Recent advances in the redox-responsive drug delivery nanoplatforms: a chemical structure and physical property perspective

Abstract

Poor water solubility, off-target toxicity, and small therapeutic window are among major obstacles for the development of drug products. Redox-responsive drug delivery nanoplatforms not only overcome the delivery and pharmacokinetic pitfalls observed in conventional drug delivery, but also leverage the site-specific delivery properties. Cleavable diselenide and disulfide bonds in the presence of elevated reactive oxygen species (ROS) and glutathione concentration are among widely used stimuli-responsive bonds to design nanocarriers. This review covers a wide range of redox-responsive chemical structures and their properties for designing nanoparticles aiming controlled loading, delivery, and release of hydrophobic anticancer drugs at tumor site.

1. Introduction

One of the major obstacles for the development of new drug products is poor water solubility. Hydrophobic drugs are involved with poor absorption or permeation power that is described by Lipinski's rule of five in developing drug discovery (1). Difficulty of formulation, limited bioavailability, and unfeasibility of rout of administration are among other issues correlated with high hydrophobicity of drug (2). Important anticancer drugs such as Doxorubicin, Paclitaxel, Docetaxel, Camptothecine and Vinblastine are amongst highly hydrophobic drugs, limiting their clinical application due to nonspecific biodistribution, rapid metabolism, clearance, and drug resistance (3–5). Advances in nanoparticle (NP) design as a drug carrier has attracted tremendous attention during last two decade (6). Capability of drug delivery systems has been enhanced through nanoparticle technology for delivery of hydrophobic drugs, for which pharmacokinetic and pharmacodynamics are subject to improvement (4, 7).

Several strategies for preparation of nanoparticle such as conjugation to synthetic polymer or biopolymer have been performed to overcome the limitation of hydrophobic drug delivery (8, 9). In general, physicochemical and biological advantages of utilizing nanomedicine is biocompatibility, targeted delivery, site-specific stimuli responsive delivery, superior pharmacokinetic performance, and drug solubilization (10). Liposomes, polymeric micelles (PMs), dendrimers (11) and nanogels (12) are classified as organic nanoparticles, while silica (13, 14), gold, carbon, magnetic nanoparticles (15), and quantum dots (16) are considered inorganic nanoparticles (17). Hybrid nanoparticle constructed formed by at least two chemically differentiated nanostructures has also attracted attention in recent years as theranostics (18).

One important class of nanoparticles under investigation for anticancer drug delivery is stimuli-sensitive carriers (19, 20). Sustain release and site-specific drug delivery prevents premature drug release which in turn reduces toxicity to healthy tissue. Demand for controlled drug release fuelled the dynamic growth of stimuli-responsive nanoparticles (17, 21, 22). This idea is related to the fact that the tumor cells possess a variety of unique features compared with the normal cells including specific pH, redox potential, overexpressed proteins, and enzymes. It has been proved that tumor tissues contain acidic pH, high levels of glutathione (GSH) in the cytoplasm, overexpressed specific enzymes or receptors and higher temperature in the tumor tissues compared with the normal tissues (23, 24).

Redox-responsive agents such as diselenide bond (-SeSe-), disulfide bond (-S-S-), platin conjugation (–Pt-), thioether bond (-S-) and thiol group (-SH) are frequently used in drug delivery systems for targeting the redox responsive sites (1, 25, 26). Hydrophobic drugs can be loaded into the nanoparticles internal core, pores, or chemically conjugated onto nanoparticles surface with the redox-sensitive linkage (19). The chemical structure of nanocarriers could also harbor redox-sensitive linkage which allows the nanoplatform to have stimuli-responsive controlled release of drug at site on interest. Electrostatic interaction between positive charge carrier and negative charge gene or drug is an alternative important approach specially in gene delivery system (8). Herein, we briefly review redox-sensitive chemical moieties, classification of redox-responsive nanoplatforms, current status of responsive nanoparticle drug delivery, potential pros and cons of each class of nanocarriers, and finally identify remaining gaps and propose future directions for this area of research.

2. Redox-sensitive bonds

Diselenide bond (-Se-Se-) has high sensitivity to low concentrations of the oxidative agents. Higher sensitivity to cleavage of the Se bonds, is mainly due to weaker bond energy of the -Se- and -Se-Se- bonds compared to the -S -and S-S bonds (27–29). Se bonds are usually used as cross-linking agents and in diblock copolymers for which Se bonds are located in between hydrophilic and hydrophobic segments. Responsiveness of Se bonds to low concentration of redox environment is utilized in the form of smart drug delivery systems as Se atoms also shows anticancer properties (30, 31).

Over the last few decades, platinum-based anticancer drugs are used in the treatment of various types of tumors (32). Pt(II) and Pt(IV) square planar and octahedral complexes have been developed as a prodrugs. Platinum-based anticancer property is based on coordinate bonds formation between reactive complexes of platinum with DNA bases. Pt (IV) derivatives have been utilized in the preparation of redox-sensitive smart drug delivery system. Platinum (IV) based prodrugs are known to have low toxicity compared to Pt(II) Cisplatin. Reduction of Pt (IV) derivatives is used to release Cisplatin in redox-sensitive drugs carriers (33).

Disulfide bond can be used as a redox-responsive linkage, which in the presence of reducing agent could be reduced to thiol group. Thioether bond in the other hand oxidized to a hydrophilic sulfoxide or sulphone in the presence of an oxidizing agent. While thioether moieties are responsive to oxidation, disulfide bonds are cleavable not only by reducing agents, but also by oxidizing agents (34). Many redox-sensitive linkers containing disulfide have been developed for construct drug delivery carriers (Table1).

Table 1.

Chemical structure of redox-sensitive linkers containing disulfide

3. Redox-sensitive nanocarrier classification

Incorporation of redox-responsive chemical linker in the context of nanoparticle structure endow added value of controlled degradation and drug release. Several class of nanoparticles such as liposomal NPs, inorganic NPs, polymeric micelle NPs, nanogels, and polyplex NPs modified by redox-sensitive bonds. Table 2 shows classification of redox-sensitive nanoplatforms. Although liposome nanocarriers are the first nanoplatforms approved by FDA as drug delivery system, polymeric micelles NPs are the one mostly utilizing redox-responsive properties due to flexibility of preparation methods (35–38). Herein, we briefly review redox-responsive inorganic NPs, and focus largely on reviewing synthetic polymers and biopolymers used for polymeric micelles synthesis.

Table 2.

