pH-Sensitive Nanomedicine for Treating Gynaecological Cancers

Freely Available Online JOURNAL OF WOMAN’S REPRODUCTIVE HEALTH ISSN NO: 2381-862X Review Article DOI: 10.14302/issn.2381-862X.jwrh-19-3143 pH-Sensitive Nanomedicine for Treating Gynaecological Cancers Pramod Vishwanath Prasad1*, Kakali Purkayastha2, Utkarsh Sharma3, and Mayadhar Barik4 1 Center for Biomedical Research, Population Council, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA 2 Department of Paediatrics, All India Institute of Medical Sciences, New Delhi-110 029, India 3 Patna Medical College and Hospital, Patna University Campus, Ashok Rajpath, Patna- 800001, Bihar, India 4 Department of Biochemistry, Mewar University, NH-79, Gangrar, Chittorgarh, Rajasthan-312901, India Abstract Emergence of various nanoscale drug carrier platforms as Drug Delivery Systems (DDS) has revolutionized the field of medicine. Nonetheless, the side-effects due to non-specific distribution of anticancer therapeutics in normal, healthy tissues remain to be a prime pitfall in curing cancers. Therefore, to achieve a better therapeutic efficacy, the use of a target-specific delivery, combined with a stimuli-responsive nanocarrier system, particularly pH-sensitive nanosystems offer an attractive strategy. Targeted drug delivery through pH-sensitive nanosystems offer the potential to enhance the therapeutic index of anticancer agents, either by increasing the drug concentration in tumor cells and/or by decreasing the exposure in normal host tissues. Therefore, nanoscale-based drug delivery through pH-sensitive nanosystems seem to be a boon for treating gynaecological cancers (as well as other cancers) without side-effects or with least harm to normal healthy tissues. * Corresponding author: Pramod Vishwanath Prasad, Center for Biomedical Research, Population Council, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Email: [email protected] Keywords: Gynaecological Cancers; pH-Sensitive nanomedicine; Liposomes; Polymeric micelles; Dendrimers; Nanogels. Received: Dec 24, 2019 Accepted: Jan 28, 2020 Published: Feb 11, 2020 Editor: Qiuqin Tang, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, China. www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 35 Freely Available Online their structure and surface characteristics, causing drug Introduction A hope of successful treatment of cancers without side effects has challenged oncologists and onco-scientists since decades. Burgeoning research in nanotechnology and the depth of understanding in gynae-oncological pathophysiology at the cellular and molecular levels have led to the development of different well-tailored nanosized carriers for drug loading and controlled delivery at the targeted site. In recent years, nanosized carriers (nanocarriers) have gained attention as unique drug delivery agents due to following qualities: (i) they have abilities to incorporate payloads with different solubilities [1], (ii) they improve the in vivo pharmacokinetics (PK) of drugs [2], (iii) they enhance bioavailabilities (i.e., the drug stability and longevity in the blood circulation with or without additional structural modifications) [3], and (iv) they modify the carriers with targeting ligands on their surface for tumor tissue or cell-specific delivery to minimize side-effects on healthy cells/ tissues [4]. Some of the nanocarriers developed till today are liposomes, dendrimers, polymeric nanoparticles (NPs), gold or other metallic NPs, inorganic NPs made of iron oxide, quantum dots etc. [5-7]. Few of them possess unique nature of stimuli-responsiveness. Such release or contrast enhancement at a particular pathological site [11, 12]. This ease of controlled drug delivery at the desired site, has incepted the preliminary idea of developing pH-sensitive drug delivery nanosystems. Moreover, the pH-responsive NPs are one of the most extensively studied stimuli-responsive nanosystems. This is due to its sensitivities to the changes in pH condition at the tumor or diseased tissue site [13, 14]. Generally, pH-responsive nanoparticles are fabricated either using acid-sensitive linkers or ionizable groups [15]. Varieties of pH-sensitive nanoparticles have been designed in recent decades and have characteristic functionalities in the molecular structure, where pKa (negative logarithm of the acid dissociation constant) values are close to the tumor interstitial pH. When these nanoparticles reach tumors where the microenvironmental pH is slightly acidic, a pH-dependent structural transformation occurs. The acidic environment at the tumor site triggers the protonation of pH-sensitive moieties, thereby disrupting the hydrophilic-hydrophobic equilibrium within the nanoparticle, in turn causing structural transformation and the release of therapeutic cargo loaded inside. Despite stimuli-responsive nanocarriers have emerged as an of few problems with nanoparticle-based DDS “intelligent” or “smart” DDS. Thus, these nanocarriers nanomedicine, have