion solvent evaporation technique, and
solid-core nanoparticles were synthesised by Toorisaka et al. recently sustained the release of the drug for up to 15 days. The release rate was
[136]. Here, solid, powdered hydrophilic drug (theophylline) was dis dictated by the ratio of PEG: PLA, which in turn affects the crystallinity
solved in water and dispersed in hexane containing sucrose palmitate. of the polymer system, and the polymers’ molecular weights.
The emulsion was then lyophilised, producing a solid, surfactant-coated PLGA has been heavily featured in recent publications in the drug
drug in powdered form. The emulsion/solvent evaporation technique delivery literature, PLGA nanoparticles have been the subject of studies
was then used to create solid drug-core PLGA nanoparticles. The ad to encapsulate hydrophilic drugs 5-fluorouracil [145], tacrine [147],
vantages of particle synthesis by the solid-oil-water method, as opposed and diclofenac sodium [13]. In these examples, modifications of the
to the solvent diffusion method or traditional double emulsion solvent PLGA particles either by co-polymerisation or functional coating, have
evaporation, were facile size control and greatly increased encapsula been used to improve the properties of the particles for specific appli
tion efficiency (almost three-fold for comparable formulations of cations. The modification of PLGA with another biologically compatible,
aqueous core PNPs). biodegradable polyester (3-hydroxybutyrate-co-3-hydroxyvalerate
The biodegradable polyesters PLA and especially PLGA (which have acid), PHVB was investigated by Handali and co-workers recently [145].
received attention in the drug delivery landscape at large), have also In the optimum formulation, the entrapment efficiency was 54%, and in
been extensively investigated for drug-encapsulating nanoparticles, due vitro release was slow, with 20% fluorouracil released within 5 h and
to attractive features of biodegradability, biocompatibility, approval by 54% released after 48 h.
regulatory bodies, applicability to sustained and targeted release, and its PLA has also been employed as a drug entrapment matrix in the
applicability to encapsulation of high and low molecular weight drug entrapment of isoniazid, an antibiotic, by Zhang et al. [150]. In their
11
Table 4 Table 4 (continued )

