Ver Very Import

International Journal of Pharmaceutics 621 (2022) 121782
Contents lists available at ScienceDirect
International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Review
Antibiotic-loaded lipid-based nanocarrier: A promising strategy to

overcome bacterial infection
Mirla Anali Bazán Henostroza a, Guilherme Diniz Tavares b, Megumi Nishitani Yukuyama a,
Aline De Souza a, Eduardo José Barbosa a, Valdir Carlos Avino c, Edson dos Santos Neto d,
Felipe Rebello Lourenço a, Raimar Löbenberg e, Nádia Araci Bou-Chacra a, *
a
Faculty of Pharmaceutical Sciences, Department of Pharmacy, University of Sao Paulo, Avenida Professor Lineu Prestes 508, Butantan, 05508-900 Sao Paulo, SP,
Brazil
b
Faculty of Pharmacy, Department of Pharmaceutical Sciences, Federal University of Juiz de Fora, Rua José Lourenço Kelmer, s/n, Campus Universitário, Juiz de Fora,
36036-900 Minas Gerais, Brazil
c
Pearson Saúde Animal S/A, Sao Paulo, SP, Brazil
d
Clinical Hospital of the Faculty of Medicine, Ophthalmology Division, University of São Paulo, Avenida Dr. Eneas de Carvalho Aguiar, 255, Cerqueira César, 05403-
000 São Paulo, SP, Brazil
e
Division of Pharmaceutical Sciences, Faculty of Pharmacy & Pharmaceutical Sciences, Katz Group-Rexall Centre for Pharmacy & Health Research, University of
Alberta, 11361 - 87 Avenue, Room 3-142-K, Edmonton, AB T6G 2E1, Canada
A R T I C L E I N F O A B S T R A C T
Keywords: According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC),
Bacterial infection bacterial infections are one of the greatest threats to global health, food production, and life expectancy. In this
Susceptible strain sense, the development of innovative formulations aiming at greater therapeutic efficacy, safety, and shorter
Resistant strain
treatment duration compared to conventional products is urgently needed. Lipid-based nanocarriers (LBNs) have
Biofilm
Lipid-based nanocarrier
demonstrated the potential to enhance the effectiveness of available antibiotics. Among them, liposome, nano
emulsion, solid lipid nanoparticle (SLN), and nanostructured lipid carrier (NLC) are the most promising due to
their solid technical background for laboratory and industrial production. This review describes recent advances
in developing antibiotic-loaded LBNs against susceptible and resistant bacterial strains and biofilm. LBNs
revealed to be a promising alternative to deliver antibiotics due to their superior characteristics compared to
conventional preparations, including their modified drug release, improved bioavailability, drug protection
against chemical or enzymatic degradation, greater drug loading capacity, and biocompatibility. Antibiotic-
loaded LBNs can improve current clinical drug therapy, bring innovative products and rescue discarded anti
biotics. Thus, antibiotic-loaded LBNs have potential to open a window of opportunities to continue saving
millions of lives and prevent the devastating impact of bacterial infection.
1. Introduction strains are emerging worldwide (Janik et al., 2020; Dhingra et al.,
2020). According to the World Health Organization (WHO) and Centers
Bacterial infections have a tremendous impact on public health and for Disease Control and Prevention (CDC), this situation is one of the
antibiotic therapy has been very effective in controlling common in greatest threats to global health, food production, and life expectancy.
fections (Hutchings et al., 2019). However, these antibiotics have been Although a lack of resources and infrastructure facilitate the prolif
becoming far less effective due to their misuse and overuse in human eration of antibiotic resistance in low-income countries (Malik and
health, veterinary, and agriculture (Rawson et al., 2020; Menkem et al., Bhattacharyya, 2019; Nadimpalli et al., 2018) the Global Antimicrobial
2019; Tarrant and Krockow, 2022). Consequently, an alarming global Surveillance System (GLASS) showed that low- and high-income coun
spread of antimicrobial-resistant, multidrug-resistant, and superbug tries have a similarly high incidence of resistant strains (GLASS, 2021).
* Corresponding author.
E-mail addresses: [email protected] (M.A. Bazán Henostroza), [email protected] (G. Diniz Tavares), [email protected]
(M. Nishitani Yukuyama), [email protected] (A. De Souza), [email protected] (E. José Barbosa), [email protected] (V. Carlos
Avino), [email protected] (E. dos Santos Neto), [email protected] (F. Rebello Lourenço), [email protected] (R. Löbenberg), [email protected] (N. Araci Bou-Chacra).
https://doi.org/10.1016/j.ijpharm.2022.121782
Received 11 January 2022; Received in revised form 11 April 2022; Accepted 25 April 2022
Available online 28 April 2022
0378-5173/© 2022 Elsevier B.V. All rights reserved.
M.A. Bazán Henostroza et al. International Journal of Pharmaceutics 621 (2022) 121782
The WHO predicted that by 2050 antibiotic resistance could cause about LBNs interact first with bacterial surfaces driving nanoparticle anti
10 million deaths per year (WHO, 2014). Moreover, the economic microbial activity (Baptista et al., 2018). LBNs mechanisms against
impact is a serious concern (Dadgostar, 2019; Thorpe et al., 2018); for bacteria comprise cell wall and membrane disruption, membrane fusion
instance, the United States estimated that the annual cost to treat six and damage bacterial intracellular components (Fig. 1). These mecha
antibiotic resistance increases in 4.6 billion dollars health care system nisms are subjected to LBN composition, particle size, large surface-area-
(Nelson et al., 2021). to-volume ratio and zeta potential (ZP) combined with antibiotic drug
The rapid spread of resistant strains compromises the efficacy of the loaded (Makabenta et al., 2021; Baptista et al., 2018). Additionally, Van
currently available and last-resort antibiotics (Gogry et al., 2021; der Waals forces, hydrophobic interactions and electrostatic attractions
Shariati et al., 2020; Sherry and Howden, 2018). To face this resistance, facilitate multiple LBNs interaction with bacterial cell (Hayden et al.,
the development of new antimicrobial compounds is vital (Lewis, 2020; 2012; Joshi et al., 2020; Zhang et al., 2020). For instance, LBNs can be
Hoffman, 2020). Due to the lengthy time requirement, high cost, and designed to target specific bacteria, using surfactants and lipids that
enormous effort to develop and launch new molecules (Butler and favor increased membrane permeability to maintain an adequate anti
Paterson, 2020), combined drug therapy has been successfully employed biotic concentration with consequent membrane disruption (Wang
in clinical settings (Thu et al., 2021; Pletz et al., 2017; Tyers and Wright, et al., 2020; Makabenta et al., 2021). As an example of cationic LBNs,
2019). Nevertheless, bacteria are constantly adapting to threats against this may promote nanoparticle aggregation around bacteria by elec
their survival, limiting useful antibiotic life (Jacopin et al., 2020; Felden trostatic interaction increasing antibiotic concentration at the site of
and Cattoir, 2018; Windels et al., 2020). action (Thorn et al., 2021; Arana et al., 2021).
Hence, the search for treatments with greater therapeutic efficacy, Bacterial membrane fusion is the most distinct feature of liposomes,
safety and shorter treatment duration compared to conventional prep which allows rapid high antibiotic concentration inside a bacterium
arations in the market (tablets, capsules, suspensions, solutions, oint (Kube et al., 2017; Wang et al., 2020; Scriboni et al., 2019). The main
ments, powders and creams) is urgent (Duval et al., 2019; Morris and driving forces in the fusion process is the nature of the bacterial mem
Cerceo, 2020), In this sense, lipid-based nanocarriers (LBNs) have brane and liposome fluidity. For instance, Gram-negative Escherichia coli
demonstrated a potential for developing innovative medicines able to and Pseudomonas aeruginosa revealed different percentage of
enhance the effectiveness of available antibiotics (Makabenta et al., tobramycin-liposome fusion, 66% and 44%, respectively. This result
2021; Wang et al., 2020; Kirtane et al., 2021; Yang et al., 2021; Thorn might be correlated with the presence of 90% of phosphatidylethanol
et al., 2021; Arana et al., 2021). Among them, liposome (Gonzalez amine phospholipids and LPS in the outer membrane of Escherichia coli.
Gomez and Hosseinidoust, 2020; Ferreira et al., 2021a), nanoemulsion Similarly, Gram-positive Streptococcus agalactiae and Staphylococcus
(NE) (Wilson et al., 2022; Tayeb and Sainsbury, 2018; Singh et al., 2020) aureus showed differences in the fusion process. Additionally, the fusion
solid lipid nanoparticle (SLN) (Scioli Montoto et al., 2020; Garcês et al., was influenced by divalent cation, temperature, and pH of the envi
2018) and nanostructured lipid carrier (NLC)(Shirodkar et al., 2019; ronment (Ma et al., 2016).
Dhiman et al., 2021) are the most promising due to their solid technical Protein synthesis and DNA replication are critical events for bacterial
background for laboratory and industrial production (Shah et al., 2019; survival. Thus, LBNs can be designed to interfere with these processes.
Ganesan and Narayanasamy, 2017; de Oliveira et al., 2020; Pucci et al., After bacterial membrane disruption, LBNs trigger DNA damage, protein
2020). LBNs show unique properties such as size in nanoscale range, synthesis alteration and gene mutation (Makabenta et al., 2021).
surface charge, and high surface-area-to-volume ratio compared to Oxacillin-NLC and the free drug produced small deletions/insertions or
conventional bulk materials (Cooley et al., 2018; Abdelaziz et al., 2018). inactivating point mutations in DNA obtained from methicillin-resistant
At the nanometric scale, a drug substance can exhibit physical, chemical Staphylococcus aureus (MRSA). In contrast, proteins with 75 kDa mo