exhibited myriads of successful applications in remain as a potential strategy for cancer therapy. Some comparison with conventional DDS. nanoparticle formulations for cancer treatment have The main purpose of developing nanomedicine and nanotherapies is to avoid damage to healthy organs. So, these innovative approaches seem to have tremendous potential in improving the effectiveness of nanomedicines to treat clinical tumors with null side effects [8]. There are several nanomaterials which have been found to be responsive to external (viz., light, ultrasound) potential, and internal temperature), stimuli and (viz., have pH, been redox utilized for cancer therapy and simultaneous diagnosis i.e., theranostics [5, 9, 10]. Among the various stimuli-responsive nanosystems, pH-stimuli mode is regarded as the most general strategy because of solid tumors acidosis. When exposed to weakly acidic tumor microenvironment, drug carrying pH-responsive nanoplatforms can generate physicochemical changes in pH-sensitive associated been already approved by regulatory agencies. These formulations exert fewer adverse effects than unmodified or bare drugs [16]. Therefore, in the interest of brevity, this review article simply retrospects and compiles only pH-sensitive nanosystems among other internal stimuli-responsive pH-sensitive nanosystems systems. Some retrospected of the here are certainly not yet directly used for treating gynecological tumors but paves the way for employing them for treating gynecological cancers with some strategic modifications depending on tissue types. pH-Sensitive Nano-Systems Generally, physiological pH remains 7.4 (weakly basic) but the subcellular compartments viz., endosomes and lysosomes exhibit remarkably lower pH of about 5-6 or 4-5, respectively. Therefore, significant lower pH in www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 36 Freely Available Online subcellular compartments has been used as a route for they revealed the enhanced release and accumulation of delivering anticancer drugs by the pH-stimulated release drugs from endocytosed drug carriers [17]. Since the inception comparison with liposomes without coiled coils [24]. In of pH-sensitive NPs, myriads of innovative approaches an attempt to develop targeted drug delivery systems for cancer treatment have come into light. Past decades with cancerous cell-specificity and controlled release have witnessed synthesis and utilization of various function inside cancer cells, Miyazaki and colleagues pH-responsive liposomes, acidic lysosomal compartments in block have designed hyaluronic acid (HA)-based pH-sensitive polymers as multifunctional polymers. These polymers polymer-drug conjugates, dendrimers, nanogels, and exhibited not only pH-sensitivity but also targeting multiple core shell complexes etc. [18]. These are properties to cells expressing CD44 (a cancer cell polymeric viz., the polymerosomes, copolymers, nanosystems in micelles, briefed as follows: surface marker). They observed that HA-derivative I. Liposomes modified They are phospholipid vesicles consist of one or more concentric lipid bilayers enclosing discrete aqueous spaces. They can entrap both lipophilic and hydrophilic compounds thus employed for delivering diverse range of drugs. Moreover, its large aqueous center and liposomes can be efficiently used for cell-specific intracellular drug delivery [25]. Further research studies on the therapeutic and clinical aspects of pH-sensitive liposomes are needed to enable their commercial utility in gynecological cancer treatment. II. Block Copolymers biocompatible lipid exterior permits the delivery of Amphiphilic block copolymers are self-assembled different macromolecules, viz., DNA, proteins and into polymeric micelles (10-100 nm in diameter) in imaging agents [19]. Thus, liposomes are the most aqueous media. These micelles possess a well-defined common and widely sleuthed nanocarriers for targeted hydrophobic core and a hydrophilic corona. Block drug delivery due to their flexible physicochemical and copolymer micelles can thus significantly improve the biophysical solubility of the hydrophobic drug formulated in the properties Doxorubucin [19]. chemotherapeutic agent) has been observed to be the hydrophilic end of the block copolymer, can protect efficient as the micellar system from the RES elimination by monotherapy and tumor-specific liposomal core; whereas, the densely packed corona consists of breast a Pegylated and in (DOX: cancer in peptide treatment combination both other reducing the interaction with serum proteins and renal chemotherapeutics [20]. In 2016, Silva and colleagues with filtration [26]. The pH-sensitive block copolymers allow have reported pH-sensitive long-circulating liposomes for for controlled micelle dissociation and triggered drug selective delivery of DOX into tumor [21]. release in response to the acidic pH of tumor tissue. Karanth and Murthy have extensively analysed previous reports on the cytosolic delivery