Classification of redox-sensitive nanoplatforms

Nanocarrier	Chemical backbone structure	Ref
Liposomal nanoparticles	Disulfide conjugates of PEG and phospholipids	(39–46)
Polymeric micelles	Synthetic polymers: Hydrophobic: polyester (PCL, PGA, PLA, PLGA) Hydrophilic: polyether, polyamide (PEG, PNIPAM) Biopolymers: Polysaccharide: Hyaluronic acid, Chitosan, Heparin, and Chondroitin sulfate	(1, 25, 31, 47–61)
Polyplex nanoparticles	Cationic polyamine (PEI)	(11, 62–66)
Inorganic nanoparticles (macromolecule structure of inorganic elements such as Si, Mn, Fe, Au, Ag)	Functionalized by organic groups and polymer such as OH, COOH, PEG, PLGA, PEI Functionalized by polysaccharide (cyclodextrin, Hyaluronic acid) and peptide	(67–82)
Nanogels/Hydrogel	Synthetic polymers: Polyether, polyamide (PEG, PNIPAM) Biopolymers: Polysaccharide, Hyaluronic acid	(21, 32, 57, 83, 84)

3.1. Liposomal nanoparticles:

Liposomes are composed of phospholipids and one of first type of nanoparticle candidates used as drug delivery systems in clinical application. Liposomes exhibited high efficiency in encapsulation of both hydrophobic and hydrophilic drugs. Redox-sensitive liposomes could allow controlled drug delivery to the cancer cells in response to the presence of redox environment typical for tumors. The 3^rd generation of liposomal nanoparticles use the phospholipase-triggered redox initiated drug release systems with disulfide conjugates of PEG and phospholipids (39, 40). Behroozi et al. have been successfully built an antioxidant delivery system based on redox-sensitive liposomes containing a diselenide bonds. N-acetyl cysteine (NAC), which can protect retinal pigment, was loaded in the liposome nanoparticles and examined on stem cell-derived retinal pigment epithelial (hESC-RPE) cells. The nanoparticles released drug in response oxidative stress as an antioxidant agent with consuming hydrogen peroxide. The smart design of liposomes can be used for targeted treatment of retinal degeneration (41).

3.2. Polymeric micelles (PMs) nanoparticles:

Polymeric micelles nanoparticles are commonly composed of amphiphilic copolymers that contain definite hydrophobic and hydrophilic units. The amphiphilic copolymers self-assembly properties and high loading capacity lead to design and application of wide varieties of polymeric micelles nanoparticles (85). Hydrophobic parts of amphiphilic copolymers chain self-assemble into a core that is surrounded by the hydrophilic part as an outer shell in aqueous solutions, contribute to creating a well-designed drug loading carrier. Optimized size of polymeric micelles nanoparticles prevents quick clearance from circulation and excretion from body, resulting in drug accumulation via extensively reported enhanced permeability and retention (EPR) effect. To employ the active targeting, polymeric micelles nanoparticles could be modified by targeting agents on their surface to enhance tumor selectivity and reduce adverse side effects (86).

Synthetic polymer and biopolymer are used to prepare PMs. Polyester, polyether, polyamine and polyamide classified as synthetic polymer and polysaccharides, polypeptide, polynucleotide known as biopolymers are widely used in polymeric micelles nanoparticles synthesis. Synthetic polymers enable flexibility in designing new polymeric micelles nanoparticles given their structure variability, while biopolymers are superior in well-defined structure. Biopolymer could be considered more biocompatible compared to synthetic polymers due to less contamination with possible side products. Biopolymers and synthetic polymers can be linked with redox-sensitive bonds to form redox-sensitive nanoparticles which utilize benefits of both type of polymers (87, 88).

3.2.1. Synthetic polymer:

Synthetic polyester polymers are classified as hydrophobic polymers (89). In spite of existence of polar hydrophilic ester bonds in the main backbone of polymer, that enables hydrogen bond formation, polyesters are not water soluble. The hydrophobicity of polyesters polymers is due to hydrophobic alkyl or phenyl groups in the structure. Most of the aliphatic polyesters are biodegradable and biocompatible polymers with widespread biomedical applications. The FDA approved application of several polyester such as of polycaprolactone (PCL), poly(glycolic acid) (PGA), poly(l-lactic acid) (PLA), and poly(lactic-co-glycolic acid) (PLGA) for clinical application. Hydrophilic and hydrophobic polymers can be attached by a redox linker to form amphiphilic copolymers, able to self-assembly in aqueous medium and encapsulating hydrophobic drugs in their core as a drug redox-responsive drug delivery system. Polyethylene glycol (PEG) and its derivatives are FDA approved biocompatible hydrophilic polyether polymer (47). It is known that the amphiphilic copolymers can self-assemble into micelles at concentrations higher than the critical micelle concentration (CMC) in an aqueous medium. Figure 1 summarize different approaches and chemical structures used to date to synthesize redox-responsive self-assemble polymeric micelles using polyester, polyether, polyamide synthetic block co-polymers and lipids for encapsulating hydrophobic drug, targeting tumor site release. Herein, handful of examples are depicted to review the current literature progress, mindset in the field, and classify chemical structures. Table 3 summarized synthetic polymers recently used for fabrication of redox-responsive polymeric micelles nanoparticles.

Fig 1.

A) The PEG-SeSe-PCL-SeSe-PEG-FA triblock copolymer micelle for PTX targeted delivery. B) Pt(IV) prodrug coated by amphiphilic lipid-PEG for of Pt(IV) NPs formation exhibited improvement in pharmacokinetics properties for Cisplatin (1). C) Dox-loaded EPR-SS-TPGS-B6 exhibited significant synergistic antitumor effect. D) A hydrophobic PLGA conjugated to hydrophilic PEG via disulfide bonds was linked with adamantane forming star shaped copolymer. E) The structure of DSPE- PEG. F) The mixture of Cys-8E polymer, and DSPE- PEG self-assembled into redox-sensitive micelle. The hydrophobic lapatinib (SMA) was loaded into the internal core of the micelle. G) Mixture of curcumin-SS-vitaminE and PEG-DSPE which self-assembled into nanoparticles, has shown remarkable antitumor activity. H) Cabazitaxel (CTX) and oleic acid (OA) and thioether-/selenoether linkers as CTX-S-OA or CTX-Se-OA self-assembled into particles in the presence of pyropheophorbide a (PPa), and were modified with amphiphilic DSPE-PEG. I) A copolymer of hydrophilic polyethylene glycol and hydrophobic polypropylene sulfide containing thioether moiety has used as micelle. J) Hydrophilic pNIPA and hydrophobic PTX have been conjugated through diselenide linkages. PTX loading into the hydrophobic core of the micelles has been enhanced.

