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Amphoteric pH-responsive polymers fused with both acidic and basic polymers exhibited sharp pH-swelling behavior in both acidic and basic media.

Here, core-shell hydrogel beads for oral insulin delivery at intestine was reported, which was a target site for insulin absorption. The core-shell hydrogel beads were prepared using naturally derived alginate and chitosan polysaccharides by simple dropping technique. In order to effectively control leakage of insulin from core-shell hydrogel beads, insulin was embedded into the layered double hydroxides (LDHs). LDH/insulin-loaded complexes were firstly coated with chitosan, and then coated with alginate to generate core-shell hydrogel beads. The biocompatibility and angiogenic response of core-shell hydrogel beads were evaluated by direct contact of the beads with chick embryo chorioallantoic membrane, which indicates safety of the core-shell beads. The beads successfully retained the insulin within the core-shell structure at pH 1.2, indicating that insulin had a good protective effect in harsh acidic environments. Interestingly, insulin release starts at the simulated intestinal fluid (pH 6.8) and continue to release for 24 h in a sustained manner.

Oncolytic adenovirus (oAd) elicits antitumor activity by preferential viral replication in cancer cells. However, poor systemic administrability or suboptimal intratumoral retainment of the virus remains a major challenge toward maximizing the antitumor activity of oAd in a clinical environment. To surmount these issues, a variety of non-immunogenic polymers has been used to modify the surface of oAds chemically or physically. Complexation of oAd with polymers can effectively evade the host immune response and reduces nonspecific liver sequestration. The tumor-specific delivery of these complexes can be further improved upon by inclusion of tumor-targeting moieties on the surface. Therefore, modification of the Ad surface using polymers is viewed as a potential strategy to enhance the delivery of Ad via systemic administration. This review aims to provide a comprehensive overview of polymer-complexed Ads, their progress, and future challenges in cancer treatment.

Despite the many advanced strategies that are available, rapid gene mutation in multidrug-resistant bacterial infections remains a major challenge. Combining new therapeutic strategies such as chemo-photothermal therapy (PTT) with high antibacterial efficiency against drug-resistant Listeria monocytogenes (LM) is urgently needed. Here, we report synergistic chemo-PTT against drug-resistant LM based on antibody-conjugated and streptomycin-chitosan oligosaccharide-modified gold nanoshells (anti-STR-CO-GNSs) as all-in-one nanotheranostic agents for the first time, which was used for accurate antibacterial applications. The anti-STR-CO-GNSs showed excellent photothermal conversion efficiency (31.97 %) and were responsive to near-infrared (NIR) and pH dual stimuli-triggered antibiotic release, resulting in outstanding chemo-photothermal effects against LM. In vitro chemo-photothermal effect of anti-STR-CO-GNSs with laser irradiation caused a greater antibacterial effect (1.37 %), resulting in more rapid killing of LM and prevention of LM regrowth. Most importantly, the mice receiving the anti-STR-CO-GNSs with laser irradiation specifically at the sites of LM infections healed almost completely, leaving only scars on the surface of the skin and resulting in superior inhibitory effects from combined chemo-PTT. Overall, our findings suggest that chemo-PTT using smart biocompatible anti-STR-CO-GNSs is a favorable potential alternative to combat the increasing threat of drug-resistant LM, which opens a new door for clinical anti-infection therapy in the future.

One of the major challenges in wound healing is the development of suitable hydrogels that are injectable, biocompatible with multiple functionalities and properties such as high mechanical, tissue adhesiveness, and swelling properties. However, these hydrogels should not elicit any immunological response and synthesis steps should be easier and tunable according to the requirements. Considering these properties, we synthesized a thermo-sensitive triblock copolymer consisting of bovine serum albumin (BSA) protein capable of leveraging the needs for a proper wound closure and tissue regeneration on excisional injuries. Firstly, the triblock copolymer consisting of poly(e-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(e-caprolactone-co-lactide (PCLA) was synthesized and then the copolymer was grafted with BSA to yield BSA-PCLA bioconjugates. Aqueous solutions of free-flowing bioconjugate sol at room temperature can transform to gel at physiological temperature with high viscoelastic properties. Subcutaneous injection of BSA-PCLA bioconjugate sol into the back of Sprague-Dawley rats formed gel immediately and found to be bioresorbable after 5 weeks without significant toxicity at implantation sites. BSA-PCLA bioconjugate gel exhibited good adhesive property to major organs including liver, heart, and spleen when compared with control PCLA gel. When tested for in vivo wound closure trials, the BSA-PCLA gels showed rapid wound contraction compared to the PCLA and the control. The increased angiogenesis and collagen deposition were confirmed from the histological studies of the samples. These highly adhesive, biocompatible, biodegradable, thermos-sensitive bioconjugate gels show promising potential in wound healing and tissue regeneration without any additional biofactors or inorganic nanoparticles.