of the drugs through pH-sensitive liposomes and suggested that pH-sensitive liposomes were more efficient in delivering anti-cancer drugs than conventional and long-circulating liposomes due to their fusogenic property [22]. Recently, a team of investigators have lucidly elaborated the developmental and applicability status of pH-sensitive liposomes in cancer treatment and concluded it very successful as pharmaceutical carriers for intracytoplasmic delivery of antineoplastic drugs [23]. Few investigators have reported pH sensitive coiled coils and their incorporation into the liposome as triggers for the controlled release of encapsulated drugs. From, the drug encapsulated liposome internalization experiments with cancer cells, The pH-sensitive polymeric micelles assembled from hyperbranched amphiphilic block copolymer loaded with DOX have exhibited remarkable cytotoxicity against HeLa cells in a dose- and time-dependent manner. Thus, proved to be a potential carrier candidate for pH-responsive drug delivery in treating cancer [27]. Moreover, a dual pH-sensitive micelle loaded with Paclitaxel (PTX, a chemotherapeutic agent) has been also proved to be a potential nanocarrier for effective metastatic toxicity tumor [28]. therapy Poly without (ethylene glycol) significant methyl ether acrylate-block poly(L-lysine)-block-poly(L-histidine) triblock co-polypeptides were synthesized for pH-responsive drug delivery. Such nanoparticles were found to be stable at physiological pH (7.4) but were www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 37 Freely Available Online dramatically destabilized in acidic pH due to the triblock presence urethane)-block-PEG (PEG-POEU-PEG) were found to of pHis blocks [29]. The pH-induced copolymer notably release dose-dependent sensitivity [35]. Last year, few investigators have cytotoxicity in murine cancer cells. YangZhang et. al. reported a chemo-photothermo therapy of cancer cells (2012) by using gold nanorods (AuNRs)-based pH-sensitive DOX, have followed reported pH-responsive poly ether-b-(poly lactic a by a series of DOX-loaded (ethylene glycol) methyl acid-co-poly (β-amino esters)) thiol-ended at pH 5.0 triblock due to ester destabilization of the nanoparticle enabled the controlled of accelerated PEG-block-poly(ortho copolymer (PAA-b-PDMAEMAQ-b-PCL-SH), in its pH micelles which AuNRs at (MPEG-b-(PLA-co-PAE)) block copolymer micelles as polymer was loaded with Methotrexate (MTX) as an drug delivery carriers for targeted cancer therapy with anticancer drug [36]. sustained release [30]. Investigations carried out by III. Polymeric Micelles Zhou et. al. (2015) have suggested that the polymeric micelles comprising of polyethylene glycol (PEG) and a polymethacrylamide [PEG-b-PMEA] diblock copolymer could be useful for pH-responsive delivery of poorly soluble anticancer drugs [31]. The pH-sensitive copolymer viz., methoxy poly(ethylene glycol)-b-poly(hydroxypropyl methacrylamide-g-α- tocopheryl succinate-g-histidine) (PTH) forming micelles in aqueous solutions were used for co-delivery of therapeutic agents, DOX and α-TOS (α-tocopheryl succinate) in tumor cells. In this combination therapy, the micelles enabled the rapid release of both Dox and α-TOS when the pH declined from 7.4 to 4.5 in tumor tissues [32]. Mozhi and colleagues have displayed a synergistic antitumor effect of the combination of anticancer drug Docetaxel and the therapeutic peptide [D(KLAKLAK)2] in an MCF-7 cell line using a pH-sensitive copolymer viz., poly(β-amino esters)-poly(ethylene glycol) conjugated with the dual-targeting proapoptotic peptide CGKRKD(KLAKLAK)2. In which, CGKRK peptide efficiently transported mitochondria apoptosis to [33]. D(KLAKLAK)2 trigger Few towards mitochondria-dependent investigators have reported synthesis of pH-sensitive copolymer through bridging poly (2-methacryloyloxyethyl phosphorylcholine) (PMPC) block and poly (D, L-lactide) (PLA) block by a benzoyl imine linkage (Blink). These biomimetic micelles (PLA-Blink-PMPC) were prepared as carriers for PTX delivery. Such pH-triggered drug release behaviour in synchronization with tumoral acidic conditions was found to be helpful for improving the utilization of drug and facilitating antitumor efficacy [34]. Furthermore, Wang and colleagues have exhibited antitumor efficiency of DOX-loaded micelles. In which, ortho ester degradation of DOX-loaded, pH-sensitive micelles consisted of They are self-assembling nano-constructs of amphiphilic copolymers and are widely regarded as efficient nano-carriers for myriads of applications, including drug delivery, diagnostic imaging etc. These became feasible because of their variety of favorable properties viz., biocompatibility, bioavailability, capacity to effectively solubilize myriads of poorly soluble drugs, enhancing release profile of the incorporated pharmaceutical entities, ability to accumulate in the targeted tissue based on the EPR effect and ability to attach various targeting ligands to the micellar