Recent publications detailing lipid drug-conjugate vehicles used in the sustained Ref Drug compound Description of particulate Release characteristic
and targeted delivery of hydrophilic drugs. system
Ref Drug compound Description of particulate Release characteristic [147] Tacrine Nose-to-brain transport: Up to 45% release over
system Drug-loaded, protamine- 120 h
[129] Sodium Compressible PDMSa Initial burst release of coated cell-penetrating
fluorescein elastomer films containing 10% in 30 min in PLGA nanoparticles
drug filled microcapsules absence of force, [148] Doxorubicin Dual-functionalised core/ Biphasic; negligible
for mechanically- followed by a force- shell nanoparticles of release for initial 5 h,
stimulated release sensitive response with chitosan-graft-polyacrylic followed by near-linear
no further release in acid-conjugated drug, release for 11 days
the absence of coated in dual- (>80%) for the dual-
mechanical functionalised chitosan- ligand particle. Single
stimulation. glycyrrhiznic acid/ and no-ligand particles
[128] 5-fuorouracil Microsphere capsules of 83% drug release after lactobionic acid ≤20% release over
natural gum katira with 12 h same period.
Eudragit pH-sensitive [149] Doxorubicin PHEMA-ran-glycidyl Burst phase (50% in 10
polymers methacrylate polymer h) followed by lag
[132] Caffeine Hydrogen-bonded PCL 90% cumulative nanoparticles phase (80% in 48 h)
nanoparticles release at ca. 4 h cf. [13] Diclofenac PLGA stabilised by Initial burst release
100 min for free sodium Pluronic F68 (25% in <2 h) followed
caffeine. by linear release (75%
[131] Verapimil HCl Glutaraldehyde- VP release sustained in 48 h)
crosslinked Chitosan- for 8 h, cf. < 2 h for a [150] Isoniazid Spray-dried PLA In-vivo drug
κ-carrageenan marketed tablet microspheres concentration
polyelectrolyte complex product Isoptin ®, with sustained for 4 weeks
beads significantly lower
initial burst release
[136] Theophylline PLGA nanoparticles Release not work, microspheres were produced by spray drying methodology.
prepared by solid-in-oil-in- determined, but Solid-core microspheres were favoured over the w/o/w double emulsion
water method encapsulation method, as the absence of an external aqueous layer assists in main
efficiency much
greater than w/o/w
taining the stability of the drug in the nanoparticle with respect to
emulsions diffusion into the external aqueous layer. The drug was first micronized
[137] Donepezil Nanocomposite particles Release of drug by ball milling, prior to dispersion in an organic solvent, and subsequent
formed from one-pot sustained for ≥120 h spray drying to form microparticulates. The release of isoniazid from
microwave assisted
these particles was slow and sustained over a period of over 21 days
synthesis: ZnO with 2-
acrylamido-2-methyl-1- (70% encapsulated drug released) though the majority of the encapsu
propanesulfonic acid, lated drug was released in the initial ca. 8 days.
acrylamide, and Protamine-coated PLGA nanoparticles have been recently developed
methylene-bis-acrylamide for the transport and sustained release of hydrophilic drug tacrine to the
[138] Blue dextran Keratin microspheres Sustained release for 6
h
brain, via the nose [147]. The function of the protamine coating is to
[139] Gemcitabine PEG-PLA nanoparticles Sustained release for enhance cell permeation, since protamine belongs to a family of
>14 days in-vivo cell-permeating peptides which have been shown to assist in the transfer
[140] Theophylline PLA nanoparticlesa Sustained release for of even high molecular weight proteins across the blood-brain barrier.
≥24 h in in-vitro
The protamine-coated nanoparticles were embedded in a poly(acrylic
studies
[141] Rivastigmine Poloxamer 407-stabilised Initial burst of 55% in acid) gel by mixing a suspension of nanoparticles in aqueous media with
hydrogen Eudragit RL nanoparticles 2.5 h, followed by the dissolved polymer. In vivo studies showed that this
tartrate (RHT) prepared by gradual release up to particle-embedded gel enabled the drug to penetrate much more suc
nanoprecipitation 60% in 6 h. Cf. 100% in cessfully than the particles or solution alone, with maximal concentra
« 40 min for free RHT.
[130] Bovine serum Auricularia auricular Sustained delivery of
tion 2.5 x greater after 1 h.
albumen; Bovine polysaccharide and 81.6% over 12 h. While such synthetic polymers have advantages in versatility thanks
haemoglobin chitosan polyelectrolyte to their readily tuneable properties, natural polymers can be processed
complex nanoparticles into nanoparticles with relative ease and with their own advantages in
[142] Methylene blue Nanoparticles formed Pseudo-zero order
sustainability, improved biological compatibility and biodegradation
from nanoprecipitation of release at a particle
regenerated cellulose size dependent rate, for [151]. Nanoparticles of biopolymers such as gum katira [128], keratin
up to 96 h (100%) [138], and chitosan [130,131,148] have all featured in recent literature.
[143] Doxurubicin HCl PLA-encapsulated Fe3O4 64.8% release in 50 h Chitosan has been used in the formation of polyelectrolyte complexes
microspheres with naturally derived polyanions such as κ-carrageenan [131]. and
[144] Gentamicin Supercritically foamed Initial release of 60%
PLGAa particles in 8 h, followed by
auricularia auricular polysaccharide (AAP) [130]. To enhance drug
sustained release up to encapsulation, novel techniques such as the deposition of polymer/drug
80% in 2 weeks solution on superhydrophobic glass and the subsequent cross-linking of
[145] 5-fluorouracil Nanoparticles of PLGA and Sustained release for chitosan by glutaraldehyde vapours have been developed [131].
PHVBa 48 h (50%) after initial
Other pH-sensitive nanoparticles have included the mixed material
burst (30% in 6 h).
[146] Epirubicin HCl Poly (3-hydroxybutyrate) Sustained release for 2 synthetic/natural polymer microparticles detailed by Karan and co-
(PHB) and Poly (3- days (PHB) or 8 days workers [128], in which 5-fluorouracil was entrapped in a gum katir
hydroxybutyrate-co-3- (PHBV), moderate a/Eudragit® system. The particles were synthesised using the double
hydroxyvalerate) (PHBV) drug release of 60% emulsion solvent evaporation technique, in which the aqueous gum
nanoparticles and 30% respectively,
katira/drug core was encapsulated in the hydrophobic Eudragit®
coating. Due to the pH-sensitivity of the Eudragit polymer, the particles
withstand the acidic conditions of the stomach, permitting
12
pH-controlled delivery to the more alkaline environment of the colon for Table 5
treatment of colon cancer. Recent publications detailing nano and mesoporous nanoparticulates used in the
PNPs, since their inception as drug delivery devices, have been a sustained and targeted delivery of hydrophilic drugs.
mainstay of the researchers’ arsenal in the targeted, efficient, and bio Ref Drug Description of porous Release characteristic
logically compatible delivery of drugs to the human body. In this section compound particle system
of the review, we have seen interesting recent advances including the [14] Doxorubicin pH- and glutathione- Release sustained for 5 h
use of targeting moieties and pH-sensitive conjugates, as well as material HCl sensitive hyaluronic acid after exposure to pH 5.5.
advances which have led to novel drug delivery mechanisms rarely seen and PAMAMa dendrimer- None detected if pH
coated mesoporous silica maintained at 7.4.
previously. The typical obstacles to commercial uptake and viability as
nanoparticles.
pharmaceutical devices have included processability, upscaling, stabil [156] Gemcitabine -COOH, –SH, and –NH2 Initial 12–26% release of
ity, and ease of sterilisation prior to clinical uptake. Nevertheless, a surface-functionalised loaded drug in 10 h,
significant number of nanoparticulate drug delivering formulations mesoporous silica sustained release up to
have been approved by the appropriate bodies and have entered and nanoparticles 15–30% in 48 h
(dependent on surface
succeeded in clinical trials [152]. The relevant properties are stability of functionality)
PCL, PLA, PGA, and PLGA nanoparticles showed that long-term stability [157] Levofloxacin Mesoporous silicate 90% release in 80 min @
as a room temperature, water-borne suspension is relatively poor, with functionalised with pH 2.01; 50% release in
particle sizes and molecular weights significantly decreasing after 12 biodegradable PLA shell 80 min @ pH 7.01
[158] Acetaminophen Mesoporous silica Sustained release
months for each polymer and polymer blend [153]. PGA is particularly
nanoparticles biphasic, 90% in 60 h;
unstable, with almost entire degradation of the nanoparticles in 5 functionalised with initial burst of 50% in 10
months in a PLGA formulation of 2:1 PGA:PLA. However, the materials polydopamine and h
withstood sterilisation both by filtration and γ-radiation [153]. graphene oxide
[159] 5-fluorouracil Urea-pyridyl ligand- Release of drug sustained
functionalised for 12 h
4.3. Mesoporous silica nanoparticles mesoporous silica hybrid
material
Mesoporous silica nanoparticulates (MSNs) have been in use in drug [160] Methylene blue Nanoporous silica Sustained release, linear
nanoparticles dual loaded phase 175 days followed
delivery applications since 2001 [154], and are widely successful due to
with hydrophilic by lag phase up to 1 year.
favourable properties such as high drug entrapment, favourable release methylene blue and
profile, and ease of surface modification to grant targeting and/or hydrophobic fluorescein
environmentally responsive release. The synthesis of these particles is
relatively straightforward, and is driven by the polymerisation of a sil
icone precursor such as tetraethyl orthosilicate (TEOS) around a tem 3-mercaptopropyl trimethoxysilaine (MPTMS). Carboxylic
plate of micellar rods [155]. Calcination of the structure removes the acid-functionalised MSNs were produced by reaction of the
micelle template, leaving a hexagonal, mesoporous structure. Typical amino-functionalised MSNs with succinic anhydride. The surface func
pore sizes are therefore relative to the size of the micelles formed, which tionalisation influenced the loading efficiency of hydrophilic gemcita
is in turn directly proportional to the alkyl chain length of the surfactant bine and hydrophobic quercetin, due to the relative compatibility of
tail. This process is illustrated in Fig. 6, and Table 5 lists recent publi functional groups with the drugs and the modified MSN surface. Gem
cations in which drug-releasing MSNs were developed. citabine loading was enhanced by a factor of ca. 2 for –COOH coated
Drug entrapment in these pores is usually achieved by passive ab MSNs as opposed to bare MSNs. For the same reason, release of gem
sorption (i.e. by adding MSN to a solution of dissolved drug). While this citabine was also slowest from the –COOH coated MSNs, with only 15%
approach is typically associated with burst release and poor drug life of the encapsulated drug released over 48 h, followed by thiolated MSN
time for non-porous, matrix particles (due to limited superficial surface (ca. 17%), amino-MSN (ca. 25%) and bare MSN (35–40%).
adsorption), the porosity of MSNs leads to much slower outward diffu Biodegradable, PLA-coated MSNs have been used in the sustained