Core-shell structured nanoparticles (NPs) render the simultaneous coloading capacity of both hydrophobic and hydrophilic drugs and may eventually enhance therapeutic efficacy. In this study, we employed a facile squalenoylation technology to synthesize a new amphiphilic starch derivative from partially oxidized starch, which self-assembled into core-shell starch NPs (StNPs) only at a squalenyl degree of substitution (DoS) of ∼1%. The StNPs characteristics could be tuned as the functions of the polymer molecular weight, DoS, and NPs concentration. The biopharmaceutical features of the StNPs, including colloidal stability, carrier properties, and biocompatibility, were carefully investigated. The interaction study between StNPs and mucin glycoproteins, the main organic component of mucus, revealed a moderate mucin interacting profile. Furthermore, the StNPs also showed good penetration through Pseudomonas aeruginosa biofilms. These results nominate StNPs as a versatile drug delivery platform with potential applications for mucosal drug delivery and the treatment of persistent infections.

Adenoviruses (Ads) are attractive nonviral vectors and show great potential in cancer gene therapy. However, inherent properties of Ads, including immunogenicity, nonspecific toxicity, and coxsackie and adenovirus receptor (CAR)-dependent cell uptake, limit their clinical use. To surmount these issues, we developed a pH- and glutathione-responsive poly(ethylene glycol)-poly(ꞵ-aminoester)-polyethyleneimine (PPA) for conjugation with Ad. The pH sensitivity of the PPA copolymer was elegantly tuned by substitution with different amino acids (arginine, histidine, and tryptophan), piperazines (Pip1, Pip2, and Pip3), and guanidine residues in the backbone of the PPA conjugate. PPA copolymer was further functionalized with short-chain cross-linker succinimidyl 3-(2-pyridyldithio)propionate) (SPDP) to obtain PPA-SPDP for facile conjugation with Ad. The PPA-conjugated Ad (PPA-Ad) conjugate was obtained by reacting PPA-SPDP conjugate with thiolated Ad (Ad-SH). Ad-SH was prepared by reacting Ad with 2-iminothiolane. The size distribution and zeta potential results of PPA-Ad conjugate showed an increasing trend with an increase in copolymer dose. From in vitro test, it was found that the transduction efficiency of PPA-Ad conjugate in CAR-positive cells (A549 and H460 cells) was remarkably increased at the acidic pH condition (pH 6.2) when compared with PPA-Ad conjugate incubated under the physiological condition (pH 7.4). Interestingly, the increase in transduction efficiency was evidenced in CAR-negative cells (MDA-MB-231 and T24 cells). These results demonstrated that biocompatible and biodegradable PPA copolymers can efficiently cover the surface of Ad and can increase the transduction efficiency, and hence PPA copolymers can be a useful nanomaterial for viral vector delivery in cancer therapy.

Hepatocellular carcinoma is the most common malignancy with a high incidence rate and is the leading cause of cancer-related deaths. Herein, we developed a thermo-responsive hydrogel comprising poly(e-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(e-caprolactone-co-lactide (PCLA) that exhibits acidity-accelerated delivery of the tumor-targeting glucuronic acid-bearing doxorubicin (DOX-pH-GA) conjugate into tumor tissues. The PCLA copolymer was post-modified with boronic acid (BA-PCLA) to covalently cross-link with the pH-responsive DOX-pH-GA conjugate. The BA-PCLA copolymer effectively coordinated with the DOX-pH-GA conjugate through the boronate ester formation and showed a lower critical gelation temperature. The DOX conjugated via boronate ester exhibited a sustained release in vitro. Subcutaneous administration of PCLA copolymers formed in situ gels in the subcutaneous layers of Sprague-Dawley rats and degraded after 6 weeks. Similarly, BA-PCLA copolymers coordinated with DOX-pH-GA formed a stable in situ gel in vivo. In vivo imaging studies demonstrated that DOX-pH-GA was released in a sustained manner. The anti-tumor activity of the DOX releasing injectable hydrogel was examined using a HepG2 liver cancer xenograft model. The in vivo antitumor effect demonstrated that the DOX releasing hydrogel depot remarkably suppresses the tumor growth. These results demonstrate that the pH-responsive DOX releasing thermo-responsive hydrogel depot has great potential for application in localized anticancer therapy.