surface. The combination of these approaches have been found to further improve specificity and efficacy of micelle-based drug delivery to promote the development of smart multifunctional micelles [37]. Ko and colleagues have evaluated anti-tumor activity of pH-responsive polymeric micelles made up of methyl ether poly (ethylene glycol) (MPEG)-poly(β-amino ester) block copolymers, by injecting the DOX-loaded polymeric micelles into tumor-bearing mice. These micelles notably suppressed tumor growth and prolonged survival of the tumor-bearing mice, compared with mice treated with free DOX [38]. Giacomelli and coworkers have reported pH-triggered micelles composed of a pH-responsive PDPA [poly(2-diisopropylamino) ethyl methacrylate] inner core and a PEO [poly(ethylene oxide)] outer shell as a promising drug delivery system for the cancer therapy. In which, pH-responsive PDPA core was loaded with PTX [39]. In vivo evaluation of DOX-loaded pH-sensitive polymeric micelles made up of poly(L-histidine-co-L-phenlyalanine-b-PEG and poly(L-lactic acid)-b-PEG-folate was carried out in multidrug-resistant (MDR) ovarian tumor-xenografted mice. It was observed that the drug-carrying micelles www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 38 Freely Available Online were exhibiting enhanced intracellular DOX-delivery by pH-sensitive drug delivery nanosystems. Uthaman and circulating for long-time (i.e., enhanced bioavailability) his team (2018) have reported a variety of and accumulating at tumor-selective sites. Thus, they pHis-based polymeric micelles for the delivery of exhibited enhanced cytotoxicity to tumor cells only, DOX [15, 29, 46-48]. In addition to these, nanocarriers sparing the normal healthy cells [40]. Wang and composed colleagues loaded polymeric micelles were used to deliver Nonsteroidal anti glycol)-b-poly -inflammatory drug (NSAID) Ibuprofen in breast cancer [PELA-PBAE] therapy. It was observed to possess potential anti-tumor have shown pH-responsive that PTX Poly(ethylene (D,L-lactide)-b-poly(β-amino micelles the might tissues [49]. The pH-responsive nanoparticles combining the cisplatin Ibuprofen with chemotherapy agents have provided a between novel micelles incorporated by poly with complexation cis-dichlorodiammineplatinum(II) hydrophilic utility (CDDP) (L-glutamic (2-methacryloyloxyethyl in chitosan metastatic breast tumor therapy [41]. In another study, prepared potential biocompatible activity, while avoiding side-effects on normal, healthy polymeric the amphiphilic, the were have ester) of and (PLG-b- PMPC) diblock copolymers. Investigators observed the sustained release of CDDP from the micelles was faster in acidic pH (5.0 - 6.0) than the physiological pH 7.4. Thus, CDDP-loaded polymeric micelles were developed for targeted cancer therapy to reduce the detrimental side effects of cisplatin CDDP [42]. Zhou and coworkers have reported a pH-responsive pentablock copolymer made up of 1,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)] conjugated poly(β-amino esters) (DSPE-b-PEG-b-PAE-bPEG-b-DSPE) was able to self-assemble into polymeric micelles. These DOX-loaded polymeric micelles displayed pH-triggered high toxicity to tumor cells and HeLa cell lines whereas the copolymer had negligible cytotoxicity. Thus, these pH-sensitive micelles have the potential to be used for cancer chemotherapy with controlled release [43]. Das and his team, and Zhou and colleagues have lucidly elaborated the current advances in the development of pH-responsive polymeric micelles/ nanoparticles, their mechanisms of action, applications in chemotherapy, delivery strategies diagnostic and imaging, provided their their future perspectives [44, 45]. This is yet to be sleuthed in human cells and gynecological tissues. It is well understood that, among amino acids, Histidine (His) is an only essential amino acid having imidazole group. The presence of lone-pair electrons on the unsaturated nitrogen of this group confers pH-sensitivity to Histidine. Therefore, poly(Histidine) (pHis) has been extensively used for the fabrication of system for both primary and metastatic tumor treatment [50]. acid)-b-poly phosphorylcholine) nanoparticle Targeted efficient delivery and therapeutic efficacy of DOX have been found to be significantly increased by using a stepwise pH-responsive nanodrug delivery system [51]. This study has provided a promising strategy for efficient delivery of other antitumor agents. Similarly, some more nanocarriers like polymeric micelles, liposomes and solid NPs have been developed for hydrophobic as well as hydrophilic drugs for effective therapy of cancer [52-56]. Last year, some investigators have revealed the intracellular pH-responsive nanoparticles of hyaluronic acid which can provide insights into the design of potential prodrugs for the cancer therapy [57]. Hydroxyapatite coated iron oxide nanoparticles and pH sensitive Sodium alginate have been developed for controlled release of hydrophobic drugs [58]. Yandan