and biological properties attributable to this dimension, turning them lecular weight present significant alteration after treatment with
into the most promising strategy for antibiotic delivery system (Cooley oxacillin-NLC. Particularly, enolase and ornithine carbamoyltransferase
et al., 2018; Liu et al., 2020; Gao et al., 2021). proteins decreased reducing the pathogenesis of MRSA. Furthermore,
Antibiotic-loaded LBNs have advanced considerably in the last this preparation might interact with ribosome subunits with similar
decade providing antibiotic protection against chemical or enzymatic mechanism of metallic nanoparticles with consequent growth inhibition
degradation maximizing drug interactions with the target bacteria and cell death (Alalaiwe et al., 2018).
(Makabenta et al., 2021; Gupta et al., 2019; Baptista et al., 2018). Thus, Since these mechanisms seem to be nonspecific, LBNs may prevent
these properties can increase an antibiotics antimicrobial activity. rise of bacterial resistant strains.
Furthermore, antibiotic-loaded LBNs inhibit biofilm formation, enhance
penetration through biofilms and increase intracellular bacterial killing 3. Antibiotic-loaded lipid-based nanocarrier (LBN)
(Malaekeh-Nikouei et al., 2020; Mi et al., 2018; Wilson et al., 2022.
Therefore, this review describes recent advances in developing lipo Antibiotic-loaded LBNs have been studied for their ability to suc
some, NE, SLN and NLC antibiotic-loaded against susceptible and cessfully control bacterial infection. These studies are highlighted in
resistant bacterial strains, and biofilm. Tables 1, 2, and 3, for susceptible strain, resistant strain, and biofilm,
respectively.
2. Mechanism of lipid-based nanocarriers against bacteria
3.1. Susceptible strain
Bacterial cell wall and membrane represent a fundamental defensive
barrier against environmental factors and antimicrobial stresses (Dörr Table 1 presents antibiotic-loaded LBNs for susceptible Gram-
et al., 2019; Dmitriev et al., 2005). Gram-negative bacterial surfaces are positive and Gram-negative bacteria strains. From 16 studies, 7 used
composed of lipopolysaccharides (LPS) and phospholipids, which confer SLN as LBN; 3, NE; 3, NLC; and 3, liposome.
a high density of anionic groups (Sohlenkamp and Geiger, 2016). This LBNs employ lipids with GRAS status, generally recognized as safe by
polar nature hampers lipophilic antibiotic penetration through the the Food Drug and Administration (FDA), being nontoxic and biocom
membrane, compromising its effectiveness (Zhao et al., 2020). Gram- patible. The selected lipids should solubilize the appropriate amount of
positive present thickened and permeable cell wall with teichoic acids poor water-soluble drug substances to increase drug encapsulation ef
on its surface. Peptidoglycan is their primary structural component and ficiency, prevent enzymatic degradation, and improve stability (Har
it is the target for important antibiotics (Lambert, 2002; Pasquina- shita et al., 2020; Scioli Montoto et al., 2020). The solubilizing capacity
Lemonche et al., 2020). Despite this difference, the antimicrobial ac of the lipid depends on their chain length, acyl chain polarity and
tivity of LBNs did not reveal significant variation (Wang et al., 2020). flexibility, chain saturation and unsaturation, melting temperature, and
2
Fig. 1. Schematic representation of different mechanism of LBNs against bacteria. LBNs combine various therapeutic attributes to fight against bacterial resistance.
drug (Katev et al., 2021b; Vinarov et al., 2020; Göke and Bunjes, 2017). Hoogevest and Wendel, 2014). Therefore, surfactant chemical vari
For instance, although olive oil contains 55–80% oleic acid in its ability should be assessed aiming to determine the extent to which this
composition, it solubilizes 20 times less rifampicin than oleic acid (200 variation can impact the quality of the product.
mg/g) (Henostroza et al., 2020). Hence, the rational selection of lipids is The predominant approaches used to prepare antibiotic-loaded LBNs
a critical step in LBN development. were high energy methods (75%) (e.g., high pressure homogenization
A rational selection of lipids was performed for developing (HPH), and ultrasonication), while 25% of studies employed low energy
levofloxacin-loaded SLN (Baig et al., 2016), rifampicin-loaded NE methods (e.g., solvent injection, emulsification solvent, double emulsi
(Henostroza et al., 2020), and ceftriaxone-loaded NLC (Ebrahimi et al., fication). It is worth noting that high energy techniques may not use an
2020). The solubility of levofloxacin and rifampicin was conducted by organic solvent. Thus, they are following the objectives of green and
saturation solubility method. Stearic acid solubilized 110 mg/g of lev sustainable chemistry (Ganesan and Narayanasamy, 2017; Kanwar
ofloxacin hemihydrate. This value was an approximately 75-fold in et al., 2019).
crease compared to water solubility (1.44 mg/mL), whereas rifampicin Table 1 showed a particle size range of 30 to 406 nm and poly
achieved 155-fold solubilization in oleic acid compared to water (1.5 dispersity index (PdI) values < 0.3. NE varied from 30 to 133 nm; SLN,
mg/mL). Meanwhile, ceftriaxone solubility was performed by from 80 to 307 nm; NLC, from 86 to 255 nm; liposome, from 190 to 406
hydrophilic-lipophilic balance (HLB) determination combined with a nm; 63% of LBNs varied from 50 to 200 nm. Particle size is a critical
mathematical model (Hoftyzer-Van Krevelen’s and Hoy’s models) (van attribute of LBN, which determines its behavior through its journey in
Krevelen and te Nijenhuis, 2009; Hoy, 1989). These models use the drug the biological system (Danaei et al., 2018; Barar, 2017; Perry et al.,
solubility calculation based on drug and lipid chemical structure. The 2017). Particle size lower than 100 nm crosses the biological membrane
results revealed glyceryl monostearate, oleic acid and soy lecithin mainly by the endocytosis pathway (Zhang et al., 2015; Danaei et al.,
enhanced 5-fold ceftriaxone solubility. Therefore, lipid characteristics 2018), Particles smaller than 10 nm are easily cleared by kidney
play a crucial role in ensuring adequate formulation (Katev et al., 2021a; glomerular filtration (Adhipandito et al., 2021; Pearson et al., 2014;
Lee et al., 2018), increasing bioavailability, thus reducing dosing fre Ohta et al., 2020). In contrast, those higher than 100 nm shows a
quency, avoiding side effects, and enhancing patient compliance (Var reduced half-life in the bloodstream due to the active participation of the
gason et al., 2021; Mishra et al., 2018). mononuclear phagocytic system (macrophages and dendritic cells) by
Similarly, the choice of surfactant or surfactant combinations at systemic administration (MacParland et al., 2017). Although the
adequate concentrations grant LBN stability (Chauhan et al., 2020; sequestration of nanoparticles by macrophages seems to be a disad
Karn-orachai et al., 2014). Tween® 80 and lecithin (from soybean or egg vantage for other infections, in the case of pulmonary infection by
yolk) were preferred in 75% of studies (Table 1). Although these ex Mycobacterium tuberculosis, it could be advantageous due to the fact that
cipients are well-established in pharmaceutical products, they can show mycobacterium predominantly replicates within macrophages (Upad
variability in their composition due to natural sources of obtention. hyay et al., 2018), becoming an excellent target for tuberculosis therapy
Characterization of 16 batches of Tween® 80 found oleic acid from (Shivangi and Meena, 2018; Pandit et al., 2020).
67.8% to 96.6%, linoleic acid and palmitic acid presented substantial Additionally, zeta potential (ZP) is another important property that
fluctuation from 0.0% to 14.6% (Ilko et al., 2015), whereas lecithin may directly affects the stability of LBNs. Thus, zeta potential can be applied
present less or more than 80% of phosphatidylcholine with a variable to optimize formulations, predict interactions, address particle surface
percentage of fatty acid depending on the start source material. It can act modifications, and to estimate long-term stability. In general, particles
as a surfactant and drug solubilizer (van Hoogevest, 2017; van with ZP above 30 mV, in module, are considered stable against
3
Table 1
Antibiotic-loaded lipid-based nanocarrier (LBN) against susceptible strain.
LBN Drug Composition Z-ave PdI ZP (mV) Microorganism In vitro References
substance (nm) performance
(compared to free
drug)
NE Rifampicin oleic acid (1% w/w), Tween®80 133.1 ± 0.20 − 32.7 to Mycobacterium tuberculosis ND Henostroza
(0.9% w/w), 1.1 ± 0.01 + 51.3 ± H37Rv (ATCC 25618) et al., 2020
chitosan chloride (0.5% w/w) 1.5
NE Clarithromycin CLA: CHEMS (mol ratio 1:2), Medium 200.3 ± 0.12 – Streptococcus pneumoniae ND Gong et al.,
chain triglyceride (15% w/v), 58.3 ± 0.01 (ATCC49619) 2016.
PL®100 (2.0% (w/v), glycerol (2.5% Staphylococcus aureus (
w/ v) ATCC29213)
Haemophilus influenzae (
ATCC49247)
£
Pseudomonas aeruginosa
NE Clarithromycin olive oil (10 μL), Tween®80 (1500 30.0 ± – – Bacillus subtilis (MTCC 121) 1.8-fold increase Vatsraj et al.,
μL), 0.1 2014
polyvinyl alcohol (0.1% w/v) Bacillus megaterium (MTCC 428) 1.5-fold increase
SLN Tobramycin stearic acid (0.70 mmol), 80.1 ± 0.15 − 25.7 ± Chetoni et al.,
EpikuronTM200 (0.14 mmol), 11.1 ± 0.03 2.1 Pseudomonas aeruginosa
£
Greater 2016
sodimun taurocholate (0.72 mmol) intracellular
bactericidal
efficacy
SLN Levofloxacin stearic acid (6.31% w/w), Tween®80 237.8 ± 0.25 – Baig et al.,
(3.0% w/w) 0.1 ± 0.01 Escherichia coli ND 2016
sodium deoxycholate 1.0% w/w) Staphylococcus aureus
SLN Clarithromycin stearic acid alone or in combination 307.0 ± 0.21 − 29.1 ± Staphylococcus aureus Sharma et al.,
with tristearin (200.0 mg), soya 23.0 ± 0.01 5.0 (MTCC86) 12-fold increase 2016
lecithin (40.0 mg), Tween 80 (0.5 w/
v)
SLN Ceftriaxone Cholesterol (1.0 g), lecithin (1% w/ 212.0 ± – − 36.9 ± α