sion of drugs due to the small diameter of the pores, effectively creating delivery of levofloxacin (LF), with rate of release controlled by the
a bottle neck for outward molecular diffusion. Nowadays, this favour degradation of the PLA coating [157]. The PLA coating was incorporated
able drug release profile has been enhanced through the grafting of site- on the surface of the MSN through the APTES route, with the drug
specific, stimuli-responsive polymers or functional groups to the MSN encapsulation taking place following amine modification but prior to
surface via anchoring of carboxyl-, amino- or thiol-terminated trie instillation of the PLA layer. LF release from these particles was moni
thoxysilanes. For example, in recent work by Zaharudin and co-workers tored in aqueous buffer over 5 h; a maximum release of 90% in 150 min
[156], 3-aminopropyl triethoxysilane (APTES) was used to formulate was observed at pH 2.01, and a slower release of ca. 48% in 180 min at
amino-functionalised MSNs, while thiolated MSNs were synthesised by pH 7.4.
reaction of the bare MSNs with the analogous compound, A notably long drug lifetime of up to 232 days has been observed for
Fig. 6. Representation of the synthesis of MSNs via assembly around a micelle rod template.
13
hydrophilic dye, methylene blue, in the nanoporous silica nanoparticles of polar headgroups [163]. Liposomes, on the other hand, form a bilayer
[160]. These hybrid, core-shell morphology particles were synthesised sheet with an oily core sandwiched between two hydrophilic shell
using typical MSN formulation methodology for the porous silica core, layers, which results in the formation of a hydrophilic core particle, with
followed by encapsulation in a porous organosilica shell layer. This was an inner oily layer, and an outer hydrophilic shell [164]. This lamellar
achieved by dispersing the initial MSNs in a solution of surfactant and configuration thus permits the formation of not only single layer lipo
adding the organosilica precursor, 1,4-bis(triethoxysilyl)benzene somes (both small unilamellar vesicles, SUVs, and large unilamellar
(BTEB). The unusual and important features of these particles are that vesicles, LUVs), but also multilamellar vesicles (MLVs) which may
both the core and shell are entirely porous, with contain numerous smaller vesicles enclosed in a larger vesicle, not
Brunauer-Emmett-Teller (BET) surface area measurements of 1000 m2 necessarily in a concentric configuration [164] (see Fig. 7).
g− 1 and 600 m2 g− 1 for the core-only and core-shell particles, respec The terms ‘micelle’ and ‘liposome’ originally referred only to par
tively. Dual loading of hydrophobic and hydrophilic dyes demonstrated ticulate structures of surfactants and ionic headgroup-containing lipids,
that hydrophilic model drug release was significantly slower in the respectively [163]. These terms now also commonly include similar
presence of a hydrophobic dye, due to the deeper absorption of cationic structures made from amphiphilic block copolymers [163–165]. Rather
methylene blue into the particulate pores. Comparatively nonpolar than being polar/nonpolar head/tail types, these copolymers instead
fluorescein, on the other hand, resides closer to the surface, effectively have hydrophilic polymer blocks hydrophobic polymer blocks. To
blocking the pores and inhibiting methylene blue efflux. Hence, the distinguish them from ‘traditional’ liposomes, polymeric liposomes can
hydrophobic drug must first be liberated before significant hydrophilic be more correctly termed ‘polymersomes’ [164]. Common hydrophobic
drug release can occur, giving a lifetime for methylene blue of 232 days, and hydrophilic blocks include poly(caprolactone), PCL, and poly
following an initial near linear release of 80% in ca. 175 days. (ethylene glycol), PEG, respectively. Other configurations have included
The uniquely high surface area and surface functionalisation capa niosomes (based on nonionic, surfactants) [164], and bilosomes (lipo
bility of MSNs makes them a powerful tool in the delivery of drugs in somes synthesised using bile acid salts) [166].
almost any pathology of the human body. As we have seen, even ionic, Synthesis of amphiphilic block copolymers of controlled structure
hydrophilic model drugs such as methylene blue can be sustained in the and size distribution has been made possible in recent years since the
system for almost 6 months upon a single dosage in-vivo. Their fate in- advancement of reversible deactivation radical polymerisation tech
vivo is of gradual degradation to biocompatible orthosilicic acid, a niques such as reversible addition/fragmentation chain transfer (RAFT)
source of silica absorbed by the body [161]. However, MSNs have yet to polymerisation, and atom transfer radical polymerisation (ATRP)
be approved for drug delivery applications by the relevant regulatory [163–165]. Both techniques allow finely tuned, structured block co
bodies and are difficult to process at the industrial scale, unlike the lab polymers to be synthesised from multiple monomers, but through
scale [162]. Significant research remains to be performed on MSN safety differing mechanisms. Their versatility and compatibility with
in the body, with regards to accumulation in the spleen, liver and tissues numerous different functional groups enables hydrophobic and hydro
[161], and robustness of the trigger mechanism (since MSNs can philic polymer chains to be combined into micelle and polymersome
encapsulate far more drug per unit volume than other particulate for precursor copolymers with relative ease and speed [165].
mulations, any failure of the slow release mechanism may result in the In the following sections, a selection both of typical representative
burst release of high concentrations of drug with life-threatening con technologies and novel modifications from the recent literature are
sequences) [161]. However, if subsequent research and clinical trials compared for their synthesis, encapsulation efficiency, and drug de
give evidence for safety and efficacy, MSNs are likely to offer huge livery efficacy. As with other technologies, their viability as real-world
promise for drug formulations in future. devices will be discussed and summarised for each type of material
and vehicle. The subsections are divided into the two major classes of
self-assembled amphiphilic compound-based capsule structures: lipo
4.4. Self-assembling nanocapsules somes and micelles.
Self-assembling capsules and vesicles used in drug delivery have 4.4.1. Liposomes, polymersomes and vesicular structures
primarily comprised micelles and liposomes, which are stable aggre Whether from lipids or amphiphilic block copolymer starting mate
gates of amphiphilic surfactant molecules and lipids, respectively, rials, drug-loaded vesicles are commonly synthesised using the thin film
relying on secondary interactions of nonpolar tails in an otherwise polar hydration technique or the organic solvent dissolution/evaporation
continuous phase. Micelles form above the critical micelle concentration technique [164], though many derivatives and alternatives of these
(CMC), a threshold concentration above which the nonpolar tails of a methods have been developed in recent years [167]. Both processes
surfactant aggregate to form an oily-core capsule, surrounded by a shell
Fig. 7. Structural configuration of the three major liposomal configurations: small, unilamellar vesicles, large multilamellar vesicles, and large unilamellar vesicles.
14
result in the spontaneous formation of vesicles, but they are usually the hydrophobic membranes of 1,2-dimyristoyl-sn-glycero-3-phospho
large and polydisperse; therefore, further processing and refinement is choline (DPMC) liposomes. Release of the hydrophilic penicillin G was
often required to form the desired nano-sized, predictably-sized nano controlled by the cleavage of the hydrophobic moiety, thus resulting in
capsules. Common homogenisation techniques include sonication, the rapid expulsion of the hydrophilic drug from the lipid membrane.
freeze-thaw cycling, extrusion through pores of controlled size, or high Drug release was sustained over a period of 6–12 h (under constant
pressure homogenisation [164,167]. While lipid and polymeric starting irradiation at 365 nm). Such a device is unlikely to be of significant use
materials for liposomes in drug delivery applications have tended to internally due to the need for light activation, though it may be useful in
remain similar throughout the years, recent trends in the literature have external applications such as skin wound healing. However, penetration
placed emphasis on the incorporation of targeting moieties or of UV light into any liposome-infused dressing is likely to be poor and
stimulus-responsive functionality. Table 6 shows a selection of recent limited to the surface.
publications in which liposome, polymersome, or other vesicular drug Non-spherical polymersomes were synthesised using the organic
delivery vehicles have been used for the sustained or targeted delivery of solvent removal technique in Ref. [171]. Briefly, diblock PEG-PLA co
hydrophilic drugs. polymers were dissolved in DMSO and dialysed against water to slowly
Photocleavable liposomes were synthesised by Goto et al. for the remove the DMSO and result in vesicle formation. The spherical vesicles
ultraviolet light (UVA)-triggered release of hydrophilic penicillin G were then exposed to hypertonic conditions, resulting in the formation
[169]. This was achieved by modification of the drug first with a hy of an osmotic gradient and the outward diffusion of water from the li
drophobic, photocleavable moiety, 2-nitro-3-naphthalenemethanol posomes, leading to their collapse into a prolate structure. Reported
(2-NNM), making it sufficiently hydrophobic to be incorporated into advantages of vesicles of this structure over spherical structure include
increased cellular uptake due to the similarity in morphology to
endogenous cells. Hydrophilic FITC-dextran conjugate was loaded into
Table 6 the vesicles during their synthesis, and was slowly released over a
Recent publications detailing polymer and lipid vesicles devices used in the monitored period of 48 h in citrate buffer (pH = 4.8). The release profile
sustained and targeted delivery of hydrophilic drugs. was equivalent to spherical polymersomes in vitro, with total release
Ref Drug Description of liposome system Release after 48 h of 25–30% of the encapsulated drug. Neuronal cell penetra
compound characteristic tion studies confirmed an increase in FITC fluorescence intensity of
[168] Calcein Transdermal; Calcein skin prolate polymersomes over the spherical morphology, and both were
Liposome and ethosome permeation significantly higher than a free drug solution.
nanovesicles formed from greatly improved Conjugation of targeting bodies to liposomes and polymersomes can
cholesterol and Phospholipon through use of
90G, and Phospholipon 90G only, ethosomes in
be utilised to increase specificity and result in rapid drug release at a
respectively. combination with target tissue. For example, overexpression of folic acid receptors in tu
sono/ mours is a well-known property of many cancers, thus folate-
electroporation, conjugation represents an effective method of improving drug delivery