and his colleagues have shown that multifunctional sharp pH-responsive nanoparticles made up of poly(2-(diisopropylamino) ethylmethacrylate) (PDPA) polymer have great potential to serve as a new generation nanomedicine for effective breast cancer treatment [59]. IV. Polymersomes or Polymeric Vesicles They are preferably prepared from amphiphilic, biocompatible and biodegradable polymers [60]. They have the potential to be versatile drug delivery systems because of their tunable membrane formulations, stabilities in vivo, various physicochemical properties, controlled release mechanisms, targeting abilities, and capacities to encapsulate varieties of drugs etc. [61, 62]. The pH-sensitive polymersomes have been developed to quickly respond to small changes in the environmental pH of tumor’s microenvironment [60, 63]. Following pH www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 39 Freely Available Online alteration, the pendant acidic (carboxylic acids/sulfonic multifunctional dendrimer-based theranostic nanosystem acids) or basic groups (amine) undergo protonation or (in which Gold nanoparticles conjugated with DOX were deprotonation. Consequently, the structural transition entrapped in dendrimer) to be utilized for simultaneous induces formation/deformation of polymeric vesicles, chemotherapy and computed tomography (CT) imaging which confers a higher therapeutic index as a result of of various types of cancer cells [69]. Dendritic polyester the fast release of therapeutics at the target site. system based on monomers 2,2-bis (hydroxymethyl) However, the major obstacle to the application of propanoic acid attached to DOX or hydroxyl-terminated pH-sensitive polymersomes is the slow response to the generation 4 PAMAM in conjugation with PTX through a stimulus, resulting in a slow drug release, which union with succinic acid have shown great anticancer eventually induce drug resistance in the adjacent cells. activity against ovarian cancer cells [65]. However, at Therefore, polymersomes need to respond quickly as a present the dendrimers used as drug-carriers do not result of the decreased pH at pathological sites. Thus, satisfactorily meet the necessary characteristic of an pH-responsive further ideal dendrimer for targeted drug delivery. However, the designed to carry, deliver, and control the release of development and study of new dendrimers drug-carriers therapeutic agents to the tumor tissue by relying the low continues to be an important tool in the cancer therapy. pH in the vicinity of tumor tissues [60, 63]. Anajafi and (b) Acid-responsive polymers have provided enhanced Mallik polymersomes (2015) have need explicitely to be elaborated recent developments of polymersomes [60]. Their utilities in treating gynaecological cancers are yet to be sleuthed. cis-aconityl linkers are two types of acid-sensitive linkers (a) Dendrimers or dendritic molecules are highly branched with a central core, nanosized, symmetric with well-defined, homogenous and monodisperse structure with diameter 2-10 nm. They are classified by its form as polymers, hyperbranched polymers or brush-polymers and also classified by their molecular weight as low or high molecular weight [64, 65]. Dendrimer act as a carrier for the delivery of drug to tumor by encapsulation or conjugation. Among polymer-drug conjugates, most widely studied dendrimers non-biodegradable, poly-amidoamine to cationic (PAMAM) date are amine-terminated dendrimers [66]. Drug delivery to tumor site is mostly accomplished through PAMAM, poly(propylene imine) [PPI], and poly(L-lysine) [PLL] dendrimers by either passive or active targeting [64]. Wen and colleagues have explained the multifunctional dendrimer-modified multi-walled carbon nanotubes for targeted and pH-responsive delivery of DOX into various types of cancer cells [67]. In 2018, Zhang and coworkers have reported the development of pH-sensitive multifunctional DOX-conjugated PAMAM dendrimers as a unique platform for targeted cancer chemotherapy [68]. Some other investigators have presented the environment, acid-sensitive linkers have provided tools for targeted intracellular drug release. Hydrazone and V. Polymer-Drug Conjugate molecules endosomal delivery of drugs. In the acidic micro construction of pH-responsive which have been commonly used for this purpose. Both are relatively stable at physiological pH and can release the bound drugs only under low pH conditions. The hydrazone linker gets rapidly cleaved under low pH conditions (which occur in endosomes, lysosomes and tumor tissue). Through the hydrazone linker, the drug was found to be released in the acidic tumor microenvironment or in the acidic organelles after cellular uptake by endocytosis [70-75]. Some more sleuthed polymer-drug conjugates containing hydrazone linkages are HPMA-DOX, PEG-DOX [76, 77], PEG-epirubicin [78] and PEG-PTXL [79]. Hydrazone linked acid sensitive PEG-based drug delivery in lysosomes was also studied by Zhu et al., 2012 [74]. They