Bacillus polymyxa 068, αBacillus Kumar et al.,
v), Tween®80 (1 mL), PVA solution 0.1 0.1 cereus 240, αPseudomonas ND 2016
(5% w/v) aeruginosa 105, αEnterobacter
aerogenes 106
SLN Meropenem monostearate (500.0 mg), glycerol 112.6 ± – − 20.4 ± Escherichia coli (ATCC Prolonged Mhango et al.,
(1600.0 mg) Tween®80 (400.0 mg) 0.7 0.9 25922) antibacterial 2017
activity
SLN Rifabutin glyceryl dibehenate (10%), 7.3% ≤190.1 <0.2 − 18.0 ± Mycobacterium avium ND Gaspar et al.,
glyceryl tristearate, 2 to 7% ± 7.0 ± 0.01 0.8 (ATCC 15769) 2017
polysorbate 80, curosurf, mannitol,
d-(+)-trehalose dihydrate.
SLN Ciprofloxacin Softisan® 100 (100 mg), DDAB 315 ± 0.32 +50.5 ± Escherichia coli (ATCC 25922), 1.5-fold increase Pignatello
(0.15% w/w), Tween® 80 (0.25% w/ 1.51 ± 0.01 1.71 Pseudomonas aeruginosa (ATCC et al., 2018
w), 27853),
Staphylococcu aureus (ATCC
29213),
Enterococcus faecalis (ATCC
29212)
NLC Mupirocin ¥
cetyl palmitate, capric/caprylic acid 100.1 ± 0.01 − 19.5 ± Streptococcus pyogenes (ATCC 4-fold increase Alcantara
(9:1), Tween® 80 0.8 ± 0.01 1.3 19615) et al., 2019
Lipoid® S 80
Staphylococcus aureus (ATCC 2-fold increase
29213)
NLC Ceftriaxone glyceryl monostearate (0.3 g), oleic 86.0 ± – – Escherichia coli (ATCC 35218) 1-fold increase Ebrahimi
acid (0.09 g), soy lecithin (0.055 g), 0.1 et al., 2020
Tween ®80 (0.275 g/L)
NLC Polymyxin B Cetyl palmitate (6% w/w)Capric 255.7 ± 0.19 +2.4 ± Pseudomonas aeruginosa 2-fold increase Rocha et al.,
caprylic triglycerides (4% w/w) 4.1 ± 0.04 0.5 2021
,Lipoid S 100 Bordetella bronchiseptica 3-fold increase
(0.6% w/w)
LP Azithromycin DPPC, CHOL (6:1) 406.07 ± 0. 3 ± – £
Pseudomonas aeruginosa 8-fold increase Solleti et al.,
45.0 0.03 (PAO1) 2015
LP Rifabutin DMPC:DOPE:CHEMS (4:4:2),DMPC: 110.01 ± ≤ 0.1 –22.0 ± Staphylococcus aureus (ATCC ND Ferreira et al.,
DMPG (8:2) 0.01 ± 0.01 3.0 25923) 2021b
,DMPC:SA 150.01 ± − 21.0 ±
(9:1) 0.01 3.0
120.01 ± +13.0 ±
0.01 2.0
4
Abbreviations: NE: nanoemulsion, SLN: solid lipid nanoparticle, NLC: nanostructured lipid carrier, LP: liposome, Z-ave: particle size, PdI: Polydispersity index, ZP:
zeta potential, DMPC: dimyristoyl phosphatidyl choline, DMPG: dimyristoyl phosphatidyl glycerol, DPPC: dipalmitoyl phosphatidyl choline, DOPE: dioleoyl phos
phatidyl ethanolamine, SA: stearylamine, CHEMS: cholesteryl hemisuccinate, CHOL: cholesterol, DDAB: dimethyldioctadecylammonium bromide, PL-100: egg yolk
Lecithin, CLA: clarytromycin,
ND: No difference.
¥: The authors intentionally not mentioned percent quantities of each raw material since have applied of NLC to the Intellectual Property Office of the Philippines
(IPOPHIL).
£: clinical isolate strain.
α: Collection from National Collection Of Dairy Cultures, India.
aggregation due to the presence of electrostatic repulsive forces between antimicrobial activity, providing enhanced stability and modified drug
the charged nanoparticles. Conversely, steric stabilization embraces the release. Hence, these LBNs have potential to improve safety and patient
stabilization by nonionic surfactants and polymers (Napper, 1977; van compliance.
Oss, 2008). These macromolecules adsorb on the nanoparticle’s surfaces Conversely, clarithromycin-loaded NE (Vatsraj et al., 2014) revealed
impeding aggregation counteracts attractive Van der Waals forces enhanced activity against Gram-positive microorganisms, Bacillus sub
(Selvamani, 2019). tilis and Bacillus megaterium. Moreover, clarithromycin-loaded SLN
The ZP of NE varied from –32.7 to +51.3 mV, SLN, from − 18 to +50 presented the highest increase (12-fold) in antimicrobial activity against
mV, NLC, − 19 to +2.5 mV, and liposome, from –22 to +13 mV (Table 1). Staphylococcus aureus among all studies (Sharma et al., 2016b).
The LBNs that presented higher than 30 mV in modulus were rifampicin- Levofloxacin-loaded SLN showed no enhancement activity compared
NE chitosan coated and uncoated +51.3 and − 32.7 mV, respectively, to the free drug against Staphylococcus aureus and Escherichia coli (Baig
and ciprofloxacin-SLN prepared using DDBA, a cationic lipid (+50 mV). et al., 2016). In contrast, cationic ciprofloxacin-loaded SLN revealed
This formulation presented nine months stability, while rifampicin- increased antimicrobial activity against the same microorganisms
loaded NE provided seven months. The remaining preparations (75%) (Pignatello et al., 2018). The improvement in growth inhibition was
are assumed to be stabilized using the steric approach. The tobramycin- ascribed to the positive zeta potential of nanoparticles. However, it may
loaded SLN (− 25.7 mV) presented 24 months stability possibly due to not exclude the possibility of DDAB (cationic agent) enhanced bacterial
steric effect of the surfactants (Table 1). cell membrane disruption due to its surfactant property. These quino
ZP also plays an important role in the LBN mechanism of action due lones are the first-line empirical therapy to treat urinary infection (Chao
to Gram-negative and Gram-positive bacteria have negative net charge and Farrah, 2019; Daneman et al., 2020) in which approximately
surfaces (Halder et al., 2015). The positive zeta potential of antibiotic- 65–75% of cases are caused by Escherichia coli (Medina and Castillo-
loaded LBNs may improve their efficacy, increasing their interaction Pino, 2019).
with the bacterial cell’s negative charges surfaces facilitating antibiotic Additionally, ceftriaxone-loaded SLN inhibited Gram-positive and
penetration into the microorganism (Fig. 2). Cationic amoxicillin-loaded Gram-negative bacteria comparable to free drug (Kumar et al., 2016).
NE presented higher growth inhibitions of Helicobacter pylori compared This similarity may be due to the presence of lecithin and cholesterol in
to noncationic NE (Lin et al., 2012). Membrane cell disruption of Pseu the preparation, which facilitated bacteria-nanoparticle interaction
domonas aeruginosa treated with cationic-NE (+20.9 mV) compared to even at low percentage of drug release (6% after 24 h). Consequently,
non-cationic-NE (− 10.8 mV) revealed more points of disruption as a dose reduction might be possible to avoid side effects of ceftriaxone
consequence of electrostatic interaction between the opposite charges of (rashes on the skin, elevation in liver enzymes, etc.). Differently,
LBNs and bacterial membrane (Singh et al., 2015). Despite this apparent ceftriaxone-loaded NLC showed improved antimicrobial activity against
cationic nanoparticle’s advantages against bacteria, the majority of the Escherichia coli compared to the free drug. This preparation presented
LBNs showed negative zeta potential (18%) (Table 1). higher growth inhibition than free ceftriaxone, even containing half of
The in vitro antimicrobial activity of antibiotic-loaded LBNs were the drug concentration (Ebrahimi et al., 2020). Furthermore,
evaluated aiming to predict the clinical efficacy of different prepara meropenem-loaded SLNs presented prolonged antibacterial activity
tions. The minimum inhibitory concentration (MIC), minimum bacte attributable to their inherent modified drug release property (40% after
ricidal concentration (MBC), agar diffusion assay, cell viability, and 10 h and 60% gradual release for 72 h). Besides, SLNs may protect
colony-forming unit (CFU) quantification were the main methods used meropenem from carbapenemases inactivation (Mhango et al., 2017).
with modifications to optimize the results. Gram-negative, Gram-posi Increased antimicrobial activity was also observed for mupirocin-
tive, and Mycobacterium were used in 42%, 46%, 13% of the studies, loaded NLC against Streptococcus pyogenes and Staphylococcus aur
respectively. eus compared to free drug. Minimum bacterial concentration (MBC)
A total of 7 studies (47%) revealed increased in vitro antimicrobial against Staphylococcus aureus was half of MIC value, showing the bac
activity against susceptible strains: Pseudomonas aeruginosa, Staphylo terial inhibition at low antibiotic concentration. Although the MBC of
coccus aureus, Escherichia coli, Bacillus subtilis, Bacillus megaterium, the free drug was almost double the MIC value, this concentration was
Enterococcus faecalis, Streptococcus pyogenes and Bordetella bronchiseptica. not able to kill 99.9% of the Staphylococcus aureus. This enhancement
These enhancements varied from 2 to 12-fold. The remaining 53% of might be due to the easy diffusion of mupirocin-NLC through the bac
studies revealed similar activity compared to the free drug substance. terial phospholipid membrane facilitated by the presence of phospha
Clarithromycin-loaded NE and azithromycin-loaded liposomes tidylcholine on the composition and smaller particle size (Alcantara
revealed different efficacy against Pseudomonas aeruginosa. The et al., 2019).
clarithromycin-loaded NE showed MIC similar to the free drug (Gong More often LBNs are used to deliver poorly water-soluble antibiotics.
et al., 2016), while the azithromycin-loaded liposome showed improved However, it is possible to associate hydrophilic drugs on the nano
activity over the free drug (Solleti et al., 2015). This enhancement may particle surface promoting an increase of their antimicrobial activity.
be related to the membrane fusion property of liposomes, which allows Polymyxin B-NLC surface modified showed 2- and 3-fold enhancement
direct incorporation of liposome phospholipids into the bacterial cell of antimicrobial activity against Bordetella bronchiseptica and Pseudo
membrane (Solleti et al., 2015). Despite in vitro clarithromycin-loaded monas aeruginosa, respectively. Also, no in vitro cytotoxic effect was
NE (Gong et al., 2016), rifampicin-loaded NE (Henostroza et al., 2020), observed in mammalian fibroblast cells when polymyxin B was acting as
rifabutin-loaded SLN (Gaspar et al., 2017) and rifabutin-loaded lipo cationic surface modifier (Rocha et al., 2021). Polymyxin B is the last
some (Ferreira et al., 2021b) presented similar efficacy to the free drug, resort therapy to treat severe Gram-negative infections by Acinetobacter,
these preparations overcame poor drug water solubility preserving their Pseudomonas, and various Enterobacteriaceae (Velkov et al., 2013). Their
5
Table 2
Antibiotic-loaded lipid-based nanocarrier (LBN) against resistant strain.
LBN Drug Composition Z-ave PdI ZP (mV) Microorganism In vitro performance References
substance (nm) (compared to free drug)
NE Levofloxacin D-Limonene, Tween® 80, propylene 119.1 ± 0.31 ± − 16.0 β