Table 3.

Redox-responsive synthetic polymers classification used for polymeric micelles nanoparticles synthesis

polymers	copolymer	hydrophilic	hydrophobic	ref
Polyether/polyester	PEG-SeSe-PCL-SeSe-PEG-FA	poly(ethylene glycol)	poly(εcaprolactone)	(49)
lipid-polyether	L-PEG/ Pt(IV) prodrug	poly(ethylene glycol)	Pt(IV) prodrug /lipid	(1)
lipid-polyether	L-PEG/ Pt(IV) prodrug	poly(ethylene glycol)	Pt(IV) prodrug /lipid	(33)
Polyether/polyester	PCL-SS-PEG-FA	poly(ethylene glycol)	poly(εcaprolactone)	(25)
TPGS	EPR-SS-TPGS-Vitamin -B6/DOX	poly(ethylene glycol) Vitamin -B6	EPR /Vitamin E	(50)
Polyether/polyester	(AD-[P(LA-co-GA)-SS-mPEG]4)/DOX	poly(ethylene glycol	poly(lactic-co-glycolic acid	(51)
cys-8E polymer /Polyether/lipid	cys-8E polymer / DSPE- PEG3k/ lapatinib	polyethylene glycol	cys-8E polymer, 1,2-Distearoylphosphatidylethanolamine	(52)
Polyether/lipid	curcumin-SS-vitaminE /mPEG2k-DSPE	Poly ethylene glycol	vitaminE, 1,2-Distearoylphosphatidylethanolamine	(53)
Polyamide	PNIPAM -SeSe-PTX	Poly(N-isopropylacrylamide)	PTX	(92)
Polyether/ Polythioether/	PEG-PPS	polyethylene glycol	polypropylene sulphide	(91)
Polyether/lipid	CTX-S-OA/ DSPE- PEG	polyethylene glycol	oleic acid, 1,2-Distearoylphosphatidylethanolamine /oleic acid	(90)

Wei and coworkers obtained nanoparticles containing diselenide bonds and hydrophilic PEG chains (22). A biodegradable nanoparticles possessing diselenide bonds bearing poly(ester urethane) and poly (ε-caprolactone) provided an enhanced efficacy of drug release in cancer cells (48). The redox-sensitive polymeric micelle containing diselenide bonds using triblock copolymer poly(ε-caprolactone)-bis(diselenide-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate), (PEG-SeSe-PCL-SeSe-PEG-FA ) were used for targeted delivery of the hydrophobic Paclitaxel (PTX) anticancer drug (Figure 1-A). Poorly water-soluble PTX could be successfully loaded into the hydrophobic core of the polymeric micelles. PEG was used as a hydrophilic external shell of particles responsible for high stability and preventing rapid clearance of particles from the body. Micelles were modified with folic acid to target cancer cells overexpressing folate receptors. Overexpressing of folate receptor of cancer cells led to higher selectivity of micelles against cancer. Micelles showed enhanced release of drug to 4T1 breast cancer cells. Breaking the diselenide bonds in the presence of high ROS content, induced disassembly of the PTX-loaded micelles and drug release in tumor tissue (49).

Ling et al. engineered a redox-responsive system based on Pt(IV) nanoparticles for Pt(II) delivery. Nanoparticles were composed of hydrophobic Pt(IV) prodrug coated by amphiphilic lipid-PEG which self-assembled to Pt(IV) nanoparticle (Figure1-B). Upon reduction by GSH, NPs degraded and released active Pt(II) metabolites. Owing stealth properties utilizing PEGylation of Pt(IV) NPs, improved pharmacokinetics properties such as longer blood circulation and higher uptake by tumor cells were observed. More importantly, GSH reduction of Pt(IV) NPs resulted in covalent binds with Pt(II) centers. The GSH-exhausting process prevented detoxification of Pt chemotherapeutics by free GSH in cells, resulting in construction of stable Pt-DNA adducts, inducing apoptosis, and improving inhibition of cisplatin resistance in the cancer cells (1). Furthermore, pH and redox responsive polymeric prodrug were formed by octahedrally coordinated cisplatin (Pt IV) by ortho ester monomer using condensation polymerization. The prodrug could self-assemble into micelles in the presence of Doxorubicin (DOX) aqueous solution for the combination drug delivery. The micelles degraded and release cisplatin (Pt II) and DOX in low pH and redox environment of cancer cells. The low pH stimuli led to hydrolysis of ortho ester bonds, while redox environment led to reduction of Pt (IV) to cisplatin. Synergistic antitumor combination therapy by polymer micelle nanoparticles is promising avenue for suppressing tumor growth (33). Redox-sensitive micelles containing disulfide bonds and modified with targeting agents are synthesized and examined. Shi et al. developed four-arm PCL-PEG copolymer in which hydrophobic PCL was conjugated to hydrophilic PEG via a disulfide bond. The star-shaped micelles exhibited desirable targeting effect by folate (FA) ligands at the end of PEG chains. The disulfide bonds were degraded in response to the high level of GSH in the cancer cells, resulting in quick DOX release (25).