found that Gemcitabine (GemC18) in the acid-sensitive micelles was more toxic toward cancer cells than acid-insensitive micelles. There are reports of a pH-sensitive hydrazone bridged and peptide-guided prodrug incorporating DOX for targeted ablation (removal of harmful parts of the body) of cancer cells with least cytotoxicity on normal healthy cells [80]. The pH-sensitive N-(2-hydroxypropyl) methacrylamide-DOX (HPMA-DOX) conjugates bearing an acid-responsive hydrazone linker in their structure have also been widely studied as anticancer drug delivery systems. They have www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 40 Freely Available Online been found to significantly increase therapeutic efficacy in different in vitro and in vivo cancer models. Liao were constructed by encapsulating a photothermal dye (IR 825) in the carbonized zwitterionic polymer. Before et al. [57] have reported the synthesis of tumor accumulating in the tumor site, these nanoparticles targeting and pH-responsive nanoparticles for the displayed enhanced delivery of DOX. The nanoparticles were hydrophobic interaction with neutral pH and π-π prepared through the covalent bonding of DOX to stacking. The slight change in the pH in TME enabled hyaluronic acid (HA) backbone by hydrazone linkage. In the charge of the nanoparticles to be altered, leading to aqueous acid-hydrazone the release of IR 825 and recovered fluorescence. These linkage-doxorubicin (HA-hyd-DOX) could self-assemble types of nanoparticles can simultaneously be used for into nanoparticles. Active targeting of the nanoparticles diagnosis and photothermal therapy [90]. was achieved through receptor-mediated binding of HA VI. Multiple Core Shell Complexes solution, hyaluronic to CD 44, which are overexpressed in most cancer cells. Studies on polymers that use cis-aconityl linker in designing anticancer drug delivery systems included HPMA-DOX [81], polyamidoamine acid-sensitive polyamidoamine-DOX (PAMAM)-DOX cis-aconityl [83]. linked [82] and Furthermore, Polyehtylene glycol-Chitosan (PEG-CS) micelles were found to have a greater Docetaxel loading capacity, less cytotoxicity toward normal cells, enhanced cellular uptake and better accumulation in tumor tissue compared to acid-insensitive PCS micelles (PEG directly linked to CS) [84]. Moreover, the pH-responsive NPs have also been developed by conjugating nanocarriers with some other acid-labile linkages such as orthoester [85, 86], imine [87, 88], phosphoramidate [89], whose hydrolysis ensured rapid release of the drug at the targeted tumor. (c) Zwitterionic polymers incorporated nanoparticles have been designed to demonstrate a pH-dependent change in surface charge. One of the most commonly investigated systems is based on zwitterionic polymers, as they have cationic and anionic groups that control surface charge in response to pH. In acidic pH, these zwitterionic polymers have a positive charge, and in basic pH, they have a negative charge. However, when these zwitterionic polymers are in neutral pH, they are overall neutral with balanced populations of positive and negative components and they become more hydrophobic. However, upon entering tumor cells, the balance between positive and negative charges alters and thereby cause conformational changes, facilitating drug release in tumor cells. Kang and colleagues have reported the fabrication of tumor microenvironment responsive theragnostic with a pH-dependent fluorescence turn on/off property. The nanoparticles quenching of fluorescence The pH-responsive due to the drug encapsulation and release from multiple core-shell nanoparticles become feasible due to the presence of polyelectrolyte multilayers [91]. Huang and coworkers [92] first Gd2O3:Yb3+:Er3+, synthesized a functionalized mesoporous silica nanoparticle core, which was then coated by multi-layers of polyelectrolytes. DOX was then loaded onto the polyelectrolyte shell. The resulting DOX-loaded core-shell nanoparticles exhibited more than 60% DOX release within 72 h at pH 5.2. In vitro cytotoxicity studies on MCF-7 breast cancer cells showed that DOX-loaded nanoparticles exhibited higher cytotoxicity than the free DOX. Tian et al. [93] synthesized an azide-terminated diblock copolymer from oligo(ethylene glycol)methyl ether methacrylate (OEGMA), 2-(diisopropylamino)ethyl methacrylate (DPA), and glycidyl methacrylate (GMA). The resulting copolymer was then functionalized with DOTA(Gd) and 4-(prop-2-ynyloxy) benzaldehyde and the resulting copolymers were further co-assembled into mixed micelles. The presence of GMA moieties inside the cores enabled encapsulation of tetrakis[4-(2-mercaptoethoxy) phenyl]ethylene (TPE-4SH), and thus the resulting micelles dual were capable imaging. surface-conjugated of MR Moreover, with these pH low and fluorescence micelles insertion were peptide (pHLIP), which enabled them for selective targeting toward tumor tissues and in situ Camptothecin (a cancer drug) release, confirmed by in vivo MR images