cf. liposomes and
vehicle penetration into cancerous tissues [175]. The folate conjugation
dissolved calcein
only of acrylate polymer liposomes was the subject of Kim et al.‘s recent work
[166] Risedronate Intestinal; anionic and cationic Anionic [172]. In this system, hydrophobic blocks of amphiphilic hydroxyethyl
bilosomes formed from soya bilosomes acrylate-co-allyl methyl sulfide (HEA-co-AMS) were incorporated into
phosphatidylcholine, cholesterol, withstand the the lipid bilayer of the liposomes, and targeting functionalisation was
sodium deoxycholate, sodium gastrointestinal
glycocholate, and bile salts. tract and
achieved through carbodiimide coupling of folic acid to HEA. The sul
sustained fide moiety of AMS is readily oxidised to a sulfone, thus providing a
intestinal release trigger mechanism in the presence of reactive oxygen species (ROS)
for up to 2 h generated in the tumour environment. The sulfone formation would
[169] Penicillin G Photocleavable modified Release triggered
greatly increase the hydrophilicity of the hydrophobic AMS block,
penicillin G in only after
dipalmitoylphosphatidylcholine exposure to UVA destabilising the liposome, and resulting in drug release. Release of
(DOPC) liposomes radiation model hydrophilic fluorescent drug, calcein, from these liposomes, was
[170] Tetracycline Lysine-based gemini surfactant- Sustained release complete in 80% within <20 s of exposure to H2O2 in test experiments,
cholestrol niosomes for 24 h with 0% released in its absence. DOX (4 μg mL− 1) encapsulated in
(20–50%),
folate-conjugated HEA-co-AMS stabilised liposomes were found to
15–40% at initial
8h reduce tumour cell viability by ca. 70% when compared to 40–50% for
[171] Fluorescein Prolate (oval) polymersomes Sustained release free DOX.
isothiocyanate- formed from PLA-PEG block for 48 h Biorecognition-equipped liposomes system were developed as a
dextran copolymer
novel treatment for osteoarthritis by Bishnoi et al. [173].; these incor
[172] Doxorubicin Tumour-specific: folate- Rapid release
conjugated, oxidation-responsive (80% in ≤30 s) porated the polymer, chondroitin sulfate, and the opioid, tapentadol
liposome containing DOPE and when in an into a liposomal formulation. Chondroitin sulfate, a natural component
polyhydroxyethyl acrylate-co- oxidising of chondrocytes, has a high affinity for cartilaginous tissues, and is
allyl methyl sulfide environment; therefore employed as a targeting moiety and permeation enhancer. The
zero release
chondroitin-conjugated nanovesicles were assessed for drug delivery
otherwise
[173] Tapentadol Sublingual treatment for 60% release over properties in in-vivo studies in rats, which revealed that, following
osteoarthritis; chondroitin- 8 h, after burst sublingual administration, drug recovery from both conjugated and
conjugated drug-containing release of 20% in non-conjugated liposomes was improved significantly to that of an
nanovesicles of cholesterol, soy 2h
orally administered free drug in serum and tissues (knee cartilage, kid
phosphatidylcholine, and
stearylamine
ney, liver, heart, lungs), with the drug recovery from the conjugated
[174] Rhodamine B Hybrid nanoparticles of DOPC Sustained release liposomes persisting for longer in the cartilaginous tissues. In-vitro
and and Poloxamer 407a for 24 h, cf. 4 h release studies followed Higuchi model release, with ca. 60% drug
doxorubicin free rhodamine released over 8 h in PBS (pH 6.8).
HCl
Due to the leakage of hydrophilic drugs associated with lipid vesicle
encapsulation, the work of Ahmed and co-workers fortified the lipid
15
layer of their DOPC liposomes using Poloxamer 407, forming a hybrid PLGA/PEG, to form polyester-b-polyether amphiphilic block copolymer
liposome/polymersome nanoparticulate drug delivery vehicle [174]. micelles [183]. These biodegradable, biologically compatible, hydro
The hybrid nanovesicles were prepared by either coating pre-formed philic core nanoparticles were synthesised by the dropwise addition of a
DOPC liposomes in a Poloxamer solution, or by hydrating DOPC in an solution of polymer in DMSO, into an aqueous solution of HCl, thus
aqueous solution of Poloxamer, thus producing either a polymer-coated displacing the ‘good’ solvent, DMSO, with the ‘bad’ solvent, aqueous
vesicle or a hybrid liposome/polymersome material. The mixed acid. Ciprofloxacin, a hydrophilic drug, was entrapped in the hydro
polymer-lipid liposomes were more effective than the polymer-coated philic corona as well as in the entangled, hydrophobic polyester core.
liposomes, due to the decreased stability of the liposomes resulting In-vitro release studies revealed that the PLA-Dextran nanoparticulates
from poloxamer’s disruption of the liposomal lipid membrane. On the released up to 67.5% ciprofloxacin in the initial 2 h, followed by a lag
other hand, when poloxamer was a part of the hybrid particle formu phase of 96.7% in 144 h. The PLGA-PEG particles had a slightly slower
lation, the formation of gel-core vesicles rather than aqueous core ves initial burst release, of 56.1% in 2 h, followed by 96.4% at 144 h. For
icles was found to enhance their stability, with no change in size noted comparison, a free drug solution released 83.2% of the free drug within
over 58 days at 4 ◦ C. A typical loading concentration of RB and DOX of 2 h.
up to 80% at 0.5 mg mL− 1 was possible, with controlled release over 24 As with all drug delivery systems, targeting specificity and/or trig
h (75%) and 30 h (80%) for each drug, respectively, compared to ≤ 6 h gered release of drugs from micelles is desirable not only for maximal
for the free drug. dosage efficiency and productive absorption, but also in reducing
cytotoxicity (e.g. of chemotherapeutic agents) to healthy tissues [163,
4.4.2. Micelles 184]. Stimuli-responsive amphiphilic block copolymers have been
Whilst diblock copolymeric micelles are useful in stabilising insol employed to instil a triggered release system to polymer micelles in
uble lipophilic drug in their hydrophobic core, with hydrophilic tails recent publications. The environmental stimuli exploited for triggered
oriented outwards into aqueous solution, hydrophilic drugs can also be release have included temperature, pH, and reduction – the latter of
encapsulated in triblock copolymer micelles comprising a double- which are often exploited in cancer treatments, since cancerous tissues
hydrophilic body (A1BA2 type, where A is hydrophilic polymer and B have a lower pH and produce more reducing agents than healthy tissues
is hydrophobic polymer), rather than the single hydrophobic head/hy [163,184].
drophilic tail model used in the formation of hydrophobic drug core The thermoresponsive micelles of Xu et al. were synthesised through
micelles, (BA1 type). Thus, water-soluble drugs can be encapsulated in RAFT block copolymerisation of PNIPAM (temperature sensitive) with
the aqueous core A1, with micellar stability granted by the hydrophobic poly(tetraphenylethylene acrylate) (PTPEA, hydrophobic) and poly
B-block, and aqueous solution stability is improved by the hydrophilic (oligoethylene glycol methacrylate (POEGMA; hydrophilic) [177].
corona A2 [176]. Table 7 lists recent research articles which have Thus, at temperatures below 35 ◦ C, the polymer exists as random coiled
encapsulated hydrophilic drugs in micelles of this type. chains in solution; an increase in temperature to above the LCST of
Self-assembled reverse micelle-structured nanoparticulates were PNIPAM leads to a micelle formation with hydrophobic PNIPAM core,
recently prepared by nanoprecipitation of copolymers of PLA/dextran or PTPEA hydrophobic block, and POEGMA hydrophilic corona. FTIR data
confirms that the hydrophilic immunostimulant drug, thymopentin, is
retained in the PNIPAM core through hydrogen bonding of the amide
Table 7 carbonyl group with the amine of PNIPAM. Release of the drug from
Recent publications detailing self-assembling micelles used in the sustained and these micelles was sustained over ca. 9 h, compared to just 6 min for the
targeted delivery of hydrophilic drugs. free drug.
Ref Drug Description of micelle system Release In the recent work of El Jundi et al. [182], pH-responsive, doxor
compound characteristic ubicin⋅HCl-releasing double-hydrophilic micelles were synthesised
[177] Thymopentin Micelles formed from a Sustained release for through functionalisation of PEG-PCL amphiphilic block copolymers,
PNIPAM-co- tetraphenylethene 9 h cf. 6 min for free with advantages in increased degradability and biocompatibility
acrylate-b- poly[oligo(ethylene TP5 compared with some existing double-hydrophilic block copolymer mi
glycol) methacrylate triblock
celles. The thiol-yne click chemistry reaction was used to instil either
copolymer
[178] Capecitabine Dual-responsive micelles Sustained release for
carboxylic acid groups onto propargylated PCL, with high yields. Elec
formulated from PEG-b-poly up to 26 h trostatic interactions between the DOX⋅HCl cation and the carboxylated
(lysine) and 2-formylphenyl interior groups inhibited drug release at pH 7.4, with DOX release
boronic acid. reaching a maximum of ca. 30% after 7 h over the course of a 24 h
[179] Nicotinamide pH-responsive magnetic Sustained release for
experiment. At pH 5.0, on the other hand, due to protonation of the acid
micelles of gelatin-g-poly >36 h at pH 6.6;
(NIPAAm-co-DMAAm-co-UA)- comparatively very groups (pKa ca. 6.0), electrostatic interactions were reduced, and the
g-dextran/Fe3O4 (GPDF) little release at pH drug was gradually released (ca. 70% after 7 h).
= 7.2 Ma et al. developed a dual-responsive micellar drug delivery system,
[180] Dexamethasone Ocular delivery; Sustained delivery sensitive both to pH and to the reducing environment of cancerous tis
PLA–PCL–PEG–PCL–PLAa to > 90% in 12 h
micelles
sues [178]. This system was composed of the hydrophilic polymer, poly
[181] PCl-PEG-PCL micelles Uveitis inhibition in (lysine)-co-PEG, and a drug complex of a diol-containing chemothera
animal model peutic agent, capecitabine and 2-formylphenylboronic acid. Borate ester
sustained for 36 h; complex formation between the boronic acid group and the diol within
results not
capecitabine, as well as the reaction of the aldehyde group and the
significantly
different to ε-amine group of lysine to form an imine, led to formation of a stable
commercial topical complex at the core of the self-assembled micelles of 127 nm in size.
eye drops Relative stability of the imine bond under neutral pH compared to acidic
[182] Doxurubicin pH-sensitive, –COOH, –OH, 50% release in 2 h; pH resulted in pH sensitivity of the micelle, while the boronate ester
HCl and –NH2 functionalised PEG- 70% release at 7 h at
PCLa block copolymer micelles pH = 5; maximum
complex is sensitive to reduction. Thus, this dual responsive system,
release <30% at pH drug release still occurred at pH 7.4 and in the absence of a reducing
=7 agent, glutathione (reaching a maximum of 60–65% over 24 h in each
[183] Ciprofloxacin PLA-dextran and PLGA-PEG Sustained release for case) but was much more rapid at pH 5.0 and in the presence of at least
nanoparticles up to 6 days
10 mM glutathione (reaching a maximum of ca. 90% over 24 h, in each
16
case). Given this relative non-specificity of the programmed trigger Table 8