To increase the stability of drug delivery systems and preventing premature drug release by leaky polymer micelles, covalently conjugated hydrophobic drugs to polymer chain are explored. Co-delivery of Epalrestat (EP) and DOX to obtain combination therapy is assessed in redox-responsive polymer micelles. Epalrestat is an inhibitor of aldose reductase with potential application in cancer treatment. However, EP is highly hydrophobic and exhibits short half-life. The EP were conjugated to tocopherol polyethylene glycols (TPGS) using -S-S- bonds and further modified with water soluble vitamin-B6, to target cancer cells. The self-assembled micellar prodrug EPR-SS-TPGS-B6 was obtained and was loaded with chemotherapeutic DOX (Figure 1-C). Dox-loaded EPR-SS-TPGS-B6 exhibited significant synergistic antitumor effect in breast cancer cells and confirmed higher efficacy using co-delivery of redox-responsive covalently attached drug to polymer chains of polymer micelle nanoparticles (50). The hydrophobic PLGA conjugated to hydrophilic PEG via disulfide bonds linked to adamantane formed star shape enzymatically degradable copolymer structure (Figure 1-D) to self-assemble to polymer micelle for loading DOX (51). Wang and coworkers reported hydrophobic cysteine-based poly (disulfide amide) polymer for delivery of small-molecule agents (SMA) – lapatinib. SMs exhibit poor solubility, low bioavailability, and various side effects therefore they need to be loaded into carrier. DSPE-PEG (Figure 1-E) stabilize the nanoparticles, by surrounding the polymeric core with lipids monolayer and significantly protect the NPs from clearing by the reticulo endothelial system. The mixture of Cys-8E polymer, containing derivative of cystine, and DSPE- PEG self-assembled into redox-sensitive nanoparticles (Figure 1-F). In such way hydrophobic lapatinib was loaded into the core of the micelle (52). Figure 1-G depicts curcumin-SS-vitaminE and PEG-DSPE which self-assembled into nanoparticles (53). ROS-triggered prodrug nanoplatform for synergistic chemo-photodynamic therapy in Figure 1-H fabricated by cabazitaxel (CTX), oleic acid (OA), and thioether-/selenoether linkers. CTX-S-OA or CTX-Se-OA was able to self-assemble into nanoparticles in the presence of pyropheophorbide a (PPa) for combination therapy. CTX was released not only by overproduced ROS in tumor tissue, but also by PPa-generated ROS via laser irradiation (90). The thioether (-S-) and disulfide (-S-S-) bonds are often used as a redox-sensitive factor. The thioether bonds are responsive to ROS, while disulfide (-S-S-) bonds are sensitive to both ROS and GSH. Novel copolymer (PEG-PPS) bearing andrographolide for treatment of atherosclerosis as drug delivery system were studied. The drug-andrographolide, exhibits great anti-inflammatory activity. A copolymer of polyethylene glycol and hydrophobic polypropylene sulfide containing thioether moiety exhibited self- assembling in the presence of andrographolide and had formed micelles (Figure 1-I) (91). The amphiphilic Se-containing copolymers are extensively used for fabrication of redox-responsive nanoplatforms. Take for instance, hydrophilic pNIPA and hydrophobic PTX have been conjugated through diselenide linkages (Figure 1-J) formed pNIPA-based micelles (pNIPA-SeSe-PTX) as a drug release carrier. The π–π stacking interactions, between PTX and PTX (drug-drug), enhanced the PTX loading into the hydrophobic core of the micelles during self-assembly process. The high encapsulation efficiency has been obtained and the release of PTX was controlled by temperature and redox-agents (GSH, H₂O₂) (92).

The PCL, PGA, PLA and PLGA biodegradability property increased the interest in exploring this type of nanocarriers for controlled drug delivery. Biodegradation process is related to hydrolysis of ester group in the polymer structures that lead to drug release and diffusion. However, the biodegradation rate is inconstant in different organs and tissue which results in uncontrolled release rate. In addition, hydrophobic drug is mainly encapsulated in internal core of nanocarrier and drug release profile could be influenced by covalent or non-covalent interactions between polymer and drug. Incomplete drug release or premature release by disintegration of nanoparticle could result in off target drug delivery. Incorporation of redox-sensitive linkers in the structure of polymer backbone gives an additional edge for engineered controlled drug release.

3.2.2. Biopolymer:

Hyaluronic acid (HA), dextran, chitosan, heparin, and chondroitin sulfate derivatives are polysaccharide biopolymers, which were extensively used in the drug delivery systems (54, 55). Hyaluronic acid is hydrophilic glycosaminoglycans with disaccharide units and exhibits targeting effect as ligand for CD44 receptors (Figure 2-A) (56). Redox-sensitive polymer micelles synthesized by hydrophilic hyaluronic acid attached to hydrophobic curcumin via disulfide linker (HA-SS-CUR) used for gliomas targeting. Tween 80 was used for improved brain penetration (Figure 2-B)(93, 94). Stimuli-sensitive nanocarriers designed by HA conjugates to PLA with a disulfide bonds (HA-SS-PLA) were synthesized incorporating D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and PTX for combination therapy (Figure 2-C)(95). Further studies investigated for combination therapy and site targeting by vitamin E-based redox-sensitive salinomycin (SAL) prodrug nanoparticles synthesized by HA for delivery of paclitaxel. Salinomycin was used as an inhibitor for cancer stem cells (CSCs), while glutathione-triggered release of both SAL and PTX was effective initiating synergistic effect for anti-CSCs treatment in cancer tissue. Moreover, the cellular targeting and uptake efficiency was enhanced through targeting of HA into CD44 receptors (Figure 2-D) (96). Anti-osteosarcoma (OS) effect has been investigated by a novel strategy through OS-targeting liposome. Alendronate (ALN) conjugated with hyaluronic acid (HA) was coupled with DSPE-PEG by disulfide linker to gain a functionalized lipid. In the next step liposome loaded with DOX was organized for combination therapy. ALN-HA-SS-L-L/DOX showed significant cellular uptake alongside high cytotoxicity in human OS MG-63 cells. Tumor suppression effect and extend survival time in the body have been obtained by orthotopic OS nude mouse via the OS-targeting liposome. Moreover, this smart drug delivery system has been enhanced by co-administration of iRGD (internalizing-RGD) which is known as a tumor-penetrating peptide (58). The hydrophilic HA attached to stearic acid (SA) has been reported in the new smart drug delivery system to form micelle by using redox-sensitive linker, HA-SS-SA, (HCS). SA is 18-carbon saturated fatty acid which acts as hydrophobic part. DOX-loaded HCS (HCSD) has exhibited rapid release in the presence of GSH. In vivo study represented that response of HCT116-xenografted tumor was more significant than the CT26-xenografted tumor (97). An echinus-like micelle containing glycyrrhetic acid (GA) and oligomeric hyaluronic (HA) was engineered for targeting and treatment of HepG2 human liver cancer cells, with GA-HA-SS-Cur structure. The mPEG-DSPE facilitates self-assemble of structure into echin-like micelles (59). The fabrication of Arginine based poly(ester amide)s connected to hyaluronic acid (HA) by disulfide linker (ArgPEA-SS-HA) was reported as biodegradable and redox-sensitive nanocomplex for the co-delivery of photosensitizers AlPcS2a (aluminum phthalocyanine disulfonate) and DOX therapeutic agents. The light-induced endosomal escape and cytosolic release of DOX by AlPCs2a conjugate, enabled the consistent and preferential in vivo accumulation of nanocomplex in MDA-MB-231breast cancer cells( Figure 2-E) (98).

Fig 2.