Staphylococcus 2-fold increase Mehanna
glycol (5:4:1) 0.3 0.05 ± 0.7 Aureus et al., 2020
NE Erythromycin 20% w/w Labrafil® M2125CS, 157.0 ± 0.12 ± – Helicobacter pylori 4-fold increase TRAN et al.,
Gelucire®50/13–PL90G 4.0 0.02 CCUG38771 2017
NE Rifampicin Castor oil, Solutol® HS15, 25.7 ± 0.18 ± − 8.2 ± α

Mycobacterium Halicki et al.,
hydrogenated soybean, 0.1 0.01 4.5 tuberculosis katG ND 2018
Phospholipon ®80 (S315T)
Mycobacterium
tuberculosis rpoB
(S531L)
SLN Vancomycin 0.5% Compritol® 888 ATO, 3 % 136.7 ± 0.26 ± − 31.3 β
Staphylococcus 2-fold increase Kalhapure
Lutrol® F68 1.1 0.01 ± 1.9 aureus et al., 2014
SLN Vancomycin 0.2 % SA-3 M, 1.2 % poloxamer 188 132.9 ± 0.16 ± − 26.0 β
Staphylococcus ~4 to 8-fold increase Kalhapure
9.1 0.01 ± 4.4 aureus et al., 2017
NLC Oxacillin 2% squalene, 2% hexadecyl 177.0 ± 0.29 ± + 18.7 β
Staphylococcus ~ 4-fold increase Alalaiwe et al.,
palmitate, cationic lipid, 0.4% SME 9.5 0.03 ± 0.8 aureus (ATCC 33591) 2018
(soyaethyl morpholinium
ethosulfate)
1.5% soy phosphatidylcholine
(Phospholipon 80H®), 1%
deoxycholic acid,
1.5% Pluronic F68
NLC Ciprofloxacin squalene (400 mg), hexadecyl 171.4 ± 0.42 ± –38.8 ± β
Staphylococcus ~ 2-fold increase Liao et al.,
palmitate (100 mg), soybean 5.8 0.04 0.6 aureus 2021
phosphatidylcholine (Phospholipon
80H, 150 mg)
LP Ciprofloxacin HSPC, DSPG/DMPG, CHOL 107.2 ± 0.14 ± – £
Pseudomonas Wang et al.,
and Colistin (phospholipids: cholesterol = 3:1 w/ 21.0 0.07 aeruginosa ~4 to 8-fold increase 2018
w) H131300444
£
Pseudomonas
aeruginosa
H133880624
LP Azithromycin DPPC, Lipoid S75, DODAB ≤217.3 0.09 to − 43.1 £β

Staphylococcus ~4 to 7-fold increase Rukavina
± 5.8 0.20 to + aureus et al., 2018
62.0
LP Azithromycin DSPC, DOPE, CHOL ≤ 496.0 0.20 to – α£
Escherichia coli ~13-fold increase Aljihani et al.,
(2:4:1) ± 12.3 0.40 SA057 2020
α£
Escherichia coli
SA10
LP Mupirocin HSPC, CHOL, mPEG DSPE ≤85.6 ± < 0.05 ± – β

Staphylococcus ND Goldmann
(3:1:1) 0.01 0.01 aureus USA300 et al., 2019
LP Vancomycin SPC, CHOL, cyanur-PE (mole ratio ≤111 ± 0.08–0.17 +0.4 ± β

Staphylococcus ND Hajiahmadi,
5.5:3.5:1) 2.71 0.01 aureus et al., 2019
LP Daptomycin and HSPC, CHOL,mPEG2000-DSPE 98.20 ± 0.25 ± – β

Staphylococcus Significantly reduced Li et al., 2015
Clarithromycin (15:10:1) 2.21 0.06 aureus 252 MRSA bacterial load
with low antibiotic
concentration
LP Vancomycin CHOL, SPC, PRL 86.28 to 0.15 to − 11.8 β
Staphylococcus Increase activity at pH 7 Makhathini
(1:3:1 w/w) 282.0 0.20 ± 2.9 aureus HFH-30364 and pH 6. et al., 2019
LP Vancomycin CHOL, EPC, DOPE, DPPC, CHEMS, ≤200 ± 0.09 to − 16.9 β