Articular cartilage injury is characterized by limited self-repair capacity due to the shortage of blood vessels, lymphatics, and nerves. Hence, this study aims to exploit a classic injectable hydrogel platform that can restore the cartilage defects with minimally invasive surgery, which is similar to the natural extracellular microenvironment, and highly porous network for cell adhesion and proliferation. In this study, an injectable scaffold system comprised of silk fibroin (SF) and hyaluronic acid (HA) was developed to adapt the above requirements. Besides, methylprednisolone (MP) was encapsulated by SF/HA scaffold for alleviating inflammation. The SF/HA hydrogel scaffold was prepared by chemical cross-linking between the lysine residues of SF via Schiff base formation, and pore diameter of the obtained hydrogels was 100.47 ± 32.09 µm. The highly porous nature of hydrogel could further benefit the soft tissue regeneration. Compared with HA-free hydrogels, SF/HA hydrogel showed more controlled release on MP. In ovo experiment of chick embryo chorioallantoic membrane (CAM) demonstrated that SF/HA hydrogels not altered the angiogenesis and formation of blood vessels, thus making it suitable for cartilage regeneration. Furthermore, in vivo gel formation was validated in mice model, suggesting in situ gel formation of SF/HA hydrogels. More importantly, SF/HA hydrogels exhibited the controlled biodegradation. Overall, SF/HA hydrogels provide further insights to the preparation of effective scaffold for tissue regeneration and pave the way to improve the articular cartilage injury treatment.

The development of injectable hydrogels with tunable multifunctional properties, for example, adhesive, elastic, swelling, biodegradable, and wound-healing properties that mimic the dynamic-healing process of skin regeneration, is currently a major challenge in tissue regeneration. Here, we report a fillable topical formulation of injectable gelatins (IGs) for the integration of advanced excisional wounds. Bioresorbable temperature-sensitive block copolymer was conjugated to the backbone of gelatins to form a dynamic coordinative network of IGs. The flexible IG precursors transformed to viscoelastic hydrogel at the subcutaneous tissues with cell affinity and tissue adhesive properties. The microporous dynamic network of IGs allows access to nutrients and recruits immune cells that accelerate neovascularization within a hydrogel network. Combined with adhesive and neovascularization properties, the IGs alone exhibit accelerated wound healing in open wounds featured by skin appendages without scar formation. More remarkably, in an excisional wound (1 cm × 1 cm) animal model, the IGs promoted the wound healing as observed by the skin appendages. Furthermore, histological analysis demonstrated that IGs not only accelerate the rate of wound healing but also promoted the quality of wound healing observed by collagen deposition and neovascularization. The in situ forming IGs with a superior adhesive property can be considered as promising wound dressing materials for the treatment of multiple wounds, without the need for the encapsulation of biofactors or antibacterial metals. The IGs prepared in this study can also be employed to repair tissues or organs using minimal invasive administration.

In situ-forming injectable hydrogels are attractive delivery vehicles not only for the controlled delivery of drugs and proteins but also for the controlled the delivery of nanometer sized particles. In this study, pH- and temperature-responsive pentablock copolymers were synthesized by the conjugation reaction between carboxylic groups of oligo (serine) and alcohol groups of temperature-responsive triblock copolymers, poly (e-caprolactone)-b-poly (ethylene glycol)-b-poly (e-caprolactone). Owing to their pH- and temperature-responsive property, the pentablock copolymers were found to be soluble at high pH, and transformed to viscoelastic gel at the physiological condition (pH 7.4, 37 °C). Furthermore, the free-flowing pentablock copolymer sols form a stable hydrogel depot on the back of Sprague-Dawley rats. The hydrogel depot was found to be degradable in a controlled manner and bioresorbable after one month. Insulin-incorporated nanosized chitosan particles were prepared via the electrospraying method and mixed with the pentablock copolymer solution to control the release of insulin. At high pH, the negatively charged pentablock copolymers and insulin-incorporated chitosan particles form an ionic complex through electrostatic interaction. Interestingly, in physiological conditions, the complex formed a viscoelastic gel and controlled the release of insulin in a spatiotemporal-controlled manner for over one month with remarkable inhibition of first-burst of insulin. These results demonstrated that modular design of injectable smart hydrogels with chitosan particles showing great prospect to control the delivery of insulin.

Microporous injectable bioconjugates, composed of hyaluronic acid–poly(β-aminoester urethane), were prepared by the amination of synthetic copolymers and successive post modification using natural polymers. Strinkingly, the free flowing bioconjugates can seal cutaneous wounds due to their sharp sol-to-gel phase transition. The sustained delivery of bioactive factors and wound regeneration performance of the bioconjugates were examined in vivo.

In recent years, injectable hydrogels that undergo sol-to-gel phase transition in response to the physiological pH- and temperature have attracted increasing attention in therapeutics delivery. In ...