A) Hyaluronic acid structure. B) Hydrophilic hyaluronic acid was attached to hydrophobic curcumin via disulfide linker (HA-SS-CUR). Tween 80 was used for better brain penetration. C) Hyaluronic acid conjugated to PLA with a disulfide bonds (HA-SS-PLA) was mixed with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). D) α-tocopheryl succinate (TOS) (vitamin E derivative) was attached to SAL(salinomycin) as TOS-SS-SAL (TS). Hyaluronic acid (HA) coated TS NPs. E) Arginine based poly(ester amide) was conjugated to HA by disulfide bonds (ArgPEA-SS-HA) for co-delivery of photosensitizers AlPcS2a and DOX. F) Chitosan was conjugated to hydrophobic octylamine (OA) using disulfide bond (CS-SS-OA) then hydrophobic GA was loaded into the inner core of the micelle. G) FMSN-SS-PNA (Cy5) Fluorescent mesoporous silica nanoparticle was used for cell permeability of antisense peptide nucleic acid (PNA). H) Modification of CD cage with an azobenzene/galactose-grafted polymer (GAP) after preparation DOX@MSN-SS-CD nanoparticles.

Similar results were shown for HA, chitosan and heparan sulfate confirming self-assembly, increased loading efficacy of hydrophobic drugs, controlled redox-responsive release of active agent from nanoparticles and enhanced anti-tumor activity (Table 5). Redox-sensitive chitosan-based copolymers, in which hydrophilic hydroxyl ethyl chitosan (HECS) was conjugated to hydrophobic octylamine (OA) by disulfide bonds self-assembled to polymer micelles in the presence of gambogic acid. The outer shell of the nanoparticle was coated by hydrophilic HA for CD44-mediated targeting potency. HA(HECS-SS-OA)/GA as a drug delivery system have shown desirable results such as targeting and drug release options (Figure 2-F) (57). Cancer cells are known to produce higher ROS concentrations during the advanced stages. Methoxy poly(ethylene glycol)-grafted chitosan (Chito-SeSe-PEG) was prepared using diselenide linkages for delivery of piperlongumine (PL) to target pulmonary metastasis of cancer cells. PL (a natural alkaloid) was loaded into the ROS-sensitive core of the nanoparticles. The release of PL was increased in the presence of H₂O₂ and under acidic conditions. The anticancer activity of this PL NPs were also evaluated in an in vitro model using A549 lung carcinoma cells and CT26 colorectal carcinoma cells that could be effectively targeted to metastatic cancer cells (83). Chitosan-based copolymer bearing hydrophobic retinoic acid conjugated by a disulfide bond (CS-SS-RA) could self-assemble in the water in the presence of hydrophobic PTX to redox-sensitive micelles. Cytotoxicity and inhibition studies have displayed that PTX-loaded CS-SS-RA micelles represented considerable antitumor activity in HepG2 cells (60). A novel redox-sensitive heparin sulfate-based (HS) nanoparticle containing hydrophobic vitamin E succinate (insoluble in water) connected to HS via disulfide bond (HS-SS-VES, HSV) was self-assemble to micelles by doxorubicin (DOX). The therapeutic efficacy of DOX/HSV micelle has been tested and notable cytotoxicity has been proven in MCF7 cancer cells (99). In addition, redox-sensitive nanoparticle composed of low molecular weight heparin (LMWH) was studied, aiming for antitumor and anti-metastasis efficacy. Hydrophilic LMWH forms covalent bonds with two hydrophobic agents, cholesterol (Chol) and lipoic acid (LA) derivatives (containing –S-S- bond), for delivery of doxorubicin DOX. The chemical modifications of carboxyl groups on LMWH by Chol and LA have diminished bleeding risk related to heparin (100, 101).

Table 5.

Cationic polyamine-based redox-sensitive nanoparticle for gene delivery system.

nanoparticle	polyamine	delivery system
BPEI-SS-PEG-cNGR	branched polyethylenimine	gene delivery	(63)
DAB-PEG-SS-Chol	diaminobutyric polypropylenimine	gene transfection	(108)
RVG-PEG-SS-BPEI /DNA	branched polyethyleneimine	oligonucleotides	(107)
PEG-SS-PEI-PE	polyethyleneimine	siRNA	(64)
PEG-PGAH-PEI	polyethyleneimine	P-glycoprotein-siRNA	(110)
LLO-SS- PEI	Polyethylenimine25	anionic DNA	(111)
PEI-SS-PEI/DNA	polyethyleneimine	anionic DNA	(112)
PEI-SS-GSP (Mn3O4) and (Fe3O4)/DOX-interlocated shRNA /hyaluronic acid.	polyethyleneimine	DOX-interlocated shRNA	(70)
MNP-SS-PEI/β-CD@CAMP	polyethyleneimine	camptothecin (CAMP)	(117)
(Ag/NGO-PEI-SS-DOX).	polyethyleneimine	DOX-delivery	(67)

Mesoporous silica nanoparticles (MSNs) with high biocompatibility, high surface areas, and abundant Si-OH groups on the surfaces provides a proper platform for redox-responsive drug delivery system (71, 72, 102). Yan-Li Zhao et al. reported MSN potentials to overcome inadequate cell permeability of antisense peptide nucleic acid (PNA) by increased endocytosis of nanoparticles by cancer cells (Figure 2-G) (69). Cyclodextrins (CD), which is a class of cyclic oligosaccharides has been utilized as a multistimuli-responsive drug delivery system (35). MSN loaded with DOX conjugated to β-CD via disulfide bond (DOX@MSN-SS-CD) was investigated as internal and external-stimuli responsive structures. Targeting ability of these nanoparticles was provided by modification of MSN surface with an azobenzene/galactose-grafted polymer. DOX loaded into MSN were released not only by glutathione, but also by UV-irradiation dissociation of azobenzene moieties from β-CD cage. This light/redox-sensitive system revealed increased cytotoxicity and decreased drug-resistance phenomenon (Figure 2-H) (103–105).

3.3. Polyplex nanoparticles:

Polyamidoamine (PAMAM) dendrimer and polyethylenimine (PEI) are among well studies polyamines and polyamides (11). Polyethylenimine (PEI) is a positively charged hydrophilic polyamine, mainly used in gene delivery. Linear PEIs contain secondary amines, while branched PEIs contain primary, secondary and tertiary amino groups. These cationic polymers are commonly utilized for gene transfection process mediated by electrostatic interactions between the negatively charge DNA and the positive charge of polymers that have been pursued via in vitro and in vivo experiments in various cell lines and tissues. It is known that the cytotoxicity of PEI is related to the destabilization of the cell membrane, leading to cell death (62). Poly-cationic structure of PEI is capable of forming stable polyplex with anionic nucleic acids, which limits nucleic acids release in the target site and result in poor gene delivery process. Therefore, modification in the structure of PEI is required to reduce toxicity and poor release rate of PEI polyplex. The PEI were modified with a hydrophilic polymer such as PEG to reduce toxic effects by decreasing interaction between cationic PEI and cells. Incorporation of redox-sensitive linkers in the structure of PEI is an alternative way to fabricate biodegradable PEI derivatives with controlled release rate in target site (106).