Staphylococcus Scriboni et al.,
SA 3.7 0.20 to + aureus ~2-fold increase 2019
62.5 (ATCC 43300)
Abbreviations: NE: nanoemulsion, SLN: solid lipid nanoparticle, NLC: nanostructured lipid carrier, LP: liposome, Z-ave: particle size, PdI: Polydispersity index, ZP:
zeta potential, SA-3 M: (2-(2,4,6-trimethoxyphenyl)-1,3-dioxane-5,5-diyl)bis(methylene) distearate, DMPC: dimyristoyl phosphatidyl choline, DMPG: dimyristoyl
phosphatidyl glycerol, DPPC: dipalmitoyl phosphatidyl choline, DOPE: dioleoyl phosphatidyl ethanolamine, SA: stearylamine, CHEMS: cholesteryl hemisuccinate,
CHOL: cholesterol, DDAB: Dimethyldioctadecylammonium, DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine, mPEG DSPE: 1,2-distearoyl-sn-glycero-3-phosphoe
thanolamine-N-[methoxy(polyethylene glycol)-2000, SPC: Soybean phosphatidylcholine, mPEG2000-DSPE: methylpolyethyleneglycol-1,2-distearyl-phosphatidyl
ethanolamine conjugate, DMAP: p-dimethylamino pyridine, PRL: pH-responsive lipid derivative, HSPC: Hydrogenated soybean phosphatidylcholine, DMPG-Na: 1,2-
Dimyristoyl-sn-glycero-3-phosphoglycerol sodium salt, DSPG-Na: Distearoyl-sn-glycero-3- phosphoglycerol sodium salt, SA-3 M: 2,4,6-trimethoxybenzilidene-pentaer
ythritol coupled with Stearic acid, CTM-Ag: Clotrimazole-silver complex, PEG-660 stearate/Solutol HS15: 12-hydroxystearic acid-polyethylene glycol copolymer.
ND: No difference.
6

β: Methicillin-resistant Staphylococcus aureus.
compared to the free drug against Pseudomonas aeruginosa. In addition,