system, it is worth noting that no studies were performed which detailed Anticipated chemical, material, biological, and pharmaceutical properties which
the effects of the drug delivery system on healthy vs. cancerous cell must be reproducible in order for regulatory approval of novel nano-sized
models. medicines and drug delivery systems [189].
Nanotechnology remains at the forefront of medical research and Chemical and Material Properties Biology, Pharmacodynamics and
drug delivery literature, with a vast array of materials and particle Pharmacokinetics
classifications (matrix nanoparticles, core/shell type capsules, self- • Detailed description of all • Bioburden control
assembled liposomes and micelles, and lipid-based nanostructures) components
available to researchers, to tailor the properties of drug-loaded nano • Chemical composition • Sterility and endotoxin levels
• Chemical structure • Pharmacokinetic parameters
particulates to any imaginable drug, disease, or delivery route. Nano • Structural attributes that relate to • Stability in blood and serum
particles of late are becoming increasingly more intelligent in terms of function (e.g., lamellarity, core-shell
their capability to target specific cells, organs, environments or diseases structure
[185–187]. Despite this progress, the translation of nanomedicines into • Crystal form • Biological fate
• Impurities • Accumulation issues
bedside pharmaceutical preparations in industry has not been straight
• Particle size and size distribution • Absorption, distribution, metabolism,
forward, not least because of the numerous clinical obstacles (e.g. un and excretion (ADME)
predictable immune responses to nanoparticles between individuals due • Shape and morphology • Plasma Protein Binding (formation of
to genetics [188]) and regulatory challenges which exist [185,187]. As PC over time)
we have seen, the umbrella term, ‘nanoparticle’ itself encompasses all • Surface properties (e.g., surface • In vivo degradation/solubilisation rate
area, surface charge, chemical and place of degradation
manner of materials, morphologies, sizes, and delivery mechanisms,
reactivity, ligands, hydrophobicity, Pharmacodynamical parameters
with lack of regulation effectively meaning that the definition of what a and roughness);
nanoparticle is can be freely defined by their manufacturer. Therefore, • Particle concentration • Biocompatibility with blood and serum
there exist additional considerations when compared to ‘traditional’, • Porosity (if it relates to a function) • Additional risks associated with the
exposure route: topical application: skin
bulk medicinal preparations, including development and validation of
penetration, distribution in lymph
regulatory body-recognised methods to regulate and standardise the nodes, subcutaneous administration:
differing behaviour of particles in terms of safety and efficacy. Leading sensitisation to allergens, inhalation:
regulatory experts of the European Commission recently published a effect on the respiratory system, iv:
white paper in which the anticipated regulatory challenges expected for hemocompatibility
• Degradation path, kinetics and • In vitro uptake and cytotoxicity of
approval of future nanomedicines were explored [189]. A summary of
degradation products nanomaterials to the phagocytes
all the quality management and clinical considerations required for • Stability, both physical and chemical • Interaction with enzymes e.g.
approval of novel investigatory medicines in the nanoscale is displayed Cytochrome P450
in Table 8. • In-use stability studies at clinically • Immunogenicity (ICH S8)
relevant concentrations and under
Nanoparticle devices which have successfully reached clinical trials
relevant storage conditions
and commercialisation have included some PNPs, micelles, and lipo • Drug loading efficiency • Complement activation
somes – perhaps simply by virtue of these technologies existing for • Assay and distribution of any active
longer and therefore being subject to more scrutiny than the more novel ingredient associated with the
systems (e.g. MSNs and lipid-based nanoparticles) [185–187,190]. nanomaterial and free in solution (e.
g., surface bound or liposome
These materials generally have well-characterised, desirable properties
encapsulated versus free active
such as efficacy, patient tolerance, body distribution/accumulation, and ingredient)
processing parameters (including shelf-life and sterilisation routes) • Physical state of the active substance
[185,186,190]. On the other hand, the more recently developed tech • In vitro drug substance/siRNA
release rate in physiologically/
nologies (MSNs, SLNs, and NLCs), require more evidence to support
clinically relevant media
their safety and efficacy – for example, MSNs are generally well toler
ated, but some ultrafine particle sizes have been known to exhibit
cytotoxic effects [191]. More research is also needed into these particles’ the recent literature, hydrophilic drug conjugates have been made with
fates after delivering their payload (e.g. the degradation of MSNs to lipids [193–195], polymers [196–198], and even with other, hydro
orthosilicic acid [161]), their shelf lives (e.g. the stability of lipid carrier phobic drugs [199,200], to create amphiphilic prodrugs which may be
nanoparticles [112,123]), and the methods used to sterilise them. For all further processed into drug-conjugated nanomaterials such as micelles
of these nanomaterials, then, given the strength of the research litera and NLCs/SLNs. The major configurations for drug-conjugate delivery
ture that surrounds their efficacy in cell and animal models, and the vehicles are illustrated in Fig. 8.
sustained interest from the medical and research communities, it seems Common linking groups used in the formation of the conjugate-drug
to be a matter of when – and not if – these materials will enter the bond have included esters, anhydrides, carbonates, carbamates, imines,
pharmacist’s library. and amides [196,197], as well as noncovalent, ionic bonds. Disulfide
We have highlighted in the previous sections the challenges and bonds have been used in many amphiphilic drug-drug conjugates, as
potential benefits of a range of different polymer-based and other carrier reduction-sensitive linkages which will degrade to release both a hy
systems. An alternative strategy involving the linking of the drug to a drophilic and hydrophobic drug only in a reducing environment, such as
carrier system in the form of drug-conjugate systems is explored in the that of a tumour [201]. Benefits of these conjugate systems are primarily
next section. that the release of the drug, or hydrophilic compound, is controlled by
the chemical hydrolysis of a covalent bond, rather than solely a weaker
5. Drug-conjugate delivery vehicles secondary interaction such as physical entrapment, diffusion barriers,
polar interaction, or electrostatic interaction. Conjugates are therefore
A drug-conjugate delivery vehicle, or prodrug, is a non- useful for sustaining the release of hydrophilic drugs and compounds,
pharmaceutically active compound which undergoes a chemical con since these compounds’ hydrophilic nature otherwise results in rapid
version in the form of a bond cleavage to generate the active form of a partitioning into the external aqueous surroundings. In this section, we
drug [192]. Such modifications are typically intended to give the drug review recent advances in hydrophilic drug conjugate entities including
favourable characteristics to improve its membrane permeation, specific lipid conjugates, polymer conjugates, amphiphilic drug-drug
tissue targeting, and lifetime in circulation or at the tissue of interest. In
17
Fig. 8. Various forms of drug-conjugate carrier commonly used in the entrapment and targeted or sustained delivery of hydrophilic drugs in recent years.
conjugates, and drug-dendrimer conjugates. in mixtures of lipids to an aqueous phase containing surfactants, at
various ratios. Particles of a size typically in the region of 75–160 nm
5.1. Drug-lipid conjugate nanoparticles were formed, with entrapment efficiency of 97.8% DOX. With a pKa of
4.99, oleic acid forms conjugates with cationic compounds which are
As opposed to physical entrapment of drugs in a SLN or NLC, syn stable at neutral pH. Therefore, the lipid conjugate carrier is stable at
thesis of a lipid-drug conjugate allows for facile formulation of lipid drug neutral pH, but releases doxorubicin in acidic media, making this system
delivery vehicles with the additional benefits that (i) the drug, now an suitable for pH-based targeting of cancer cells. In-vitro release studies
integral hydrophilic head of the lipid structure, is incorporated into the demonstrated the sustained release of doxorubicin for 108 h, with 80%
crystalline structure of the lipid carrier more efficiently and (ii) drug of the loaded drug released during this period (at pH 3.8). By compar
release is controlled by degradation of the drug conjugate bonds, rather ison, at pH 7.4, only 22% of the drug was released over the same period.
than solely diffusion of drug/degradation of the particle [194]. A se An ionic conjugate of the surfactant, lauryl sulfate, with the hydro
lection of recent drug-conjugated lipid nanoparticles is shown in philic drug, mirabegron, was prepared in a similar manner by Kasashima
Table 9. et al. [202], who prepared microparticles of the salt complex by spray
Zhao and co-workers [195] synthesised ionic complexes of doxoru drying various formulations of mirabegron, sodium lauryl sulfate, eth
bicin oleate lipid conjugates by vigorous mixing of drug and lipid in a ylcellulose (binder) and triethyl citrate (plasticiser). Particle sizes were
basic, aqueous solution. This complex was then encapsulated in a lipid typically in the range of 60–100 μm, with in vitro drug release of around
carrier nanoparticle via the addition of molten drug conjugate dissolved 80% encapsulated drug within 12 h, even following prior storage of the
particles in aqueous media for 30 days at 40 ◦ C. This indicates excellent
shelf life, as a result of the insolubility of the particles in aqueous media.
Table 9
The stability of the particles upon heat sterilisation, however, was not
Recent publications detailing lipid drug-conjugate vehicles used in the sustained
and targeted delivery of hydrophilic drugs. investigated.
Covalently bonded conjugates with the hydrophilic drugs, isoniazid
Ref Drug Description of drug Release characteristic
and 5-fluorouracil, were detailed in recent publications by Pandit et al.
compound conjugate system
[203] and Sauraj et al. [204], respectively. Isoniazid, an antitubercular
[202] Mirabegron Lauryl sulfate complex to Controlled release for 12 h,
drug, was covalently conjugated to stearic acid via nucleophilic acyl
modulate aqueous cf. < 1 h when complexed
solubility of hydrophilic with hydrophilic substitution of stearyl chloride to form a N-stearyl amide of isoniazid
drug κ-carrageenan [203]. This lipid solution was cooled and added to an aqueous solution
[203] Isoniazid Stearic acid conjugate Initial burst phase of 20% containing the surfactants Tween® 80 and Poloxamer 188, producing
lipid nanoparticles release in 1 h; intermediate lipid drug carrier nanoparticles of size 124 nm. Isoniazid release from
phase of 60% in 10 h; final
phase of >90% in 70 h
these lipid carriers was biphasic, with 60.7% encapsulated drug released
[204] 5- Drug-stearic acid Sustained release for 60 h over the initial 12 h, and 97.8% released after 72 h. The 5-fluorouracil
fluorouracil conjugates embedded in (55%) at pH = 5; 30% stearic acid conjugates of Sauraj et al. [204] were synthesised by the
xylan-stearic acid release over same period at hydroxymethylation of 5-fluorouracil with formaldehyde, and subse
conjugate nanoparticles pH = 7.4.
quent esterification of the hydroxyl group with stearic acid. These
[195] Doxorubicin Oleic acid conjugate pH-sensitive release profile
nanoparticles – (80% in 108 h at pH 3.8; conjugates were encapsulated in lipid core micelles of stearic acid con
20% at pH 7.4) jugated with the hydrophilic sugar polymer, xylan. Thus, the biphasic
[194] Nicotine Drug-lipid ionic salt Release not determined; release of the drug was controlled by the degradation of the micelle, and
conjugate nanoparticles of encapsulation efficiency up additionally by the subsequent hydrolysis of the prodrug conjugate
Kolliwax® S and stearic to 60%
bond. The release of the drug was pH-controlled, with a total of 28% of
acid
18
the drug released over 60 h at pH 7.4, and 58% at pH 5.0 over the same Table 10
period. Recent publications detailing polymer drug-conjugate vehicles used in the sus