Disulfide-crosslinked branched polyethyleneimine(BPEI-SS) used for gene delivery system owing PEG and cNGR as hydrophilic and targeted delivery agent (BPEI-SS-PEG-cNGR) ( Figure 3-A) (63). Disulfide-crosslinked branched PEI (-S-S-BPEI) producing biodegradable polyplexes as RVG-PEG-SS-BPEI /DNA was used for efficient intracellular release of the DNA (107). The polyplexe were stable in the extracellular environment, responsive to intracellular GSH, engaging disulfide bonds cleavage, and responsive to redox disintegration to release DNA.

Fig 3.

A) Disulfide-crosslinked branched polyethyleneimine(BPEI-SS) as redox-sensitive gene delivery system (BPEI-SS-PEG-cNGR). B) siRNA delivery via triblock copolymer : Hydrophilic polyethylene glycol as shielding group, cationic polyethyleneimine and hydrophobic phosphatidylethanolamine. C) PEGylated dendrimers (diaminobutyric polypropylenimine) were connected to cholesterol via disulfide linkages. D) Hydrophobic polymers form internal core for loading of hydrophobic anticancer drug, while cationic polymers form outer shell for anionic DNA and RN. E) disulfide-crosslinked PEI vector bearing GSP (Mn3O4) and (Fe3O4) and DOX-intercalated shRNA was coated with hyaluronic acid. F) Grafted-β-cyclodextrin polyethylenimine (PEI/β-CD) with cleavable disulfide linkers onto magnetic nanoparticles. MNP -SS-PEI/β-CD. G) Ag-connected nanographene oxide modified by PEI which connected to DOX via disulfide bonds (Ag/NGO-PEI-SS-DOX). H) GO/PP-SS-DOX/PEG-FA in which graphene oxide was modified by PEG-PLGA (PP) conjugated to DOX via disulfide bond.

Modified redox-responsive PEI is used for small interfering RNA (siRNA) deliver. Figure 3-B shows delivery of siRNA using triblock copolymer PEG-SS-PEI-PEm. Polyethylene glycol as hydrophilic moiety and shielding group, polyethyleneimine as cationic block, and phosphatidylethanolamine as a hydrophobic segment are connected via a disulfide bond. Small interfering RNA (siRNA) were condensed in polyethyleneimine block and successfully transferred to targeted cells (64).

Dendrimers based on diaminobutyric polypropylenimine were used in construction of redox-sensitive systems for gene delivery. PEGylated dendrimers connected to cholesterol via disulfide linkages forming self-assembly dendrimersome. Cholesterol promote the stability of the nanostructures and facilitate particles uptake through cell membrane (Figure 3-C)(108).

Modulation of multidrug resistance phenomena mediated by P-glycoprotein (P-gp) and siRNA is an attractive and complicated subject in chemotherapy issue (66, 109). Xu et al. developed novel targeted co-delivery of DOX and P-glycoprotein (P-gp) siRNA into breast cancer cells (MCF- 7/ADR cells) by means of a redox-sensitive triblock copolymer (PEG-SS-PGAH-SS-PEI). The copolymer composed of poly(ethylene glycol), poly (L-glutamic acid γ-hydrazide) and polyethyleneimine were attached by cleavable disulfide bonds. DOX molecules have been conjugated to PGAH blocks via hydrazone bonds, while siRNA was bonded to the PEI blocks through electrostatic interactions. A tumor-targeting agent, folic acid (FA), was attached to the distal ends of the PEG blocks to specifically bind to the folate receptors overexpressed in MCF-7/ADR cells. Triblock copolymer exhibited low cytotoxicity, inhibited cell proliferation and induced apoptosis in MCF-7/ADR cells through P-gp-siRNA (110). Another redox-sensitive gene delivery system based on average molecular weight polyethyleneimine (PEI) was designed by Choi and Lee. The protein listeriolysin O (LLO) from the intracellular pathogen Listeria monocytogenes was conjugated with cationic PEI through disulfide linkage (LLO-SS- PEI), and incorporated into anionic plasmid DNA. Reduced cytotoxicity and improved gene transfection have been obtained by this approach (111). Sun et al. obtained novel redox-responsive, binary (PEI-SS-PEI)/DNA complexes for increasing transfection efficiency. Complexes were prepared by Michael addition reaction between cystamine bisacrylamide and low molecular weight branched PEI. Targeting-ability was achieved by using arginine–glycine–aspartic acid (RGD) peptide noncovalently bonded with gene delivery system(112). In an alternative design of nanoparticles fabricated by PEI, the PEI is used as shell and hydrophobic polymers as core for loading of hydrophobic drugsc(113).

An alkyl modified polyethylenimine (C16-S-S-PEI) with disulfide bond and DOX derivative-loaded PLGA can be self-assembled to produce a novel redox/photo-sensitive nanocarrier. The hydrophobic PLGA polymer coated by cationic PEI were conveying siRNA on surface by stable electrostatic interaction. The dual responsive vehicle were effective for chemotherapy and multidrug resistances. ( Figure 3-D )(114). Table 4 summarize other reported polyamine-based redox-sensitive nanoparticle formulation for gene delivery system.

Table 4.

Summary of polysaccharides biopolymer used for fabrication of redox-responsive delivery systems

Structure	nanocarrier	Biopolymers	Hydrophobic
HA-SS-CUR	Micelle	Hyaluronic acid	CUR	(93, 94)
HA-SS-PLA/ TPGS/PTX	Micelle	Hyaluronic acid	Poly(lactide)/ TPGS/ PTX	(95)
AlPcS2a –PEG- HA-SS- / Arg-PEA/DOX	nanocomplex	Hyaluronic acid/ polyethylene glycol	Arginine based poly(ester amide)	(98)
TOS-SS-SAL/ HA-TOS/pTX	nanoparticles	Hyaluronic acid	TOS	(96)
HCS/DOX	Micelle	Hyaluronic acid	g-stearic acid	(97)
GA-HA-SS-Cur/ DSPE-PEG/CUR	nano-echinus	Hyaluronic acid	glycyrrhetic acid /1,2-Distearoylphosphatidylethanolamine / CUR	(59)
Chito-SeSe-PEG	Nanocomposit	Chitosan		(83)
HA(HECS-SS-OA)/GA	Micelle	Chitosan/ hyaluronic acid	Octylamine/GA	(57)
CS-SS-RA/PTX	Micelle	Chitosan	Retinoic acid/PTX	(60)
HS-SS-VES/DOX	Micelle	Heparan sulfate	Vitamin E succinate/DOX	(99)
Chol -LMWH- LA	nanoparticles	Low molecular weight heparin	Cholesterol / lipoic acid	(100)
CS-R(HA-R)	Micelle	Chondroitin sulfate or hyaluronic acid	Alkane	(101)
ALN-HA-SS-L-L/DOX	Liposomes	Hyaluronic acid/ PEG	Alendronate (ALN) DSPE/ liposome/ DOX	(58)
FMSN-SS-PNA (Cy5)	MSN	peptid	MSN	(69)
DOX@MSN-SS-CD/ azobenzene/galactose	MSN	β- cyclodextrin	MSN /DOX	(103)