Despite the tremendous potential of DNA-based cancer vaccines, their efficacious delivery to antigen presenting cells to stimulate both humoral and cellular response remains a major challenge. Although electroporation-based transfection has improved performance, an optimal strategy for safe and pain-free vaccination technique remains elusive. Herein, we report a smart DNA vaccine delivery system in which nanoengineered DNA vaccine was laden on microneedles (MNs) assembled with layer-by-layer coating of ultra-pH-responsive OSM-(PEG-PAEU) and immunostimulatory adjuvant poly(I:C), a synthetic double stranded RNA. Transcutaneous application of MN patches onto the mice skin perforate the stratum corneum with minimal cell damage; subsequent disassembly at the immune-cell-rich epidermis/dermis allows the release of adjuvants and DNA vaccines, owing to the ultra-sharp pH-responsive nature of OSM-(PEG-PAEU). The released adjuvant and DNA vaccine can enhance dendritic cell maturation and induce type I interferons, and thereby produce antigen-specific antibody that can achieve the antibody-dependent cell-mediated cytotoxicity (ADCC) and CD8+ T cell to kill cancer cells. Strikingly, transcutaneous application of smart vaccine formulation in mice elicited 3-fold greater frequencies of Anti-OVA IgG1 serum antibody and 3-fold excess of cytotoxic CD8+ T cell than soluble DNA vaccine formulation. As a consequence, the formulation rejected the murine B16/OVA melanoma tumors in C57BL/6 mice through the synergistic activation of antigen-specific ADCC and cytotoxic CD8+ T cells. The maneuvered use of vaccine and adjuvant poly(I:C) in MNs induces humoral and cellular immunity, which provides a promising vaccine technology that shows improved efficacy, compliance, and safety.

Silver-containing dressings have been widely used to control wound infection. In this study, we developed various amounts of silver-hydroxyapatite (AgHAP)-containing polyurethane foams (PUFs) (AgHAP–PUFs), and their biological properties including biocompatibility, antibacterial activities, and in vivo wound healing properties were evaluated in the Sprague-Dawley rat model. From electron microscopy imaging, it was found that AgHAP particles are uniformly dispersed inside PUFs. The release of Ag from PUFs was dependent on both time and concentration, i.e., the amount of released Ag was significantly higher with increasing immersion time and Ag content in the PUFs. From the cytotoxicity test, AgHAP–PUFs exhibited high antibacterial efficacy against four pathogenic bacteria, and they were not cytotoxic against L-929 fibroblast cells. AgHAP–PUF treated groups exhibited scar-free wound healing by promoting re-epithelialization and collagen deposition in the infected excision wound model. Overall, it is evident that AgHAP–PUFs may be considered as a good antibacterial wound dressing for infected wounds due to their good antibacterial activity, biocompatibility, and wound healing rate.

Cisplatin (CDDP) is a well-known anticancer agent, and it has been widely used to treat various solid tumors during clinical cancer therapy. Nevertheless, therapeutic applications of CDDP are hampered by its severe side effects. Although CDDP can be encapsulated into nano-scale drug delivery formulations to improve its physicochemical properties, the lack of stability in the formulation and cancer cell-specific targetability have prompted the exploration of novel vectors for the targeted delivery of CDDP. Here, we introduce CDDP-bearing chondroitin sulfate nanogels (CS-nanogels) that are synthesized through a chelating ligand–metal coordination cross-linking reaction, and then incorporated into pH- and temperature-responsive bioresorbable poly(ethylene glycol)–poly(β-aminoester urethane) (PEG–PAEU) hydrogels for cancer cell-specific delivery of CDDP. The CS-nanogels released from the hydrogels exhibit a pH-dependent release of CDDP. CDDP was released slowly under physiological conditions (pH 7.4), whereas the release of CDDP was triggered under acidic conditions (pH 5.0). Confocal microscopy images demonstrated that fluorescein-5-thiosemicarbazide-labeled CS-nanogels released from the hydrogels selectively bound to the A549 lung carcinoma cell line through the overexpressing CD44 receptor but not to NIH 3T3 cells. An in vitro cytotoxicity test indicated that CS-nanogels released from the hydrogels effectively inhibited the growth of A549 lung carcinoma cells. Subcutaneous injection of CS-nanogel-loaded PEG–PAEU copolymer sols into the dorsal region of Sprague-Dawley rats spontaneously formed a viscoelastic gel without causing noticeable inflammation at the injection site and was found to be bioresorbable in eight weeks. Overall, the injectable hydrogel-incorporated CS-nanogels were demonstrated to be a useful formulation for the targeted delivery of CDDP.