Aside from the advantageous chemical control gained through use of tained and targeted delivery of hydrophilic drugs.
covalent drug entrapment, the benefits of these drug-lipid conjugate Ref Drug Description of conjugate Release characteristic
particles are, as for the non-conjugated SLN/NLC morphology lipid- compound system
based vehicles described earlier, their ability to protect drug mole [207] Gemcitabine Hyaluronic acid polymer ester Sustained release for
cules from hydrolytic and oxidative degradation by entrapment in a conjugate <100 h, but with burst
water-insoluble, gas-impermeable structure [112,123]. Relatively little release of 50% within
initial 4 h
research has been published specifically on the shelf life and steriliz
[208] Redox-responsive Inhibited in-vivo
ability of these conjugate structures, though one can expect that the nanoparticles of drug- tumour growth for at
properties would be largely similar to those of the SLN/NLCs described conjugated disulfide- least 55 days after
here previously. Their predictable size, structure and biological containing vinyl copolymer injection
compatibility, in comparison to other nano/microparticle types, may [209] Brush copolymer based on PEG <25% release in 120 h
and PLA-drug conjugate at pH 5.5; 90% release
grant them favourable properties toward the post-clinical trial stages of in 72 h at pH 7.4.
commercialisation, i.e. in regulation. However, to date, few to no [210] Doxurubicin Alginate microbeads Sustained release of
drug-conjugate lipid particles are currently marketed in the pharma HCl templated with internal drug ≤15% in initial 24 h, vs
ceutical sector. conjugate voids 99% over 24 h for non-
encapsulated drug
[148] Dual-functionalised core/shell Biphasic; negligible
5.2. Polymer conjugates & their self-assembling particles nanoparticles of chitosan- release for initial 5 h,
graft-polyacrylic acid- followed by near-
Polymer conjugates of various compositions and structural confor conjugated drug, coated in linear release for 11
dual-functionalised chitosan- days (>80%) for the
mations have been employed as drug releasing agents for many years
glycyrrhiznic acid/lactobionic dual-ligand particle.
[196,197]. For example, linear conjugates of drug-terminated poly acid Single and no-ligand
(ethylene glycol) have been employed in the drug delivery literature for particles ≤20% release
many years, providing improvements in solubility and biological over same period.
compatibility of drugs [205]. The drug-pendant polymer conformation [211] Reduction-sensitive disulfide- Reducing agent-
crosslinked polymer prodrug dependent release;
(the Ringsdorf model) has been associated with high drug loading, good
micelles of PEG-b-poly(2- 90% in 10 h in
transport properties and improved solubility properties of drugs [198]. methacryloyloxyethyl presence of DTTa,
These formulations contain a polymer backbone chemically conjugated phosphorylcholine) 100% at 48 h. In
to the drug, and optionally one or both of a solubilising agent and a absence of DTT,
transport or targeting agent. They may be biologically degradable, sta maximal release of
30% at 12 h–48 h.
ble, or targetable with respect to time in circulation, depending on the [212] Lisinopril Drug-conjugated amphiphilic Sustained release from
nature of the polymer backbone and the bonds used to link the drug to block copolymer micelles the polymer conjugate
the backbone [196–198]. (PLA-PEG-PLAa) up to 120 h; micelles
The advantages of these systems are a high degree of structural formed from the
polymer conjugate
control, a high concentration of inactivated, labile, drug-containing
further slow the rate of
groups in a small volume, and a drug release mechanism controlled by release. Micelles which
hydrolysis or disease-specific lysis of these bonds rather than displace physically entrap the
ment of weaker, secondary interactions [196,198,206]. Formation of polymer (rather than
covalently drug-conjugated, cross-linked or self-assembled nano chemical conjugates)
leach drug at pH 7.4;
particles has emerged as a leading trend in the drug delivery literature in conjugates are stable
recent years [206]. In these models, drug release is controlled by the infinitely at neutral
solubilities of the polymer and drug, and also the distance between the pH.
drug and the polymer backbone (i.e. the presence/number of linking
units), the charge and charge density of the prodrug system (particularly
delivery of the water-soluble analgesic and anti-inflammatory, sodium
pertinent to weakly basic or acidic drugs/polymers), and biodegradation
salicylate, from hydrophilic polymers including poly(vinyl alcohol)
in-vivo by enzyme action [196]. The lattermost of these effects is seldom
[213], PVA, poly(2-hydroxyethyl methacrylate) [214], pHEMA, and
investigated in the literature, with articles tending to test drug release
starch [215]. In each case, the hydroxyl polymer was modified with
systems in saline solution, though it provides key insight into the
chloroacetyl chloride, acting as an acetyl linking group between the
real-world application of these systems. A selection of recent articles
polymer backbone and drug. The in-vitro release of the drug in all cases
detailing sustained or targeted delivery of hydrophilic drugs via polymer
was shown to be dependent on both pH and % conversion of the hy
conjugates is given in Table 10.
droxyl groups to salicylate ester groups, and in each case was shown to
The comparative stability of covalent drug-polymer conjugates was
sustain the release of the drug for over 25 days. For each of the three
exemplified by Danafar et al., in a study in which lisinopril, a water-
polymer conjugate prodrugs studied by Jantas’ group, the rate of hy
soluble drug used to lower blood pressure, was conjugated to amphi
drolysis increased with the increasing pH of the release medium. Release
philic block copolymers of PLA-PEG-PLA [212]. Carbodiimide coupling
was also most rapid with a lower degree of substitution, facilitated by an
was used to conjugate the carboxylic acid groups of lisinopril to the
increase in hydrophilicity of the polymer, reduced steric hindrance, and
terminal hydroxyl groups of the PLA-PEG-PLA chain. The degradation of
a more efficient penetration of OH− ions [213–215].
the ester bond, releasing the drug, occurred only under acidic condi
Haam and co-authors [207] patented a dual polymer-prodrug con
tions; at a pH of 7.4, no free lisinopril was detected over 144 h from the
jugate system in which a hydrophilic drug was conjugated to an anionic
drug-conjugated polymer micelles, whereas over 70% of the physically
polymer, and a hydrophobic drug was conjugated to a cationic polymer.
entrapped drug was released. At pH 4.0, slow release of the drug from
Thus, both polymer conjugates formed a polyelectrolyte complex
the drug-conjugate micelles over a period of 120 h was observed (ca.
together. The dual release of drugs in treatment of cancers is currently of
50%), with more rapid release from non-aggregated polymer over the
great interest in the literature; thus, the hydrophilic drugs tested
same period (>80% release).
included gemcitabine, and the hydrophobic drug was paclitaxel. The
Jantas and co-workers published a series of papers detailing the
19
anionic and cationic polymers were hyaluronic acid, and chitosan, polymer prodrug type configuration has been somewhat useful in
respectively. The polymer-drug conjugate was synthesised by esterifying conferring favourable stability in comparison to the Ringsdorf model-
the hydroxyl group of gemcitabine with the carboxylate of hyaluronic type polymer prodrugs [200]. However, for drug-polymer conjugates
acid. Release studies showed that the lifetime of gemcitabine was and nanoparticles of the same to become clinically relevant, a number of
greater than 100 h at pH 5.5, though up to 50% of the drug was released regulatory considerations must be satisfied, including development of
within the first 3 h. The release was less rapid at pH 7.4, indicating slight validated methods for polymer-specific properties such as molecular
selectivity toward the lower-pH environment of tumour cells. weight, degree of substitution, shelf-life/stability and viscosity/osmo
Paclitaxel/gemcitabine dual-drug delivery systems were also studied larity of the dissolved formulation once in the body [217].
by Sun and co-workers in nanoparticles sensitive to reduction [208] and
pH [209]. Sensitivity towards the reductive environment of a cancerous
cell was achieved by conjugation of vinyl benzene chloride with a 5.3. Amphiphilic drug-drug conjugates (ADDCs)
dithiodicarboxylic acid, which was block copolymerised with oligo
ethylene glycol methacrylate via RAFT. These block copolymers Small molecular conjugates of hydrophilic and hydrophobic drugs
self-assembled into hydrophobic drug-core hydrophilic drug-surface have recently come to the forefront of the drug delivery literature,
nanoparticles of size 13 nm, which enhanced the penetration of the especially in chemotherapeutics. The obvious benefit of these vehicles is
particles into the tumours. Surface –OH groups enhanced the stability of in the simultaneous delivery of multiple drugs, but also in the enhanced
the micelles in aqueous surroundings by hydrogen bonding. In-vivo solubility and bioavailability/biodistribution properties of both drugs.
studies in mice inoculated with pancreatic tumours demonstrated a Rarely, the drugs are conjugated to one another directly through
79.5% reduction in tumour weight over 25 days for the hollow, compatible reactive moieties present natively in the structures of both
gemcitabine-only micelles, and 84.6% for the combined gemcitabine/ drugs [218]. More commonly, the drugs are linked through a short,
paclitaxel micelles. Sensitivity to reducing agents was assessed by labile linking chain, which may confer an ability for
monitoring drug release in the presence and absence of 10 mM of a environment-specific targeting – for example, a reduction-sensitive di
reducing agent, glutathione, over 24 h. Drug release was significantly sulfide bridge or a pH-sensitive carbonate linkage, for example. Table 11
greater (ca. 20–25%) than in its absence (ca. 0–4%). For the pH-sensitive details findings of recent published articles in which ADDCs were used in
micelles, a brush copolymer was synthesised from PLA, allyl-PLA and drug delivery.
acetylenyl-PLA. Click chemistry was used to incorporate PEG to the Disulfide-linked ADDCs were the subject of recent articles from Hou
alkyne-modified PLA, while the thiol-ene reactions allowed conjugation and co-workers [219,220]. In these papers, the hydrophilic drugs
of thiolated esters and amides of gemcitabine and paclitaxel, respec gemcitabine and methotrexate were linked to the hydrophobic drugs
tively, to the alkene-midified PLA. Self-assembled micelles of these camptothecin and podophyllotoxin, respectively. In both studies, the
amphiphilic block copolymer drug conjugates were sized at 45.1 nm on drugs were sequentially joined to a symmetrical dihydroxyethyldisulfide
average. A rapid release of gemcitabine of 75% was observed over 72 h via linkage of the –OH groups to a triphosgene-induced carbonate bond,
at pH 7.4; at pH 5.5, a maximum of 20% of drug was released in 48 h. or direct esterification with a carboxylic acid group of the drug. The
Ionic complexes, while less chemically stable than covalently con ADDCs self-assembled into nanoparticles sized at 16 nm [220] and 60
jugated drug/polymer systems, are also effective in sustaining the nm [219]. The trigger mechanism was assessed both by measuring
release of drug molecules from particulate systems. For example, an release of drugs in absence and presence of the reducing agent gluta
ionic complex of doxorubicin and polyacrylate were encapsulated in thione, and by repeating these tests with a non-disulfide linked version
hydrophilic-core nanocapsules in Ref. [148]. A graft co-polymer of of the ADDCs synthesised from 1,6-hexanediol. These tests showed that
O-carboxymethyl chitosan and poly(acrylic acid) was first synthesised, drug release was exclusively triggered by the cleavage of the disulfide
and the mixing of positively charged doxorubicin and negatively linkage in the presence of glutathione, as far less drug release was
charged poly(acrylate) formed the hydrophilic nanoparticle core. A observed in the absence of either glutathione or the disulfide bridge.
core-shell structure was formulated through the addition of hydrophilic ADDCs of the hydrophilic drug, Irinotecan, with the hydrophobic
drug complex suspension to a solution of a dual-ligand functionalised drug, melampomaglonide B, were linked by a hydrolysable carbonate
chitosan. These ligands are liver-specific targeting moieties, 18β-gly
