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Cancer is the leading cause of mortality and remains a major challenge for modern chemotherapy. Recent advances in cancer therapy have made a modest impact on patient survival. Nanomedicine represents an innovative field with significant potential to improve cancer treatment. Nanomedicine utilizes numerous nanoconstructs, including polymersomes, micelles, and drug conjugates, to deliver therapeutic agents at the target site of interest. In particular, polymeric vesicles, also known as polymersomes, are self-assembled amphiphilic polymers in which an aqueous compartment is enclosed by a thick bilayer membrane. Unlike liposomes, polymersomes consist of high-molecular-weight amphiphilic polymer analogues. Since polymersomes are prepared using synthetic amphiphilic polymers, the bilayer membrane thickness can be readily altered by tuning the molecular weight of hydrophobic blocks. As a consequence, the polymersomes prepared from high-molecular-weight amphiphiles strengthen their membranes, making them inherently more stable than liposomes. The intriguing aggregation of polymersomes offers numerous advantages, including stability, tunable membrane properties, and the capability of encapsulating hydrophilic and hydrophobic agents. Owing to these properties, polymersomes are attractive candidates for various applications such as drug delivery, gene therapy, and tissue engineering. Although these properties have placed polymersomes at the forefront of drug delivery applications, to attain an enhanced therapeutic effect polymersomes are supposed to rapidly release the drug at the target site. To fulfill this requirement, stimuli-responsive polymersomes that respond to various internal or external stimuli have been developed. This review focuses on recently developed stimuli-responsive polymersomes and their potential application in cancer therapy.

Hypoxia, a condition in which the tissue is deprived of adequate oxygen supply, is a salient feature of various intractable diseases, including rheumatoid arthritis, ischemic stroke, and solid tumors. In particular, hypoxic regions in tumors are often associated with invasiveness, metastasis, and resistance to radiotherapy and chemotherapy. Given its unique role in tumor progression, hypoxia has been considered to be a primary target for the diagnosis and treatment of cancer. Owing to their sizes and tailorable physicochemical characteristics, nanocarriers are an emerging class of materials that are increasingly utilized in biomedical applications. Particularly, stimuli-responsive nanocarriers, which release their payloads specifically at the tumor-microenvironment, are materials of interest. Owing to the aberrant vascular properties of tumors, the transportation of anticancer drugs to hypoxic regions is challenging because they are distant from blood vessels. In addition, hypoxia upregulates various genes involved in drug resistance such as P-glycoprotein. To surmount the issues associated with hypoxia, nanocarriers that can release imaging agents or anticancer drugs in hypoxic regions must be developed. This review focuses on recently developed hypoxia-responsive conjugates or nanocarriers and their potential applications in cancer imaging and therapy. Low oxygen levels bring forth conformational changes in hypoxia-responsive nanocarriers through the cleavage or reduction of hypoxia-responsive functional groups. A greater understanding of these changes will help to design more efficient nanocarriers to address the challenges encountered with hypoxia in conventional chemotherapy.

The major issues of self-assembled nanoparticles as drug carriers for cancer therapy include biostability and tumor-targetability because the premature drug release from and nonspecific accumulation of the drug-loaded nanoparticles may cause undesirable toxicity to normal organs and lower therapeutic efficacy. In this study, we developed robust and tumor-targeted nanocarriers based on an amphiphilic hyaluronic acid (HA)-polycaprolactone (PCL) block copolymer, in which the HA shell was cross-linked via a bioreducible disulfide linkage. Doxorubicin (DOX), chosen as a model anticancer drug, was effectively encapsulated into the nanoparticles with high drug loading efficiency. The DOX-loaded bioreducible HA nanoparticles (DOX-HA-ss-NPs) greatly retarded the drug release under physiological conditions (pH 7.4), whereas the drug release rate was markedly enhanced in the presence of glutathione, a thiol-containing tripeptide capable of reducing disulfide bonds in the cytoplasm. Furthermore, DOX-HA-ss-NPs could effectively deliver the DOX into the nuclei of SCC7 cells in vitro as well as to tumors in vivo after systemic administration into SCC7 tumor-bearing mice, resulting in improved antitumor efficacy in tumor-bearing mice. Overall, it was demonstrated that bioreducible shell-cross-linked nanoparticles could be used as a potential carrier for cancer therapy.

Stimuli-sensitive injectable polymeric hydrogels are one of the promising delivery vehicles for the controlled release of bioactive agents. In aqueous solutions, these polymers are able to switch sol-to-gel transitions in response to various stimuli including pH, temperature, light, enzyme and magnetic field. Therapeutic agents, including chemotherapeutic agents, protein drugs or cells, are easily mixed with the low-viscous polymer solution at room temperature. Therapeutic-agents-containing solutions are readily injected into target sites through syringe or catheter, which could form hydrogel depot and serve as bioactive molecules release carriers. In particular, they are convenient for in vivo injection in a minimally invasive manner. Owing to their ease of handling, hydrogel scaffolds encapsulated with a wide array of therapeutic agents including growth factors, cells or fillers have been used in regeneration or filling of the defect area. Therefore, injectable hydrogels found a variety of biomedical applications, such as drug delivery and tissue engineering. Here, we summarize the chemical designs and recent developments of polysaccharide-based injectable hydrogels, giving a special attention to hydrogels prepared using amphiphilic polysaccharides for biomedical applications. Advantages and future perspectives of polysaccharide-based injectable hydrogels are highlighted.

Poly(ethylene glycol)-b-poly(γ-benzyl L-glutamate)s bearing the disulfide bond (PEG-SS-PBLGs), which is specifically cleavable in intracellular compartments, were prepared via a facile synthetic route as a potential carrier of camptothecin (CPT). Diblock copolymers with different lengths of PBLG were synthesized by ring-opening polymerization of benzyl glutamate N-carboxy anhydride in the presence of a PEG macroinitiator (PEG-SS-NH(2)). Owing to their amphiphilic nature, the copolymers formed spherical micelles in an aqueous condition, and their particle sizes (20-125 nm in diameter) were dependent on the block length of PBLG. Critical micelle concentrations of the copolymers were in the range 0.005-0.065 mg/mL, which decreased as the block length of PBLG increased. CPT, chosen as a model anticancer drug, was effectively encapsulated up to 12 wt % into the hydrophobic core of the micelles by the solvent casting method. It was demonstrated by the in vitro optical imaging technique that the fluorescence signal of doxorubicin, quenched in the PEG-SS-PBLG micelles, was highly recovered in the presence of glutathione (GSH), a tripeptide reducing disulfide bonds in the cytoplasm. The micelles released CPT completely within 20 h under 10 mM GSH, whereas only 40% of CPT was released from the micelles in the absence of GSH. From the in vitro cytotoxicity test, it was found that CPT-loaded PEG-SS-PBLG micelles showed higher toxicity to SCC7 cancer cells than CPT-loaded PEG-b-PBLG micelles without the disulfide bond. Microscopic observation demonstrated that the disulfide-containing micelle could effectively deliver the drug into nuclei of SCC7 cells. These results suggest that PEG-SS-PBLG diblock copolymer is a promising carrier for intracellular delivery of CPT.