Despite great potential, the delivery of genetic materials into cells or tissues of interest remains challenging owing to their susceptibility to nuclease degradation, lack of permeability to the cell membrane, and short in vivo half-life, which severely restrict their widespread use in therapeutics. To surmount these shortcomings, we developed a bioinspired in situ-forming pH- and temperature-sensitive injectable hydrogel depot that could control the delivery of DNA-bearing polyplexes for versatile biomedical applications. A series of multiblock copolymer, comprised of water-soluble poly(ethylene glycol) (PEG) and pH- and temperature-responsive poly(sulfamethazine ester urethane) (PSMEU), has been synthesized as in situ-forming injectable hydrogelators. The free-flowing PEG-PSMEU copolymer sols at high pH and room temperature (pH 8.5, 23 °C) were transformed to stable gel at the body condition (pH 7.4, 37 °C). Physical and mechanical properties of hydrogels, including their degradation rate and viscosity, are elegantly controlled by varying the composition of urethane ester units. Subcutaneous administration of free-flowing PEG-PSMEU copolymer sols to the dorsal region of Sprague-Dawley rats instantly formed hydrogel depot. The degradation of the hydrogel depot was slow at the beginning and found to be bioresorbable after two months. Cationic protein or DNA-bearing polyplex-loaded PEG-PSMEU copolymer sols formed stable gel and controlled its release over 10 days in vivo. Owing to the presence of urethane linkages, the PEG-PSMEU possesses excellent adhesion strength to wide range of surfaces including glass, plastic, and fresh organs. More importantly, the hydrogels effectively adhered on human skin and peeled easily without eliciting an inflammatory response. Subcutaneous implantation of PEG-PSMEU copolymer sols effectively sealed the ruptured skin, which accelerated the wound healing process as observed by the skin appendage morphogenesis. The bioinspired in situ-forming pH- and temperature-sensitive injectable adhesive hydrogel may provide a promising platform for myriad biomedical applications as controlled delivery vehicle, adhesive, and tissue regeneration.

In an attempt to develop the hypoxia-responsive nanoparticles for cancer therapy, a polymer conjugate, consisting of carboxymethyl dextran (CMD) and black hole quencher 3 (BHQ3), was prepared. The polymer conjugate can self-assemble into nanoparticles (CMD-BHQ3 NPs) under aqueous conditions. The anticancer drug, doxorubicin (DOX), was loaded in CMD-BHQ3 NPs to prepare DOX@CMD-BHQ3 NPs. The CMD-BHQ3 NPs released DOX in a sustained manner under physiological conditions, whereas the release rate of DOX remarkably increased under hypoxic conditions throughout the cleavage of the azo bond in BHQ3. In vitro cytotoxicity study revealed that DOX@CMD-BHQ3 NPs showed higher toxicity under hypoxic conditions than normoxic conditions. Confocal microscopic images indicated oxygen-dependent intracellular release of DOX from DOX@CMD-BHQ3. In vivo biodistribution study demonstrated that CMD-BHQ3 NPs were preferentially accumulated in the tumor after systemic administration into tumor-bearing mice. Overall, CMD-BHQ3 might be a promising carrier for selective drug release in the hypoxic tumor.

Hollow and microporous organic network spheres decorated with folic acids (H-MON-FA) were prepared using silica templates by the Sonogashira coupling of organic building blocks and successive post-synthetic modifications. The drug (DOX) delivery performance of H-MON-FA to cancer cells was studied.

Sustained delivery of protein therapeutics is limited owing to the fragile nature of proteins. Despite its great potential, delivery of proteins without any loss of bioactivity remains a challenge in the use of protein therapeutics in the clinic. To surmount this shortcoming, we report a pH- and temperature-responsive in situ-forming injectable hydrogel based on comb-type polypeptide block copolymers for the controlled delivery of proteins. Polypeptide block copolymers, composed of hydrophilic polyethylene glycol (PEG), temperature-responsive poly(γ-benzyl-l-glutamate) (PBLG), and pH-responsive oligo(sulfamethazine) (OSM), exhibit pH- and temperature-induced sol-to-gel transition behavior in aqueous solutions. Polypeptide block copolymers were synthesized by combining N-carboxyanhydride-based ring-opening polymerization and post-functionalization of the chain-end using N-hydroxy succinimide ester activated OSM. The physical properties of polypeptide-based hydrogels were tuned by varying the composition of temperature- and pH-responsive PBLG and OSM in block copolymers. Polypeptide block copolymers were non-toxic to human embryonic kidney cells at high concentrations (2000 μg mL-1). Subcutaneous administration of polypeptide block copolymer sols formed viscoelastic gel instantly at the back of Sprague-Dawley (SD) rats. The in vivo gels exhibited sustained degradation and were found to be bioresorbable in 6 weeks without any noticeable inflammation at the injection site. Anionic characteristics of hydrogels allow efficient loading of a cationic model protein, lysozyme, through electrostatic interaction. Lysozyme-loaded polypeptide block copolymer sols readily formed a viscoelastic gel in vivo and sustained lysozyme release for at least a week. Overall, the results demonstrate an elegant approach to control the release of certain charged proteins and open a myriad of therapeutic possibilities in protein therapeutics.