Table 3
this preparation significantly increased tobramycin concentrations in
Antibiotic-loaded LBNs against biofilm: susceptible and resistant strains.
human polymorphonuclear granulocyte cells, reducing from 53% to
LBN Drug Microorganism In vitro References 70% of intracellular Pseudomonas aeruginosa after 90 min of treatment.
substance performance
This antimicrobial activity could be related to SLN capacity to penetrate
(compared to free
drug) phagocytic cells without altering its phagocytic function and cross
bacterial barriers (Chetoni et al., 2016).
SUSCEPTIBLE STRAIN
LP Azithromycin Pseudomonas MBIC Solleti et al.,
Although the studies (Table 1) confirmed improvement efficacy of
aeruginosa 8-fold reduction 2015 antibiotic-loaded LBNs in in vitro assays, only 2 out of the 15 evaluated
(PAO1) the efficacy using in vivo experiments to control bacterial infection. One
Biofilm study induced sepsis by Staphylococcus aureus and Streptococcus
eradication
pneumonia in murine model. The animals were treated by intragastrical
concentration:
Free drug: 1024 and and intravenous administration of different doses of clarithromycin-
512 mg/L loaded NE. The intravenous treatment revealed effective dose (ED50)
LP: 256–8 mg/L was equal to 6.7-fold and 3.5-fold comparing to the free drug, respec
tively, for Staphylococcus aureus and Streptococcus pneumonia. Besides,
LP Rifabutin Staphylococcus MBIC
aureus ATCC ND Ferreira
clarithromycin-loaded NE was 6-fold more potent compared to orally
25923 et al., 2021b administered formulations (Gong et al., 2016). After intravenous
Biofilm Growth administration, LBNs interact with a host’s immune system cells been
Lowest rifabutin easily taken up by mononuclear phagocyte. This mechanism increases
concentration
drug bioavailability by intravenous route compared to the oral admin
inhibit more than
50% of biofilm. istration. Thus, clarithromycin-loaded NE by intravenous administration
presents advantages to treat sepsis whose challenges include quick
RESISTANT STRAIN diagnosis and accurate treatment (Papafilippou et al., 2021; Yuk et al.,
NE Levofloxacin β
Staphylococcus Biofilm formation Mehanna 2018). The second study causes infection in mice injecting Mycobacte
aureus inhibition et al., 2020
Free drug: 38%
rium tuberculosis H37Rv. After two weeks, the animals were treated
reduction with rifabutin-SLN powder by inhalation. The results revealed a
NE: 72,47 % decrease in the Mycobacterium growth index values in the liver, spleen,
reduction and lung compared to the untreated group. However, an adequate dose
and pulmonary administration need to be adjusted to increase the
NLC Oxacillin β
Staphylococcus Biofilm thickness Alalaiwe
aureus reduction from 31.2 et al., 2018 concentration and efficacy of rifabutin-SLN powder in the lung (Gaspar
to 13.0 μm et al., 2017).
A total of 13% of studies evaluated cytotoxicity and pharmacokinetic
LP Azithromycin β
Staphylococcus MBIC Rukavina profiles using murine and rabbit animal models. An in vivo pharmaco
aureus ~8 to 32-fold et al., 2018
reduction
kinetic study of clarithromycin-loaded SLN in Wistar rats showed 5-fold
enhancement in relative oral bioavailability due to skipping hepatic
LP Azithromycin £
Escherichia coli MBIC Aljihani metabolism as a consequence of lymphatic absorption, and phagocytic
SA057 ~14-fold reduction et al., 2020 uptake mechanisms across the gastrointestinal tract. Hepatoxicity is the
(MDR)
primary concern of clarithromycin administered by the oral route for a
Biofilm reduction:
£
Escherichia coli High prolonged time. In vivo hepatoxicity study revealed no presence of ne
SA10 crosis or degeneration of liver cells after 14 days of repeated oral
(MDR) administration of clarithromycin-loaded SLN. Nevertheless, the free
LP Vancomycin β
Staphylococcus Better ability to Scriboni drug caused injury and steatosis in hepatocytes. The authors attributed
aureus ATCC penetrate mature et al., 2019
the nontoxic effect as a result of the sustained drug release and the
43300 biofilm
biocompatibility of the excipients. (Sharma et al., 2016b).
Abbreviations: NE: nanoemulsion, SLN: solid lipid nanoparticle, NLC: nano Histopathological study in rats revealed that mupirocin-loaded NLCs
structured lipid carrier, LP: liposome, MBIC: Minimum biofilm inhibitory con
were safe up to 250 mg/kg, showing no significant hepatocyte changes.
centration, MDR: Multidrug resistant.
An in vivo pharmacokinetic study in rabbits using mupirocin-loaded
ND: No difference,
NLC versus free drug showed higher plasma concentration (859 µg/mL
β: Methicillin-resistant Staphylococcus aureus. after 30 min), AUC (μg × h/mL) significantly increased by approxi
mately 40 times (T1/2 = 5.47 h) compared to the free drug (T1/2: 0.10 h).
The elimination half-life (t1/2) was also increased 55 times more (t1/2 =
clinical uses have been limited due to the high risk of nephrotoxicity and
0.10 ± 0.24 h). NLC prevented mupirocin rapid elimination, reducing
neurotoxicity caused by the presence of a positive charge in their cyclic
bound to serum protein, reducing enzymatic degradation, and avoiding
heptapeptide core (Avedissian et al., 2019). The reduction of the posi
blood clotting (Alcantara et al., 2019; Doktorovova et al., 2014).
tive charge of polymyxins proved to diminish the toxic effect preserving
Moreover, in vivo evaluation of tobramycin-loaded SLN in rabbit
its antimicrobial efficacy (Ferguson et al., 2014; Vaara et al., 2017).
model showed that its preparation reached the retina when adminis
Hence, polymyxin B-NLC is a promising preparation for enhanced
tered systemically (17.2 ng/g) and topically instilled (4.74 ng/g). In
pharmacological activity and safety.
contrast, commercial tobramycin product (Tobral®) could not reach the
Furthermore, hydrophilic antimicrobials complexation with lipo
rabbit’s posterior segment of the eye (retina and vitreous humor). The
philic molecules or polymers is an alternative strategy to encapsulate in
lipidic nature facilitates its intracellular transport by endocytosis uptake
LBNs to improve their efficacy (Severino et al., 2015). Tobramycin-
as well as its physicochemical parameters (Chetoni et al., 2016).
loaded SLN ion-pair complex increased 2-fold antimicrobial activity
The studies showed the LBNs to be an attractive alternative to treat
7
Fig. 2. Schematic representation of electrostatic interaction between cationic LBNs with teichoic acid and lipopolysaccharide of Gram-positive and Gram-negative
bacterial surface, respectively. A) Cell wall structure of Gram-positive bacteria. B) Cell wall structure of Gram-negative bacteria.
bacterial infection, overcoming conventional preparation drawbacks, particle size, kinetics release of hydrophilic encapsulated drug sub
including low water solubility, high toxicity, and rapid elimination from stances such as vancomycin and modulates membrane fluidity and
the systemic circulation. LBNs provide advantages of modified drug permeability of vesicles (Briuglia et al., 2015; Kaddah et al., 2018). An
release, improved bioavailability, drug protection against enzymatic adequate proportion of phospholipids and cholesterol could be consid
degradation, and greater drug loading capacity. In addition, LBNs allow ered to achieve the required drug release. Therefore, carefully selecting
versatility in their composition, facilitating target delivery, better components to prepare LBNs would allow obtaining nanoparticles
cellular uptake, and allowing multiple interaction mechanisms with responsive to specific stimuli and mimicking the biological membrane.
microorganisms. The preserving or increased antimicrobial activity Table 2 shows particle size range from 25 to 217 nm and PdI values <
shown by in vitro assays was influenced by the type of LBNs, physical 0.4. NE varied from 25 to 157 nm; SLN, from 132 to 136 nm; NLC, from
properties, type of microorganism, and method of evaluation. These 171 to 177 nm; liposome, from 86 to 496 nm.
methods present a lack of standardization of in vitro experiments for The ZP of NE varied from − 8.2 to − 16.0 mV; SLN, from − 31 to − 26
antibiotic loaded LBNs. In addition, in vivo experiments showed the mV; NLC, from − 38.8 to +18.7 mV; liposome from +0.4 to +62 mV
efficacy of LBNs to treat bacterial infections potentially improving (Table 2). Cationic LNBs were obtained using cationic lipids such as
safety. soyethyl morpholinium ethosulfate (SME) in the preparation of
oxacillin-NLC; stearylamine and DOPE, in vancomycin-liposome; and
DODAB in azithromycin-liposome. The use of these cationic compounds
3.2. Resistant strain
stands a challenge due to their cytotoxicity. In vitro cytotoxicity eval
uation of cationic azithromycin-liposome in keratinocyte cell lines
Table 2 presents antibiotic-loaded LBNs against bacteria resistant
revealed low cell viability compared to conventional liposome, none
strains. From 15 studies, 2 used NLC as LBN; 2, SLN; 3, NE; and 8,
theless, remained above 70%, which is considered noncytotoxic.
liposome.
Conversely, cell viability of fibroblasts was approximately 40% (Ruka
Most LBNs were prepared using lipids and surfactants widely
vina et al., 2018). Oxacillin-NLC showed reduction on cutaneous irri
accepted as pharmaceutical excipients (87%). Particularly, two studies
tation compared to blank-NLC (free of oxacillin) in healthy mouse skin.
(13%) synthesized nontoxic pH-responsive lipid to prepare SLN (Kal
Blank-NLC presented slight erythema and scaling caused by cationic
hapure et al., 2017) and liposome (Makhathini et al., 2019), aiming for
lipid (Alalaiwe et al., 2018). Therefore, it is fundamental to improve the
drug release at specific pH. In addition, NLCs used squalene as liquid
safety of cationic nanoparticles while maintaining or increasing the
lipid, which is approved by the FDA as an adjuvant in vaccine compo
antimicrobial activity.
sition to boost the body’s immune response (Common Ingredients in U.
The in vitro antimicrobial activity of antibiotic-loaded LBNs against
S. Licensed Vaccines | FDA). Squalene is present in small quantities in
bacterial resistant strains showed 73% of the studies used MRSA; 6%,
the human body with a high concentration in the skin (Zhang et al.,
Helicobacter pylori; 6%, Mycobacterium tuberculosis; 6%, Pseudomonas
2022). Concerning liposomes, cholesterol was the common component
aeruginosa; and 6%, Escherichia coli. A total of 12 (80%) of the studies
in all antibiotic-loaded liposomes (Table 2). Cholesterol and phospho
revealed increased antimicrobial activity against MRSA, Pseudomonas
lipids are the main components of liposome. Cholesterol influences
8
aeruginosa and Escherichia coli. This improvement varied from 2 to 13- increased antimicrobial activity at pH 6.5 compared to pH 7.4 against
fold. The other 20% of studies showed no enhancement compared to Staphylococcus aureus strains susceptible and resistant. This strategy
the free drug. allowed vancomycin to target an acidic environment to control the
MRSA is one of the major current pathogens that threatens global bacterial proliferation due to vancomycin-loaded SLN kinetics release
human health. It can be found in community and hospital settings, pH-dependent (Kalhapure et al., 2017). Similar results were reported by
causing bacteremia, pneumonia, endocarditis, skin infections, and Mhule et al., (2018). They synthetized a pH-responsive solid lipid (N-(2-
others (Lakhundi and Zhang, 2018), and its resistance mechanism is morpholinoethyl) oleamide) to prepare vancomycin-loaded SLN (Mhule
undergoing gene mutation or horizontal gene transfer. This gene mu et al., 2018). Furthermore, vancomycin-loaded SLN displayed antimi