of tumor-bearing BALB/c nude mice. Ray et. al. (2018)[91] and their collaborators have synthesized a unibody core-shell (UCS) nanoparticle using a polymer platform formed by resorcinol and 1,3-phenylenediamine monomers. In this synthesis, Gd3+was first conjugated www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 41 Freely Available Online to the polymer backbone to form the Gd-core, and then and the coating layer of layered double hydroxide (LDH) DOX was encapsulated within the shell surrounding the was used as a storehouse for MTX] as MTX delivery Gd-core. the system for targeted anticancer therapy. They have components in the core. 1,3-phenylenediamine was Resorcinol observed its excellent pH-sensitivity and ~85% of MTX chosen was released within 48h at pH 3.5 via the co-effect of as the was shell chosen unit for as its one of capability for pH-controllable release. In vitro and in vivo studies of dissolution of LDH layer and ion-exchange. This study UCS-Gd-DOX as an innovative theranostic nanoparticle has revealed that the Fe3O4@LDH-MTX would be a showed that the DOX in the shell is effectively and competitive candidate for sustained, controlled release selectively and targeted delivery of MTX because Fe3O4@LDH-MTX released in tumor acidic environments (pH 5.5). In vitro pH-dependant release of DOX after 2 h exhibited high anticancer activity with minimal toxicity to was found to be <5%, 10%, 55%, 75%, and 80%, at normal cells [97]. In addition to these reports, a pH 8.0, 7.0, 6.0, 5.0, and 4.0, respectively. Enhanced pH-responsive nanoplatform made up of a yolk-like drug release from pH 7.0 to 6.0 verified the potential of Fe3O4@Gd2O3 and functionalized by PEG and folic acid, UCS-Gd-DOX for targeted therapy towards malignant has been documented to be a potential nanotheranostic tumor tissues. In addition, in vitro T1-weighted MR for tumor targeted T1-T2 dual-mode Magnetic Resonance imaging studies also reflected the pH-switchable MR Imaging contrast capability of UCS-Gd-DOX. The pH-responsive HeLa cells [98]. Last year, pH-sensitive magnetic design of the UCS nanoparticle not only improved the composite MRI contrast at the tumor site with respect to other water-in-oil-in-water (W/O/W) emulsion using acetylated tissue/organs, but also successfully suppressed growth β-cyclodextrin as a pH-sensing material and Fe3O4 as a and chemotherapy nanoparticle using was Cisplatin prepared by and double of subcutaneous human cervical cancer in mouse component to realize magnetic response. Its in vitro xenograft models. Therefore, theranostic nanoparticles evaluation was performed for drug loading and release with Gd-conjugation and DOX-doping can be synthesized behaviour [99]. This type of study can be also extended and further applications of UCS-Gd-DOX in the field of for treating gynecological tumors. In a review, Lungu cancer treatment can be anticipated [91]. and her colleagues have explicitely elucidated the utility There are reports of pH-sensitive magnetic of pH responsive core-shell magnetic nanoparticles in delivery. In early years of this decade, a magnetic and NPs were: magnetite@silicon dioxide (Fe3O4@SiO2), nanoparticles sleuthed for targeted anticancer drug pH dually responsive nanocarrier with a multilayer core-shell architecture was constructed. In which, the Fe3O4@SiO2 nanoparticles acted as a superparamagnetic core used to target the drug loaded nanocarriers to the pathological site. Meanwhile, the mPEG [α-methoxy poly (ethylene glycol)] and PBLA [poly(benzyl-L-aspartate)] segments served as a pH-sheddable hydrophilic corona and a hydrophobic middle layer used to load the drug DOX via hydrophobic interactions. This system appeared to be highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy [94, 95]. In 2017, Karimi and his colleagues have brought in light a pH-sensitive magnetic nanoparticle system for Methotrexate (MTX) targeting of tumor [96]. In another study, Wu and his colleagues have performed in vitro evaluation of magnetic nanocomposites (Fe3O4@LDH-MTX) [in which Fe3O4 nanoparticles acted as magnetically responsive carriers diagnosis and treatment of oncological diseases. Those Fe3O4@titanium dioxide (TiO2), beta-thiopropionate- polyethylene glycol (PEG)-modified Fe3O4@mSiO2, Fe3O4 NPs core coated with SiO2 with an imidazole group modified PEG-polypeptide polyacrylic acid (PAA) the oxide NP iron (mPEG-poly-L-Asparagine), and core, folic acid methoxy glycol-block-polymethacrylic coating of polyethylene acid-block-polyglycerol monomethacrylate (MPEG-b-PMAA-b-PGMA) attached by a PGMA block to a Fe3O4 core, PEG-modified polyamidoamine (PAMAM) dendrimer shell with Fe 3O4 core and mesoporous silica coated on Fe3O4, mostly coated with an anticancer drug and used for controlled release of cytostatic drugs into the tumor site by means of pH change [100]. VII. Nanogels They are three-dimensional, water soluble, cross-linked hydrogel materials in the nanoscale size www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 