cyrrhetinic acid (hydrophobic) and lactobionic acid (hydrophilic), the Table 11
ratios of which control the solubility properties of the nanoparticles. Recent publications detailing amphiphilic drug-drug-conjugate vehicles used in
Targeted and sustained release of these particles (274 nm in size) was the sustained and targeted delivery of hydrophilic drugs.
observed over the course of 10 days for the dual-ligand particles. [219] Methotrexate Amphiphilic drug-drug Reduction-responsive
Other polymer conjugates of doxorubicin have included poly(gluta conjugate of Methotrexate release of both drugs
mic acid) as a hydrolysable drug-releasing polypeptide [216], syn with podophyllotoxin via triggered by
disulfide bridge glutathione. Sustained
thesised from polyglutamate either directly conjugated to the drug, or
release over 10 h (80%)
with various short-chains of glycine and other amino acids in a vs. max <20% in
brush-copolymer configuration. These were prepared using typical absence of glutathione.
carbodiimide peptide synthetic pathways. In each case, drug release was [220] Gemcitabine Disulfide prodrug conjugate Reduction-dependent
sustained for up to 100 h – though a maximum of <15% of the bound with another, hydrophobic, delivery triggered only
drug was released. This low figure is presumably due to the relative anti-cancer drug, in presence of DTT;
stability of amide bonds compared to the more labile ester or carbonate camptothecin sustained delivery for
<48 h (80%); 50%
bonds more common in this type of drug carrier.
release in first 6 h.
The recently published drug-polymer conjugates and complexes [221] Irinotecan Self-assembled particles of In vitro release of
have been shown to provide excellent drug stability and sustained carbonate-linked, dual-drug nearly 50% after pH 5.0
release characteristics. Overall, the main advantages of polymer pro conjugate of hydrophilic in presence of esterase
drugs include their ease of synthesis, high drug loading, and versatility irinotecan with enzyme, down to 15%
melampomaglonide B at pH 7.4 with no
with respect to conjugation of numerous species to the same backbone. enzyme
Therefore, modification of the polymer systems with ligands and [218] Floxuridine Ester-linked amphiphilic <20% release at pH 7.4
environment-specific linkers has realised potential for disease-specific drug-drug conjugate with with no esterase over
targeting conferring enhanced stability during circulation following antiangiogenic pseudolaric 24 h; >65% release at
acid pH 5.0 with esterase
administration. Furthermore, micellar stability granted to the head-tail
20
linker by Qu et al. [221]. The ADDCs were prepared by introduction of a cysteine protease enzyme, cathepsin B; in its absence, a maximum of
carbonate linkage between melampomaglonide and irinotecan via re <10% was released over 24 h, whereas in its presence, 60% was released
action with carbonyl di-(1,2,3-triazole). Stable, spherical, within 30 min, and a maximum of 90% reached after 24 h. This triggered
self-assembled particles of these drugs were sized at 122.1 nm, with drug release mechanism is useful in ensuring the drug is released only when
release found to be sensitive both to acid and esterase enzyme degra in the environment of a tumour lysosome, in which production of
dation. Decreasing pH from 7.4 to 5.0 increases rate of drug release from cathepsin B is upregulated [239].
15% in 48 h to 40%. Addition of esterase increases maximal drug release Drug-conjugated lysine dendrimers were also the focus of Ryan
to 50% over the same period. Another ADDC, of hydrophilic floxuridine et al.‘s 2017 paper [240], in which methotrexate was conjugated to the
and hydrophobic pseudolaric acid was investigated as a novel dendrimer via either short peptide linkages or an oligoethylene glycol
anti-cancer treatment which combined an antiangiogenic and a linker. Methotrexate was also optionally modified with a tert-butanol
chemotherapeutic in a single system [218]. The one step Steglich capping unit to increase its lipophilicity. In these experiments, the
esterification of the psuedolaric acid carboxyl group with the hydrox additional hydrophobic modification was found to increase the stability
yethyl moiety of floxuridine led to the synthesis of amphiphilic prodrugs of the peptide linked dendrimer conjugates in human plasma; the
which self-assembled into spherical nanoparticles, of 150 nm in size. The non-capped dendrimers were eliminated in under 24 h, while with
acid and enzyme-sensitivity were both investigated, producing similar capping, they were still detectable after 120 h. The delivery profile of the
results to the Qu’s earlier work [221]. Drug release was more rapid in free drug from the dendrimers was not explicit in this study, although
acidic media, or media containing 30 U mL− 1 esterase. At a buffer pH of previous work by the same group [241] has shown that
7.4, a maximum of 20% release was detected over 48 h. Over the same methotrexate-conjugated lysine dendrimers increase the lifetime of the
period at pH 5.0 with esterase, drug release reached 60%. In vitro cell free drug from 3 h to >120 h in plasma.
studies confirmed the desired dual effect of high cytotoxicity to tumour Methotrexate has also been conjugated to dendrimers to construct
cells and inhibition of new blood vessel growth. controlled release anti-cancer drug formulations [242]. In this study by
Evidently, ADDC synthesis represents an efficient and effective route Torres-Pérez et al., sixth generation PAMAM dendrimers were conju
to novel therapeutics comprising two drugs with relatively opposing, gated with the drug directly, using carbodiimide chemistry. Synthesised
undesirable solution properties, to give a drug delivery vehicle with dendrimers of an average diameter 8.5 nm were found to reduce
desirable solution properties and specific targeting, and with inherently cancerous cell viability by 50% over a period of 4 h, while healthy cell
high encapsulation efficiency. In the recent literature, there have been viability remained <80%. The kinetics of methotrexate release were not
ADDCs with enzyme sensitive, pH-sensitive, and reduction-sensitive explicitly studied in this work.
functionality. Relatively little investigative work has been undertaken Hydrophilic drug-dendrimer conjugates are encountered relatively
into the translation of these novel devices from bench to bedside; infrequently in the recent literature, despite offering high drug loading
however, interestingly, research comparing different bonding types and capacity per unit volume and typically excellent stability in the body,
divalent linker unit chain lengths showed that the presence of the di with biological compatibility easily demonstrated and tuneable through
sulfide bond offered some protection against hydrolysis of these groups material optimisation and/or surface conjugation as described in recent
in acidic conditions [201], suggesting improved stability in aqueous publications [234,235]. Furthermore, few existing dendrimer formula
storage. Nonetheless, ADDCs are readily synthesised, with predictable, tions have entered clinical trials [243] until very recently [244], and
reproducible properties, and thus represent an interesting and novel fewer still approved by the world’s major regulatory bodies [245], due
route for the effective delivery of multiple drugs to tissues otherwise to the complexities associated with synthesis and scale-up. There also
inaccessible to two drugs of such opposing nature simultaneously. remain concerns and obstacles towards commercial viability and
bench-to-bedside transition which include the reproducibility of prod
5.4. Dendrimer-drug conjugates ucts with predictable pharmacology and pharmacokinetics [222].
Nonetheless, dendrimers remain an innovative, interesting approach to
Dendrimers are nano-sized, symmetrical, star-shaped polymers sustained and controlled drug delivery, with unique biochemical and
which are highly ordered, highly branched, and uniformly distributed in cellular interaction properties amongst the existing materials currently
structure and size. Dendrimers have a high number of functionalised used in drug delivery science.
terminal groups and internal groups, enabling efficient encapsulation of On the whole, prodrug-conjugate delivery vehicles are relatively
drugs through ad(b)sorption in internal nanocavities, and/or through rarely seen in the contemporary drug delivery literature, which more
chemical conjugation with reactive terminal groups [222,223]. Their commonly encompasses drugs physically entrapped in polymeric matrix
small size enables dendrimers to interact with cellular components, and or capsule nanoparticles, fibres, or hydrogels. However, the clinical
therefore they have been identified as excellent candidates for intra proof of concept of such devices (especially polymer and dendrimer
cellular drug and gene delivery [224,225]. conjugates) has been established over the last 40 years, with many linear
Early dendrimers were commonly based on a poly(aminoamine), drug-polymer conjugates entering the clinical trial phase throughout the
PAMAM, core, generated by successive, exhaustive aza-Michael addition early 1990s–2000s [217,243], with favourable properties in drug life
of ethylenediamine to methacrylate [226], and more recently have been time, stability, immunogenicity and targeting specificity [246]. For
synthesised using efficient click chemistry reactions [227–229] with bench to bedside translation, the importance of extensive physico
multifunctional centres such as hyperbranched polyglycerols [230] and chemical characterisation has been emphasised due to the potential
pentaerythritol [225,231–233]. The PAMAM family of dendrimer has variances of macromolecules in structure, degree of substitution,
been associated with toxic effects, due to their small size and cationic arrangement of substituents, molecular weight and uniformity of mo
nature leading to interactions with cell membranes eventually leading to lecular weight distribution, morphology, size, and that any biological
cell lysis [234,235]. Nowadays, toxicity has been reduced by conju interactions are fully characterised and predicted [243]. ADDCs, which
gating dendrimers to biocompatible groups (e.g. PEG [236] or carbox have only recently begun to gain significant interest in the drug delivery
ybetaines [237]), or by using alternative starting materials to synthesise field, have nonetheless been subjected to similar scrutiny in research
degradable polyester dendrimers [234,235] or peptide dendrimers papers and review articles, which identify the need for long-term clinical
[238]. In recent work [239], a peptide dendrimer was synthesised from studies monitoring the effects of these systems on non-cancerous tissues,
a tris(triethylamine)-core with poly(lysine) branching units. The hy and the fate of the ADDC particles in the body in terms of transport and
drophilic drug gemcitabine was conjugated to the terminal groups of the excretion [247]. They are, however, regarded as powerful systems with
dendrimer via an enzyme-cleavable short peptide chain. These particles, capability for dual drug delivery at fixed ratio and with remarkably high
of 80 nm in size, released the drug rapidly only in the presence of the drug loading.
21
6. Conclusion Funding and conflicts of interest
The development of hydrophilic drug delivery systems is progressing We confirm that our manuscript, “Sustained and targeted delivery of
at a rapid and impressive rate, complemented by an ever-increasing hydrophilic drug compounds: a review of existing and novel technolo
advancement in understanding of polymer chemistry, pharmacoki gies from bench to bedside,” has no conflicts of interest associated with
netics, and cell biology. In this review of the recent literature, the the article, its author, or co-authors.
dominant trends have been in improving hydrophilic drug encapsula This work was made possible by funding from CooperVision, Inc.
tion in lipid and hydrophobic polymer matrices, as well as the conju (Pleasanton, CA, USA), in a collaborative effort with the University of
gation of hydrophilic drugs into novel, drug-only, self-delivering Brighton (Brighton, UK).
vehicles such as ADDCs and their self-assembling particles. These types
of conjugates, along with polymer conjugates and lipid conjugate Data availability
nanoparticles, have been associated with improved targeting and drug
lifetime in the human body. Other developments have included ad No data was used for the research described in the article.
vances in electrospinning and MSN technologies which have allowed the
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Journal of Drug Delivery Science and Technology 78 (2022) 103936