In recent years, protein therapeutics plays a promising role in the field of medicine. However, intrinsic properties of proteins, including short plasma half-life and hydrolytic stability in vivo, are severely limits their application. To surmount these issues, we developed an anionic injectable hydrogel based on temperature- and pH-sensitive poly(ethylene glycol)-poly(sulfamethazine carbonate urethane) (PEG-PSMCU) copolymers for the sustained delivery of cationic model protein, lysozyme. The PEG-PSMCU copolymers exhibit pH and temperature-induced sol-to-gel phase transition in aqueous solutions. The mechanical properties of PEG-PSMCU copolymers, such as viscosity, gelation rate, and mechanical strength, were controllably tunable by varying the polymer weight, pH and temperature. An in vitro biocompatibility test indicated that PEG-PSMCU-based copolymers, even at high polymer concentrations (up to 2000 μg/ml), was not toxic to fibroblast cells. The in vivo gel formation was confirmed by subcutaneous injection of PEG-PSMCU-based copolymer solutions (20 wt%) into Sprague-Dawley (SD) rats, which indicated in situ gel formation with uniform porous structure. Furthermore, an in vivo biodegradation study of the PEG-PSMCU anionic hydrogels showed a surface-controlled degradation of the gel matrix. Lysozyme, chosen as a cationic model protein, was loaded into an anionic hydrogel through ionic and hydrophobic interactions. Lysozyme-loaded PEG-PSMCU copolymers readily formed an in situ hydrogel after subcutaneous injection in SD rats, which markedly retarded the initial burst and led to the sustained release of lysozyme for 7 days. Overall, injectable anionic hydrogels prepared in this study can act as a localized hydrogel depot of cationic proteins, which inhibited initial burst while facilitating sustained release, and open a new paradigm for sustained delivery of cationic proteins.

Diabetic wounds are a major health concern in diabetic wound care management. Various factors influence the biological phases of diabetic wound healing, causing improper wound healing. To surmount the issues associated with diabetic wounds, designing dressing materials with antibacterial and re-epithelization properties has the potential to promote successful wound healing. Here we prepared synergistic dressing materials by incorporating silver nanoparticles (AgNP) and recombinant human epidermal growth factor (rhEGF) into polyurethane foams (PUFs) and tested these materials in an animal model of diabetic full-thickness wounds. The AgNP/rhEGF-PUFs dressings exhibited excellent absorbency, fluid retention, and fluid handling properties. The hydrophilic surface of the PUF dressing could potentially enhance its antibacterial properties against pathogenic bacteria. In vitro cytotoxicity tests demonstrated that the PUFs are cytocompatible, and the AgNP/rhEGF-PUFs significantly enhanced the growth of L-929 cells. More importantly, examination of in vivo wound healing in a full-thickness balb/c mice model demonstrated that the AgNP/rhEGF-PUFs could significantly accelerate the healing of diabetic wounds. Furthermore, histological examination demonstrated that the AgNP/rhEGF-PUF dressings successfully reconstructed the impaired epidermis, as demonstrated by proper re-epithelization and collagen deposition. The wounds treated with the AgNP/rhEGF-PUFs dressings were completely closed by day 20, while wounds treated with AgNP-PUFs and gauze only closed 87 ± 2.30 and 64 ± 4.76%, respectively. These results demonstrated that our synergistic AgNP/rhEGF-PUFs comprise a successful fusion of antibacterial and re-epithelization agents, with promising future applications in diabetic wound healing.

Development of implantable material to control the release of chemotherapeutics in the body is a promising approach to control cancer cell proliferation; however, implantation requires surgical intervention. Herein, we propose the in situ formation of injectable biogels (IBGs) for the programmed delivery of potent chemotherapeutic drugs. IBGs are developed via cohesive molecular assembly of a polysaccharide-polymer network comprised of hyaluronic acid–poly(β-amino urethane). Biocompatible IBGs could be administered subcutaneously through a hypodermic needle in vivo to subsequently assemble into a microporous network. The hyaluronic acid-shielded network mimics the natural extracellular matrix, avoiding rapid degradation of IBGs, with a soft texture and adhesiveness facilitating integration with dermal tissues after subcutaneous implantation. The natural-mimicking architecture confers the IBG network controlled degradation and bioresorbable properties. Subcutaneous administration of IBGs controlled the delivery of a therapeutic agent in a spatio-temporal manner. Therapeutic agents delivered near the tumors in a sustained manner were effectively infiltrated into the thick solid tumors and provide a durable and enhanced anti-tumor response in the B16/OVA melanoma model in vivo. These results indicate that IBGs could be potential medical interventions for the treatment of cancers.