42 Freely Available Online range with a high loading capacity for guest molecules Discussion and Conclusion and act as drug carrier systems [101]. Nanogels are the novel drug delivery systems for both hydrophilic and hydrophobic drugs [102]. There are some anti-tumor drugs viz., Cisplatin, Temozolomide incorporation etc. DOX, used through 5-Flurouracil, in cancer nanogels. Heparin, therapy by pH- and The temperature-responsive nanogels made up of maleic acid poly-(N-isopropylacrylamide) polymer loaded with DOX have been frequently employed in the cancer treatment, where DOX is delivered at a specific pH and temperature. Chitin-polymerized DOX nanogels have been also used for treatment of breast cancer [103]. Several nanogel formulations used in cancer therapy are listed elsewhere [104]. The pH-sensitive PEGylated nanogel loaded with anti-tumor drug has proved to be a promising nano-sized carrier for anticancer drug delivery systems against the human breast cancer cell line MCF-7 [105]. Bardajee and colleagues have prepared a thermo-/pH-sensitive modified graphene nanogels oxide comprising (SMGO) with salep branched N-isopropylacrylamide (NIPAM) and acrylic acid (AA). Doxorubicin loaded SMGO/P(NIPAM-co-AA) nanogels showed exhibited thermo-/pH-dependent enhanced toxicity to drug release HeLa cells and when compared to the equivalent dose of the free drug [101]. A synergistic combined chemo-radioisotope therapy of cancer using a pH-dependent hybrid nanogel (hydrogel nanoparticle) platform based on the self-assembly of carboxymethyl cellulose and bovine serum albumin was reported [106]. The pH sensitive polymeric nano-hydrogels attached with an ionizable weak acidic or basic moieties, cationic polymeric polyethylenimine (PEI), polymeric nano-micelles of pH-responsive natural polymers like albumin and gelatin have also been used as drug delivery systems for treating varied cancers [107]. Peng Wei and colleagues (2018) have synthesised a pH-sensitive nanogels by using N-[(2,2-dimethyl-1,3-dioxolane)methyl] a monomer acrylamide (DMDOMA) bearing an acid cleavable acetal group. These seemed to be a promising and conveniently prepared alternative to existing carrier systems for drug delivery [108]. Thus, nanogels seem to be potential candidate in the development of new nanocarriers for anti-cancer drug delivery. So they can be further investigated for treating gynecological cancers. Despite considerable research in the past decades and plethora of positive results in the preclinical studies, the clinical translation of pH-sensitive nanosystems assisted drug delivery platforms has not progressed incrementally. Some of the facts which appear to be obstacles, seem to hinder the progress are: (i) The differences in pH between normal and tumor tissues are not significant enough for generating the pH-responsiveness. Moreover, pH-sensitive nanoparticles remain non-responsive in the perivascular region because the acidic pH need for responsiveness is found in region far from the blood vessels [29]. (ii) In addition, selecting a polymer with a critical pH that matches the desired pH range for its application is a major factor in designing an ideal pH-sensitive system. Thus, understanding the chemical structure of the polymer’s ionizable moieties, indispensable appropriate and for their the respective design pH-sensitive and DDS pKa synthesis [109]. are of Moreover, attempts have been made to alleviate much concerned cytotoxicity of synthesized NPs by conjugating it with PEG or with any of the zwitterionic polybetaines [110-114]. Further studies are still on to nullify its cytotoxicity, if any. Considering all these, it becomes utmost important nanotechnological to advancement understand in the biomedical applications to date and the challenges that still need to be overcome. That will allow future research to improve on existing pH-sensitive nanoplatforms and to address the current translational and regulatory limitations. Continued translational success will require coordinated communication and collaboration between experts involved in all stages of pharmaceutical development of pH-sensitive drug pharmaceutical delivery design, nanosystems, including manufacturing, cellular interactions and toxicology, as well as preclinical and clinical evaluation. In other elsewhere all of the pH-responsive [50, 107, aforementioned nanosystems 115-117], the and reported conventional nano-carriers have been combined with pH-responsive systems that release drug content only under specific acidic pH. Table 1 summarises all of the pH-sensitive nanosystems reviewed in the present text having www.openaccesspub.org | JWRH CC-license DOI : 10.14302/issn.2381-862X.jwrh-19-3143 Vol-2 Issue 2 Pg. no.- 43 Freely Available Online Table 1. pH-Responsive Nanosystems utilized in gynaecological Cancer treatment potential utilities in treating gynaecological Cancers. of active compounds: concepts and applications. 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