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

Sustained and targeted delivery of hydrophilic drug compounds: A review

1. Introduction biomolecule ligands for use in targeting pathologies which overexpress

Table 1 The mechanism of hydrophilic drug delivery from hydrophobic fi

3.2. Self-healing and miscellaneous hydrogels

Self-healing hydrogels have received considerable attention in the

Sterilisation of hydrogels is relatively simple, as most are compatible

Table 3 viscosity of the formulation and reducing premature elimination of the

Table 4 Table 4 (continued )

case). Given this relative non-specificity of the programmed trigger Table 8

6. Conclusion Funding and conflicts of interest

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1 s2.0 S1773224722008474 Main PDF

Uploaded by

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Copyright

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1 s2.0 S1773224722008474 Main PDF

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Journal of Drug Delivery Science and Technology 78 (2022) 103936

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

Sustained and targeted delivery of hydrophilic drug compounds: A review

1. Introduction biomolecule ligands for use in targeting pathologies which overexpress

Table 1 The mechanism of hydrophilic drug delivery from hydrophobic fi­

3.2. Self-healing and miscellaneous hydrogels

Self-healing hydrogels have received considerable attention in the

Sterilisation of hydrogels is relatively simple, as most are compatible

Table 3 viscosity of the formulation and reducing premature elimination of the

Table 4 Table 4 (continued )

case). Given this relative non-specificity of the programmed trigger Table 8

6. Conclusion Funding and conflicts of interest

You might also like

Table 1 The mechanism of hydrophilic drug delivery from hydrophobic fi