3.4. Organic-inorganic hybrid nanoparticles:

Various inorganic nanoparticles have been developed as drug delivery systems exploiting the robust properties, cost effective, physical and chemical stability, simple design, and ease of scalability of this class of nanoparticles. Carbon nanoparticle (graphene oxide and carbon nanotubes) with unique mechanical, thermal, and optical features were used as nanocarriers due to their remarkable surface area and hydrophobic nature (67, 68). Mesoporous silica nanoparticle with high surface density of Si-OH moiety were readily functionalized on the surface and cleavable redox-responsive bonds were introduced within siloxane backbone and were widely used in pharmaceutical formulation (69, 115, 116). Magnetic nanoparticles such as Mn3O4 and Fe3O4 nanoparticle as inorganic materials represented reduce artificial signals and improve the accuracy of magnetic resonance imaging in MRI technic (70). Gold nanoparticles (Au NPs) owing unique electronic, optical, and biochemical attributes have been utilized as theranostics (17). Although inorganic nanoparticles provide a convenient platform for drug delivery application, next generation of redox-responsive nanomaterials are hybrid nanoparticles with improved combined properties of both organic and inorganic nanoconstructs. The higher loading capacity, multistage controlled release profile, and traceability, represents hybrid nanoparticles as a class of nanoparticles with promising potential for stimuli responsive drug delivery systems.

Hybrid nanoparticles composed of disulfide-crosslinked PEI vector bearing GSP (Mn3O4) and (Fe3O4) synthesized and loaded with a DOX-intercalated shRNA as an effective redox-sensitive delivery vehicle. Hyaluronic acid-coated system increased CD44-mediated intracellular uptake. The hybrid nanoparticle demonstrated a dual MRI contrast feature by reducing noise signals and increasing the accuracy of MR imaging (Figure 3-E) (70). Grafted-β-cyclodextrin polyethylenimine (PEI/β-CD) with cleavable disulfide linkers onto magnetic nanoparticles showed remarkable intracellular release of hydrophobic anticancer drug via endosomal escape (Figure 3-F) (117). Carbon nanomaterials such as graphene oxide were functionalized by organic components including hydrophilic PEG, cationic PEI, or hydrophobic PLGA, to enhance physiological solubility and circulation time. The effective release of drugs was obtained by inserting cleavable disulfide bonds in nanographene oxide (NGO) drug delivery system. Yi-Ping Cui’s group reported synthesis and characterization of redox-responsive Ag/NGO-PEI-SS-DOX hybrid nanoparticles with Raman vibration signal traceability properties (Figure 3-G) (67). The nanohybrid GO/PP-SS-DOX/PEG-FA synthesis with PEG-PLGA (PP) conjugation to DOX via redox-sensitive -S-S- bonds were reported by Huang et al. (Figure 3-H) (84).

3.5. Nanogel:

Nanogel-based nanoplatforms have become a promising candidates for efficient redox responsive drug delivery system (118). Nanogels usually composed of cross-linked polymers for which sol–gel process is involved to create solid-like materials from monomers. Nanogel structure is classified to simple, hollow, core-shell, multilayer, etc. Release mechanisms from nanogels network is controlled by swelling, diffusion, and enzymatical and chemical disintegration. Among others, polymerization, physical cross-linking, and chemical cross-linking are important methods for the nanogels preparation (12).The physical cross-links are formed by weaker van der Waals, hydrophobic, electrostatic interactions, or hydrogen bonds. The chemically cross-linked gels are generated by covalent bonds. The physicochemical properties of nanogels are governed by chemical reaction parameters such as reaction temperature, density of cross-linking agent, hydrophilic/ hydrophobic pendants in the polymer structure, surfactant concentration, and moreover the loaded drug interactions with the polymeric network of nanogel (119) (12). The redox-sensitive nanogel are synthesized by placing disulfide linker into the polymeric backbone of network or in-between drug and network. In addition, hybrid nanoparticles integrating inorganic nanoparticles with nanogel platforms were investigated to achieve high stability and avoid premature drug release (120). Gold nanorod (AuNRs) conjugated to HA and cross-linked with cystamine (Cys) for the delivery of DOX studied, for which HA increased cellular uptake efficiency(Figure 4-A) (120). Nanogel based cross-linked hydrophilic polymers such as pNIPA (poly(N-isopropylacrylamide)) containing polyamide structure absorb large level of water and are able to change their volume in response to environmental stimuli such as temperature, redox potential, pH, electric field, ionic strength, and concentration of different individuals (121, 122). Mackiewicz et al. synthesized new temperature, pH and redox-sensitive hydrogel particles as high capacity drug carrier for anticancer treatment. Gel particles were based on hydrophilic pNIPA cross-linked with N,N'-bis(acryloyl)cystine - BISS. The Semi-batch precipitation polymerization formed p(NIPA-BISS) microcapsules. The empty interior of capsules was used for loading of DOX (Figure 4-B) (34). Poly(N-isopropylacrylamide-acrylic acid) (PNA) nanocapsules for controllable drug release and enhancing targeted antitumor effects (Figure 4-C) have been investigated. Capsules were obtained by Pickering emulsion (PE) technology using the solvent evaporation. The nanocapsules were crosslinked with cystamine and attached to the markers of cell surface (cRGDfK) to obtain targeted delivery properties. Nanocapsules exhibited high encapsulation efficiency of DOX. Redox-responsive release and targeted delivery of DOX into B16F10 murine cells were observed (123). Peng et al. synthesized poly (N-vinylpyrrolidone-N-vinylformamide) copolymers via reversible addition–fragmentation chain-transfer (RAFT) polymerization (Figure 4-D). Structures were loaded with DOX. The nanogels demonstrated degradation which depended on crosslinking density of the nanogels (124). A novel pH and redox-sensitive hydrogel system, bearing water-soluble poly (methacrylic acid) (PMAA) hydrogel cubes, have been organized by Hepsin-targeting (IPLVVPL) surface peptide to promote therapeutic efficacy of hydrophobic doxorubicin. This tumor-targeting system through peptide modification showed remarkable enhancement for the uptake of the hydrogels by Hepsin-positive MCF-7 andSK-OV-3 cells (125). A brief summary of redox-responsive nanogel drug delivery systems is presented in table 6.