The combination of chemotherapeutic agents with immune stimulating agents for treating degenerative diseases, called chemoimmunotherapy, has emerged as a promising cancer treatment modality. Despite the tremendous potential, chemoimmunotherapy by the combination of drugs and immune stimulators often suffers because of the lack of controlled delivery nanostructures in the microenvironment. To this end, we show that by using pH-responsive smart nanocubes (NCs), cancer cells and tumor-associated immune cells can be precisely targeted with a chemotherapeutic agent (doxorubicin, DOX) and immune stimulating agent (plasmid ovalbumin, pOVA) for enhanced chemoimmunotherapy. The pH-responsive smart NCs protect payloads from nuclease degradation and avoid renal clearance and undergo supersensitive structural change at the extracellular tumor regions that mediate efficient release. Concurrent release of pOVA vaccines encoding tumor-specific antigen laden with polyplexes were loaded on tumor-associated immune cells and produce antigen-specific humoral immune response, whereas DOX enables effective infiltration into the cancer cells and is involved in the eradication of tumor tissues. The amount of anti-OVA IgG1 antibody produced by the intravenous administration of NC formulation was similar to that of free OVA formulation. Importantly, the combined delivery of pDNA and DOX using NCs showed significantly enhanced antitumor efficacy in B16/OVA melanoma tumor xenografts, which remarkably outperforms the monotherapy counterparts. These results suggest that pH-responsive smart NCs laden with pDNA and DOX provide a promising nanostructure for chemoimmunotherapy that simultaneously involves cancer cell killing and stimulates antigen-specific immune response to prevent cancer recurrence.

The pH- and temperature-responsive pentablock copolymers that could form in situ hydrogels, composed of pH-responsive polyamide and temperature-responsive poly(e-caprolactone)-b-poly(ethylene glycol)-b-poly(e-caprolactone) (PCL-b-PEG-b-PCL), have been synthesized. The pH-responsive polyamide blocks containing diamide linkages were synthesized using condensation polymerization of adipic acid dihydrazide and phthalic anhydride; whereas, temperature-responsive PCL-b-PEG-b-PCL was synthesized by ring-opening polymerization of e-caprolactone in the presence of bifunctional PEG macroinitiator. Pentablock copolymer was then synthesized by the chemical conjugation of carboxylic acid-terminated pH-responsive copolymer to the chain end of temperature-responsive triblock copolymer through ester bond formation. The pKa values of pH-sensitive polyamide, measured using titration method, varied depending on the average molecular weight of polymers. In aqueous solutions, the pentablock and triblock copolymers formed spherical micelles and their particle sizes were found to be 55 to 100 nm. The pentablock copolymer exhibited pH- and temperature-induced sol-to-gel phase transition. At high pH and low temperature, the copolymers were freely soluble even at 20 wt% concentration and form stable hydrogel at the physiological condition (pH 7.4, 37 °C). Furthermore, the sol-to-gel window of the pentablock copolymers was controlled by varying the composition of polyamide to PCL/PEG and covers the physiological region. Overall, these results suggest that the sharp physicochemical change of the pentablock copolymers may be exploited in controlled delivery applications.

To enhance cellular uptake and site-specific drug release in the tumor microenvironment, zwitterionic mesoporous silica nanoparticles (Z-MSN) were prepared by introducing a bioresponsive gatekeeper composed of negatively charged carboxylic groups and positively charged quaternary amine groups. When these Z-MSN encountered a mildly acidic environment, their surface charge readily switched from negative to positive by cleavage of an acid-labile maleic amide linkage, thus allowing for effective cellular uptake into tumor tissue. Doxorubicin (DOX) encapsulated in Z-MSN was not significantly released in physiological conditions (pH 7.4), whereas the release rate of DOX remarkably increased in mildly acidic conditions through disintegration of the gatekeeper. The antitumor efficacy of DOX-loaded Z-MSN (DOX-Z-MSN) was evaluated after their systemic administration to tumor-bearing mice. Compared to free DOX and DOX-loaded MSN without the gatekeeper, DOX-Z-MSN exhibited much higher antitumor efficacy in vivo. Overall, these results demonstrated that the hydrophilic negative surface of Z-MSN, with their closed gate, allowed for their effective accumulation in tumor tissue after systemic administration, and that their charge-swapping and gate-opening in the tumor environment enhanced their cellular uptake and drug release rate simultaneously, implying a highly promising potential for development of Z-MSN as a drug carrier for cancer therapy.In an attempt to address the issues of enhanced cellular uptake and site-specific drug release of nanoparticles, we herein report on zwitterionic MSN (Z-MSN) with a pH-responsive gatekeeper which can be internalized into cancer cells via switching their surface charge from negative, in physiological conditions, to positive, in the tumor microenvironment. We hypothesized that the hydrophilic negative surface of Z-MSN with a closed gate allows for their accumulation into tumor tissue after systemic administration, whereas their charge-swapping and gate-opening in the tumor environment enhance cellular uptake and drug release rate simultaneously. Overall, Z-MSN constitute a promising drug delivery carrier for 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.