tation expresses penicillin-binding protein 2A becoming intrinsically crobial activity against MRSA after 72 h attributed to the modified drug
resistant to β-lactam antibiotics (Shalaby et al., 2020). Nevertheless, release (Kalhapure et al., 2014).
oxacillin-loaded NLC revealed enhanced in vitro antibacterial activity In addition, vancomycin-loaded liposome pH-responsive revealed
against MRSA. Free oxacillin had no antimicrobial activity against improved and prolonged in vitro antimicrobial activity against MRSA at
MRSA. This improvement was attributed to the encapsulated oxacillin pH 7.4 and 6.0. The liposome using dioleoyl amino propionic acid tert-
and the presence of cationic surfactant (soyaethyl morpholinium etho butyl ester (DOAPE) and dilinoleoyl amino propionic acid tert-butyl
sulfate). Cationic LBNs targeted the bacterial cell membrane via elec ester (DLAPE) showed increased antibacterial activity at pH 6.0 with a
trostatic interaction, impermeabilizing it with subsequent lysis and high killing rate of MRSA compared to the free drug. This enhancement
cellular cytoplasmatic content discharge from the cytosol. This prepa can be related to the lipid protonation in the liposome, facilitating its
ration may interact with cytoplasmatic proteins and less with the DNA. electrostatic binding affinity with bacteria, its fusogenic property, and
Additionally, oxacillin-loaded NLC significantly reduced MRSA burden sustained drug release. Vancomycin solution presented reduced MIC
in intracellular differentiated THP-1 cells after 4 h of treatment due to it values when the pH becomes acid (Makhathini et al., 2019). Another
being easily taken up by macrophages. The free drug did not affect the fusogenic vancomycin-liposome presented increased antimicrobial ac
MRSA intracellular survival (Alalaiwe et al., 2018). tivity against MRSA independent of pH alteration. This enhancement
Levofloxacin-loaded NE revealed improvement in the antimicrobial might be attributed to the increased fluidity of the bacterial membrane
activity against MRSA. The MIC values of free drug, unloaded NE, after fusion with liposomes. Phosphatidylethanolamine (DOPE) and
levofloxacin-loaded NE were 6.25 μg/mL, 25 μg/mL, and 3.12 μg/mL, cholesterol hemisuccinate (CHEMS) as part of liposome composition
respectively (Mehanna et al., 2020). Limonene was used as lipid phase to favored this phenomenon (Scriboni et al., 2019). Conversely, Hajiah
prepare the NE. Although limonene, an essential oil, has shown bacterial madi et al. (2019) observed no increased antimicrobial activity by
growth inhibition against MRSA (Celaya et al., 2014), the encapsulated different vancomycin-loaded liposome against MRSA (Hajiahmadi et al.,
drug substance possessed superior antimicrobial activity. Nevertheless, 2019). These contradictory results could be ascribed to the variation in
this does not negate the possibility of limonene contribution to the the liposome composition. Similar results were found for mupirocin-
bacterial membrane disruption facilitating the entry of levofloxacin into loaded liposome antimicrobial activity against MRSA compared to the
the cytoplasm (Han et al., 2019; Mehanna et al., 2020). In opposition, free drug (Goldmann et al., 2019).
rifampicin-loaded NE showed equal antimicrobial activity compared to Combinatorial therapy is an effective strategy for controlling
free drug against multidrug resistant Mycobacterium tuberculosis strains intractable infections and their symptoms such as inflammation and
(Halicki et al., 2018). pain. Ciprofloxacin-colistin-loaded liposome and a mixture of free drugs
Azithromycin-loaded liposome for topical administration showed revealed synergistic and increased antimicrobial activity against clinical
increased antimicrobial activity against MRSA in in vitro assays (Ruka MDR Pseudomonas aeruginosa with prominent initial inhibition for
vina et al., 2018). This improvement depended on liposome composition Pseudomonas aeruginosa H131300444 than Pseudomonas aeruginosa
(e.g., phospholipids and cationic lipid), positive zeta potential (32-fold H133880624. The free drug monotherapy showed moderate bacteri
increasing in vitro efficacy compared to the free drug), and modified cidal activity with rapid regrowth against Pseudomonas aeruginosa
drug release. In addition, the initial burst release of up to 2 h may enable H131300444 and was ineffective against Pseudomonas aeruginosa
immediate drug action at a higher concentration without cytotoxic ef H133880624. Ciprofloxacin-colistin-loaded liposome indicated colistin
fect. Moreover, the ex vivo skin penetration/deposition studies revealed molecules were associated with the outer membrane of the liposomes.
that azithromycin-liposome with the highest degree of elasticity incre Thus, this preparation primarily interacts with lipopolysaccharide and
mented antibiotic penetration/deposition through the skin layers phospholipids of the outer bacterial membrane changing its perme
(epidermis and dermis) compared to rigid bilayers liposomes (cationic ability which favors liposomes entering the cytoplasm (Wang et al.,
liposome). In contrast, free azithromycin penetrated the skin after 2 h of 2018). Similar antimicrobial activity was observed for ciprofloxacin-
application favoring systemic drug absorption and reducing drug con colistin-liposome inhalable powder for the same microorganism (Yu
centration within the skin. Hence, azithromycin-liposome preparation et al., 2020). Additionally, the study prepared daptomycin-
could be administered to treat upper and deeper layers of the skin clarithromycin-liposome revealed significantly enhanced in in vitro as
infected by MRSA (Rukavina et al., 2018). Azithromycin is an antibiotic says against MRSA at low daptomycin concentration compared to free
most frequently used to treat skin and soft-tissue infection by oral and drug (Li et al., 2015). Hence, antibiotic LBNs could be a sustainable
intravenous administration. However, topical antibiotic therapy is strategy for combinatory antibiotic therapy due to their multiple
crucial to managing complex skin infections caused by Staphylococcus mechanisms, which prevents the emergence of tolerance for each drug
aureus resistant strains to avoid high dose and side effects (Bonamonte separately. However, every combinatory option needs to be considered
et al., 2020). carefully to prevent the transmission of resistance from one drug to a
Healthy skin tissues present neutral pH and an acid barrier mantle of partner drug (Pletz et al., 2017; Angst et al., 2021). Clarithromycin is
around pH 5.5. Skin inflammation or a chronic wound remains with effective in treating Helicobacter pylori infection of the digestive sys
slightly alkaline pH, which promotes bacterial colonization (Kuo et al., tem. Nevertheless, in 30% of the patients the treatment failed promoting
2020). Skin bacterial infection induces pH disruption of the skin envi the emergence of the resistant strain (Iqbal et al., 2020). Clarithromycin
ronment; for instance, in vitro skin infected by Staphylococcus aureus and resistance is associated with two-point mutations in the 23S rRNA genes
Pseudomonas aeruginosa presented a heterogeneous pH range between (Marques et al., 2020). In contrast to conventional preparations,
pH 4 and 9 (Bullock et al., 2020). Hence, the pH environment can be erythromycin-loaded NE disclose increased erythromycin solubility,
exploited to potentiate the delivery of antibiotics using pH-responsive protected it from hydrolysis degradation, and proved beneficial in
LBNs. Vancomycin-loaded SLN was prepared using pH-responsive vitro performance. In vitro antimicrobial activity against Helicobacter
solid lipid (SA-3M) previously synthesized. This preparation showed pylori in simulated gastric fluid (pH 1.2) revealed a 4-fold increase.
9
Furthermore, erythromycin-loaded NE improved in vitro antimicrobial associated with free antibiotics. Hence, antibiotic-loaded LBNs can treat
activity against erythromycin-resistant Helicobacter pylori compared to resistant strain effectively, avoiding safety concerns by convention
the free drug. This improvement can be ascribed to membrane cell therapy.
disruption of Helicobacter pylori, which could be an additional advan
tage for erythromycin-loaded NE against a resistant strain (Tran et al., 3.3. Biofilm
2017).
Additionally, Escherichia coli is an Enterobacteriaceae that causes Table 3 presents antibiotic-loaded LBNs against biofilm from sus
intestinal infection. Its multidrug resistance (MDR) is associated with ceptible and resistant strains. Biofilm comprises clusters of bacteria
multiple mechanisms and rapidly became an alarming public health surface-attached forming a multicellular community protected by a ex
concern. Azithromycin-loaded liposome co-encapsulated with N-ace tracellular matrix self-produced (Vestby et al., 2020; Verderosa et al.,
tylcysteine presented increased in vitro antimicrobial activity against 2019).
Escherichia coli SA057 and Escherichia coli SA10, while free drug showed The in vitro antibiofilm efficacy of LBNs was determined preventing
no activity against both strains. N-acetylcysteine’s presence reduces MIC biofilm formation (3 of 7) or disrupting mature biofilm (4 of 7). From a
values of azithromycin against Escherichia coli SA10 (Aljihani et al., total of 7 studies, 29% used susceptible bacterial strains (Pseudomonas
2020). aeruginosa and Staphylococcus aureus); and 71%, resistant bacterial strains
In vivo antimicrobial activity of LBNs against induced MRSA (MRSA and Escherichia coli) (Table 3).
bacteremia using murine model was performed in 13% of the studies. Biofilm-associated microorganisms are detrimental to health care
Mupirocin-loaded liposome enhanced antimicrobial activity after due to the dramatic reduction of bacteria susceptibility to antibiotics
parenteral administration compared to the free drug due to its increased (Donlan, 2001; Jamal et al., 2018). It is estimated that approximately
half-life. Liposome protected mupirocin’s rapid degradation in the liver 65% to 80% of human infections are a consequence of formation of
and prevented its high protein binding in plasma, which are the major bacteria biofilm (Verderosa et al., 2019; Robino and Scavone, 2020).
concerns of mupirocin for systemic administration. Thus, it opens the Therefore, an optimal treatment should be capable of inhibiting bacteria
possibility that mupirocin might not be restricted to topical use and itself and the biofilm matrix (Robino and Scavone, 2020).
could become part of the clinical arsenal to treat MRSA bacteremia LBN activity against biofilm is influenced by a diffusion coefficient,
(Goldmann et al., 2019). Ciprofloxacin-loaded NLC presented significant which is directly correlated to nanoparticle composition, particle size,
reduction of MRSA in the blood, liver and kidneys compared to the free and biofilm composition (Liu et al., 2019; Peulen and Wilkinson, 2011).
drug in mice. Nevertheless, after four days, none of the treatments LBNs against biofilm showed particle size range from 119 to 406 nm, PdI
reduced the accumulation of MRSA in the spleen. Proinflammatory values < 0.3, and ZP range from − 43 to +18 mV. The adequate particle
cytokine production induced by MRSA infection was diminished after size to treat biofilm could be <500 nm, with a preferable range between
administration of ciprofloxacin-loaded NLC co-encapsulated with roli 5 and 200 nm (Malaekeh-Nikouei et al., 2020; Sankaran et al., 2019).