Fig 4.

A) Nanogel based on gold nanorod particle (AuNRs) conjugated to HA. B) Hydrophilic NIPA cross-linked with N,N'-bis(acryloyl)cystine – BISS as hydrogel particle was used for loading of DOX. C) Poly(N-isopropylacrylamide-acrylic acid) (PNA) nanocapsules showed high encapsulation efficiency of DOX. D) Poly (N-vinylpyrrolidone-N-vinylformamide) copolymer was reduced to primary amine-functionalized copolymer.

Table 6.

Redox-responsive nanogel drug delivery systems

Nanoparticle	components	Hydrophilic polymers	ref
Nanogel	Au nanorod / HA / DOX	hyaluronic acid	(120)
Hydrogel	PMAA/DOX	poly (methacrylic acid)	(125)
Hydrogel microcapsule	PNIPA/DOX	Poly (N-isopropylacrylamide)	(34)
Nanogel	PNIPA/ PAA/DOX	Poly (N-isopropylacrylamide-co-acrylic acid)	(123)
Nanogels	PVP/ PNVF/DOX	Poly (N-vinylpyrrolidone-co-N-vinylformamide)	(124)
Nanogels	HA/DOX	hyaluronic acid	(120)

4. Future direction and perspective:

The redox-responsive chemical structures show a great potential in the field of nanomedicine. Nanoparticles have been extensively investigated with regards to their synthetic strategy, self-assembly in water, redox-responsive properties, and their application as delivery carriers for antigens, genes, and drugs in the forms of liposomes, polymeric micelles, nanogels and dendrimers. The advantages and dis advantages of these constitutions is summarized in Table 7.

Table 7.

Advantages and disadvantages of redox-sensitive nanocarrier

Carrier	Advantages	Disadvantages
Polymeric micelles	Improvement solubility of hydrophobic drug and pharmacokinetic barriers/ targeted delivery/ controlling drug release/	Low drug loading capacity/ application only for hydrophobic drug /dependency for critical micelle concentration
Polyplex nanoparticles	High stability in extracellular and low stability in intracellular media/ High loading capacity of hydrophobic and ionic drugs, DNA, RNA /targeted delivery/	Cellular toxicity/ limited delivery of hydrophilic active agents high cost
Nanogels/Hydrogel	High drug loading capacity/ rapidly release anticancer drug /Delivery of hydrophobic, hydrophilic and ionic drug/ high permeation capability due to small size.	Expensive methods for removing solvent and surfactant. Side effect due to remaining surfactant or monomer.
Inorganic nanoparticle	Additional property such as mechanical, optical, thermal, electrical/ high surface area/	Dependency to functionalization process/ cellular toxicity

Although various types of inorganic nanoparticles were developed for delivery of active agents, limited control over loading, release profile, and biodegradability restricted their translation to clinical application. It is suggested to use hybrid nanoparticles to exploit collective properties and selectively cross barriers to the site of delivery. The hybrid redox-responsive drug delivery nanoplatform has nearly high potential for passing pharmacokinetic barriers and enhancing drug bioavailability, drug circulation time, controlled drug release, and targeted delivery.

New class of redox linkers containing engineered chemical structures is proposed to be developed with synergistic effect specific to the loaded drug. Thiomer (Thiolated polymers ) derivatives have been proposed as the potent efflux pump inhibitor. Better understanding of the mechanism of interaction between redox structures and drugs, intracellular metabolism, and synergistic effects needs to be explored. Computational approaches such as molecular dynamic simulations could be applied to predict redox-responsive drug delivery nanoplatform efficiency for self-assembly/ aggregation, drug loading/releasing, and translocation of lipid bilayer. Moreover, new computational methods could be helpful to shed light on structure property/ activity correlation.

Selenide- or diselenide-containing carriers with different morphology have been developed and studied for their potential use as redox-responsive drug carriers or antioxidants. The selenium-based polymers are much more sensitive to H₂O₂ than their sulphide-containing counterparts. Moreover, the diselenide-containing polymers may be applied as drug carriers for the combination of chemotherapy with radiotherapy or photodynamic therapy. The intrinsic and selective anticancer activity makes the selenium-based materials promising candidates, as both prodrugs and anticancer drug vehicles, for combined chemotherapy. The effects of chemical structure and topology of the polymers on their redox degradation behaviours have not been studied systematically. However, the preliminary data demonstrate that these materials may find applications in the fields of H₂O₂ detection, and selective cancer therapy.

Redox-responsive systems are still far away from real applications despite the aforementioned advances. More detailed studies are necessary regarding some basic issues such as biocompatibility, analysis of intracellular products, in vivo performance, and so forth. Moreover, as a challenging task, the explanation of the intracellular fate of these particles in normal and cancer cells will be helpful for designing new redox-responsive nanomedicines to overcome crossing different barriers to the site of delivery.

Selective killing of cancer cells rather than normal cells by proper functional groups that can be specifically activated at the disease sites represents an attractive strategy for the development of new anticancer drugs. Although several H₂O₂- activated prodrugs that show potential to selectively kill cancer cells have been developed, there is no reports regarding a polymeric prodrug that can be triggered by ROS stress. Agents which can react with DNA and block its transcription and replication have been used in cancer therapy. If these agents are incorporated into a polymer that can release them upon exposure to H₂O₂, one may develop a new type of polymeric anticancer prodrug. Some small molecules, such as piperlongumine, can selectively kill malignant cells by increasing the intracellular concentration of H₂O₂. By combination of piperlongumine and oxidationresponsive polymeric drug vehicles, nanomedicines that target cancer cells may be developed.

5. Conclusion

Redox-responsive nanoplatforms offers promising prospects and advantages for cancer treatment. Unique properties of redox-responsive nanoparticles can be utilized as imaging agents to study intracellular redox homeostasis. Future studies of redox-sensitive particles are recommended to focus on detailed investigation of degradation mechanisms, fate of degradation by products within targeted tissues and cells, evaluation of in vivo short and long term biocompatibility, development of different particulate formulations for precision medicine, and design of novel self-assembling polymeric structures for co-delivery therapeutic agents.