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.

Nanobiohybrid hydrogels, which are composed of inorganic nanoparticles and biodegradable polymeric hydrogels, have received special attention in the field of drug and protein delivery. These systems exploit the unique advantages of each component to improve the efficacy of the therapeutic agents and minimize undesirable side effects. The objective of this study was to develop a gemcitabine-loaded nanobiohybrid hydrogel to overcome the limitations of this anticancer drug, such as the very short half-life of gemcitabine (GEM) in plasma, the systemic toxicity from high-dose therapy, and the need for repeated administration during treatment. The proposed injectable nanobiohybrid hydrogel for controlled release of GEM was prepared through intercalation and adsorption of GEM to interlayer galleries and surfaces of montmorillonite (MMT) nanoparticles (forming MMT–GEM complexes), followed by the dispersion of the MMT–GEM complexes into the injectable, biodegradable, temperature-sensitive poly(e-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(e-caprolactone-co-lactide) hydrogel. The MMT–GEM complex and the nanobiohybrid hydrogel were characterized by X-ray diffraction analysis, particle size and zeta potential measurements, Fourier transform infrared spectroscopy, and scanning electron microscopy. Improvements in the properties of nanobiohybrid hydrogel in comparison with the pristine hydrogel were confirmed through sol–gel phase transition diagram, rheological measurement, and in vivo stability. The non-cytotoxicity of the nanobiohybrid hydrogel was proven by MTT assay using the 293T cell line. Compared with the pristine hydrogel, the in vitro GEM release from the nanobiohybrid hydrogel showed a considerably prolonged GEM release time and a much lower initial burst. The antitumor efficacy studies on pancreatic tumor-bearing mice revealed a significant inhibition of tumor growth. Hence, these findings demonstrate that the nanobiohybrid hydrogel is a desirable carrier for controlled release of GEM in the treatment of pancreatic cancer.

Hypoxia occurs in a variety of pathological conditions including stroke, rheumatoid arthritis, atherosclerosis, and tumors. In this study, an amphiphilic block copolymer, composed of poly(ethylene glycol) as the hydrophilic block and poly(e-(4-nitro)benzyloxycarbonyl- l -lysine) as the hydrophobic block, was prepared for hypoxia-sensitive drug delivery. Owing to its amphiphilic nature, the block copolymer formed micelles and encapsulated doxorubicin (DOX) in an aqueous condition. The DOX-loaded micelles exhibited rapid intracellular release of DOX under the hypoxic condition, implying high potential as a drug carrier for cancer therapy. Statement of significance Hypoxia occurs in a variety of pathological conditions including stroke, rheumatoid arthritis, atherosclerosis, and tumors. In this study, we developed a novel type of hypoxia-sensitive polymeric micelles (HS-PMs) that can specifically release the drug under the hypoxic conditions. HS-PMs were prepared using poly(ethylene glycol) as the hydrophilic block and poly(e-(4-nitro)benzyloxycarbonyl- l -lysine) as the hydrophobic block. Owing to its amphiphilic nature, the block copolymer formed micelles and encapsulated doxorubicin (DOX) in an aqueous condition. The DOX-loaded micelles exhibited rapid intracellular release of DOX under the hypoxic condition. Overall, it is evident that the HS-PMs prepared in this study have the potential to effectively deliver hydrophobic drugs into the hypoxic cells involved in various intractable diseases.

In the present study, a type of bioconjugate was synthesized by post modification of alginate by conjugating temperature-responsive poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide) and O-phosphorylethanolamine as phosphorylation functional groups. Freely flowing bioconjugate sols at low temperature can transform to stable viscoelastic gels at the physiological temperature (37 °C). Subcutaneous administration of temperature-responsive bioconjugate sols into the dorsal region of Sprague-Dawley rats formed in situ hydrogel. in situ formation of bioconjugate gels in stimulated body fluids at 37 °C showed nucleation and hydroxyapatite mineral growth. Furthermore, hydroxyapatite growth was also found in in vivo gels, which suggested the potential of alginate-based bioconjugate gels as a scaffold for bone engineering. Bone morphogenetic protein 2 (BMP-2)-loaded bioconjugate formed stable gel in vivo, and demonstrated sustained release. BMP-2-loaded bioconjugates exhibited in situ biomineralization in vivo. These results imply that the in situ formation of injectable biomimetic materials has potential for bone tissue engineering applications.