pram (anti-inflammatory), which promoted the survival of animals. Cationic LBNs revealed better penetration, distribution throughout
Histopathological analysis revealed that NLC prevented congestion and negative biofilm surfaces and reduction of biofilm integrity (Ong et al.,
necrosis of organs due to it inhibited neutrophils entering into organs 2019). However, strong electrostatic interaction might retain nano
preventing their disruption. These significant improvements can be particles on the biofilm surface, limiting its penetration (Ferreira et al.,
explained due to high drug encapsulation, ciprofloxacin protection form 2021b). Conversely, negative and neutral LBNs showed potent anti
enzymatic inactivation, and small particle size (177 nm), which allowed biofilm activity against Pseudomonas aeruginosa, Klebsiella oxytoca
NLC circulation in bloodstream for a long period of time (Liao et al., and Staphylococcus aureus (Ferreira et al., 2021b; Alhariri et al., 2017).
2021). Hence, the zeta potential of LBNs role against biofilm remains poorly
The remaining in vivo studies (3 of 15) evaluated antimicrobial ac understood.
tivity against MRSA skin infection in a murine model. Oxacillin-loaded Pseudomonas aeruginosa typically colonizes 80% of patients with
NLC presented a 4-log reduction of MRSA in skin abscess compared to cystic fibrosis. This infection is aggravated to chronic lung infection
the free drug after topical administration. In addition, this preparation when an antibiotic loses its ability to eradicate planktonic bacteria
protected skin structure and function and prevents neutrophil skin allowing growth of polysaccharide alginate biofilm (Høiby et al., 2010;
infiltration in the wound (Alalaiwe et al., 2018). Additionally, Rossitto et al., 2018). In addition, antibiotic therapy’s failure in early
vancomycin-loaded liposome presented a significant reduction of MRSA stages promotes biofilm adaptation. This generates new extracellular
in a surgical wound infected compared to free drug. After the treatment, polysaccharides influenced by genotype and phenotype modification
bacteria were not detected in the blood, spleen, and liver, demonstrating and mutation in the quorum sensing system (Kovach et al., 2017; Van
the success of preventing postsurgical infection due to prolonged van deplassche et al., 2019). Azithromycin-loaded liposome and the free
comycin release, increased bacterial membrane interaction, and high drug against susceptible Pseudomonas aeruginosa PAO1 revealed similar
intracellular liposome uptake (Hajiahmadi et al., 2019). Moreover, complete bacteria biofilm eradication at high drug concentrations (1024
vancomycin-loaded liposome pH-responsive after intradermal adminis and 512 mg/L). Nevertheless, azithromycin-loaded liposome showed
tration showed superior antimicrobial activity in skin MRSA infection increased antimicrobial activity at lower concentration: 3.7-log bio
than the free drug. Histomorphological evaluation of infected skin burden reduction at 128 mg/L. This amount is twice lower than the free
revealed a reduction in immune response with minimal inflammation drug concentration required to achieve the same inhibition. This
and abscess formation (Makhathini et al., 2019). improvement might be ascribed to liposome biofilm penetration
As shown, antibiotic-loaded LBNs represent a strong trend towards a increasing drug contact with bacteria and the reduction of quorum
new therapeutic approach to control the current bacterial resistant. This sensing molecules, which may inhibit biofilm formation (Solleti et al.,
strategy could prevent the raising of new resistant organism against 2015). Consequently, initial administration of LBNs as part of an
available antibiotics. Due to the unique properties of LBNs described in aggressive therapy in the treatment of cystic fibrosis might prevent
the previous topics, these can circumvent the main acquired bacterial worsening lung infection and the appearance of resistant bacterial
resistance mechanisms such as drug inactivation or modification, target strain.
alteration, and cell wall permeability changes. In vitro assays revealed Staphylococcus aureus biofilm formation is determined by a so
that antibiotic-loaded LBNs could inhibit bacterial growth and increase phisticated genetic factor becoming a challenge to bacterial clearance,
the antimicrobial activity compared to free drug counterparts, which did reducing antibiotic susceptibility and leading to chronic infections
not present antimicrobial activity against resistant strain. Besides, the in (Lister and Horswill, 2014; Moormeier and Bayles, 2017). MRSA biofilm
vivo assay showed antibiotic-loaded LBNs did not present toxic effects growth increased morbidity and mortality in humans and became
10
clinically relevant due to extend hospital stay associated pneumonia, properties owing to their composition versatility, and surface
endocarditis, chronic wound infection, osteomyelitis and septicemia modification.
(Archer et al., 2011; Lister and Horswill, 2014). Antibiotic-loaded LBNs revealed increasing or preserving antimi
Thus, alternatives therapeutics have been forthcoming. Rifabutin- crobial activity compared to the free drug in in vitro and in vivo assays
loaded liposome in vitro assays against susceptible Staphylococcus against susceptible and resistant strains, and biofilm. Nevertheless, the
aureus preserved rifabutin antimicrobial activity with slight improve studies showed the importance of a rational based approach in
ment in antimicrobial activity compared to free drug. In addition, its antibiotic-loaded LBN development. The careful selection of compo
antibiofilm activity revealed similarity compared to free drug. However, nents plays a vital role in its efficacy. In addition, the in vitro method
free rifabutin already presented a high Staphylococcus aureus antibiofilm requires standardization procedures aiming to ensure its uniformity and
activity. Hence, negative liposomal preparation could improve thera reduce the variability in results. Additionally, in vivo studies were
peutic effectiveness in the treatment biofilm Staphylococcus aureus scarcely performed. For antibiotic-loaded LBNs to treat antibiofilm, in
infection and overcome rifabutin toxicity and low water solubility vivo activity was not reported. Thus, moving forward to the proof of
(Ferreira et al., 2021b). concept addressing antibiotic-loaded LBN efficacy is critical to achieve
Unfortunately, even the last-line antibiotic monotherapy has not its commercial potential.
escaped the rapid rise of MRSA. Nevertheless, antibiotic-loaded LBNs Antibiotic-loaded LBNs can improve current clinical drug therapy,
revealed improved activity against biofilm compared to conventional deliver innovative products and rescue discarded antibiotics. Besides,
preparation. For instance, MRSA mature biofilm viability was reduced the growing threat of bacterial resistant strains can be slowed down,
3.5-log by fusogenic vancomycin-loaded liposome while the free drug alleviating the lack of new molecules. Therefore, antibiotic-loaded LBNs
was 2.5-log. Vancomycin-loaded liposome inhibited MRSA biofilm for open a window of opportunities to continue saving millions of lives and
mation at double concentrations compared to the free drug due to prevent the devastating impact of bacterial infection.
encapsulated and late kinetics release of vancomycin. Hence, it seemed
that the free drug had a preferable effect on early stages of biofilm CRediT authorship contribution statement
formation while liposomes presented enhanced inhibition activity in
mature biofilm (Scriboni et al., 2019). Furthermore, azithromycin- Mirla Anali Bazán Henostroza: Conceptualization, Data curation,
loaded liposomes revealed enhanced effectiveness against MRSA bio Formal analysis, Writing – original draft. Guilherme Diniz Tavares:
film formation. Liposome showed 4- to 8-fold and cationic liposome 32- Conceptualization, Data curation, Formal analysis, Writing – review &
fold improvement compared to free drug. Cationic LBNs penetrate editing. Megumi Nishitani Yukuyama: Validation, Methodology.
rapidly and release antibiotic preventing biofilm formation (Rukavina Aline De Souza: Data curation, Formal analysis, Resources. Eduardo
et al., 2018). Moreover, oxacillin-loaded NLC revealed significant bio José Barbosa: Data curation, Validation. Valdir Carlos Avino: Visu
film disintegration and bacterial eradication of MRSA compared to free alization, Investigation. Edson dos Santos Neto: Funding acquisition,
drugs in the in vitro assay. The initial biofilm thickness (31.2 µm) was Investigation. Felipe Rebello Lourenço: Methodology, Resources.
reduced to 13.0 µm and 25.2 µm after treatment with oxacillin-NLC and Raimar Löbenberg: Supervision, Validation, Visualization. Nádia
oxacillin solution, respectively. The presence of lipids and emulsifiers Araci Bou-Chacra: Conceptualization, Data curation, Formal analysis,
could have favored oxacillin-loaded NLC better interaction with extra Supervision, Writing – review & editing.
cellular polymer substance (EPS) (Alalaiwe et al., 2018). Finally,
levofloxacin-loaded NE presented reduction in MRSA biofilm formation
Declaration of Competing Interest
even at low concentration (1/8 MIC). At high concentration (1/2 MIC)
the free drug and levofloxacin-NE inhibited biofilm by 38% and 72%,
The authors declare that they have no known competing financial
respectively. In addition, delayed biofilm regrowth was observed after
interests or personal relationships that could have appeared to influence
biofilm treatment with levofloxacin-NE. The unspecific cell disruption
the work reported in this paper.
by nanoemulsion may hamper cell adherence preventing biofilm for
mation (Mehanna et al., 2020).
Escherichia coli is another prevalent biofilm microorganism that is Acknowledgement
associated nosocomial urinary tract infection related to use of catheters
and medical devices (Sharma et al., 2016a). Azithromycin-loaded lipo This work was supported by CNPQ foundation-Brazil (Conselho
some co-encapsulated with N-acetylcysteine showed improved effec Nacional de Desenvolvimento Científico e Tecnológico, grant number:
tiveness against mature biofilm formed by resistant Escherichia coli 41992/2019-0).
SA057 and Escherichia coli SA10 compared to free drug. The significant The authors thank Orlando Paes Filho for the illustrations (www.
effect might be due to the liposome adherence on biofilm allowing its angussaga.com). Jim Hesson revised the manuscript (https://www.
intake, and N-acetylcysteine biofilm disruption property (Aljihani et al., academicenglishsolutions.com/editing-service).
2020).
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International Journal of Pharmaceutics 621 (2022) 121782

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

Antibiotic-loaded lipid-based nanocarrier: A promising strategy to

SLN Ceftriaxone Cholesterol (1.0 g), lecithin (1% w/ 212.0 ± – − 36.9 ± α

NE Levofloxacin D-Limonene, Tween® 80, propylene 119.1 ± 0.31 ± − 16.0 β

NE Rifampicin Castor oil, Solutol® HS15, 25.7 ± 0.18 ± − 8.2 ± α

LP Azithromycin DPPC, Lipoid S75, DODAB ≤217.3 0.09 to − 43.1 £β

LP Mupirocin HSPC, CHOL, mPEG DSPE ≤85.6 ± < 0.05 ± – β

LP Vancomycin SPC, CHOL, cyanur-PE (mole ratio ≤111 ± 0.08–0.17 +0.4 ± β

LP Daptomycin and HSPC, CHOL,mPEG2000-DSPE 98.20 ± 0.25 ± – β

LP Vancomycin CHOL, EPC, DOPE, DPPC, CHEMS, ≤200 ± 0.09 to − 16.9 β

£: clinical isolate strain.

compared to the free drug against Pseudomonas aeruginosa. In addition,

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