Highly Prolonged Release of the Cancer Vaccine and Immunomodulator via a Two-Layer Biodegradable Microneedle for Prophylactic Treatment of Metastatic Cancer.

Simultaneous sustained release of cancer vaccines and immunomodulators may effectively trigger durable immune responses and avoid multiple administrations. Here, we established a biodegradable microneedle (bMN) based on a biodegradable copolymer matrix made of polyethylene glycol (PEG) and poly(sulfamethazine ester urethane) (PSMEU). This bMN was applied to the skin and slowly degraded in the epidermis/dermis layers. Then, the complexes composed of a positively charged polymer (DA3), cancer DNA vaccine (pOVA), and toll-like receptor 3 agonist poly(I/C) were synchronously released from the matrix in a pain-free manner. The whole microneedle patch was fabricated with two layers. The basal layer was formed using polyvinyl pyrrolidone/polyvinyl alcohol that could be rapidly dissolved upon applying the microneedle patch to the skin, whereas the microneedle layer was formed by complexes encapsulating biodegradable PEG-PSMEU, which was stuck at the injection site for sustained release of therapeutic agents. According to the results, 10 days is the time for the complexes to be completely released and express specific antigens in antigen-presenting cells in vitro and in vivo. It is noteworthy that this system could successfully elicit cancer-specific humoral immune responses and inhibit metastatic tumors in the lungs after a single shot of immunization.

CD44-Targeted and Enzyme-Responsive Photo-Cross-Linked Nanogels with Enhanced Stability for In Vivo Protein Delivery.

One of the biggest challenges of the protein delivery system is to realize stable and high protein encapsulation efficiency in blood circulation and rapid release of protein in the targeted tumor cells. To overcome these hurdles, we fabricated enzyme-responsive photo-cross-linked nanogels (EPNGs) through UV-triggered chemical cross-linking of cinnamyloxy groups in the side chain of PEGylation hyaluronic acid (HA) for CD44-targeted transport of cytochrome c (CC). The EPNGs showed high loading efficiency and excellent stability in different biological media. Notably, CC leakage effectively suppressed under physiological conditions but accelerated release in the presence of hyaluronidase, an overexpressed enzyme in tumor cells. Moreover, thiazolylblue tetrazolium bromide (MTT) results indicated that the vacant EPNGs showed excellent nontoxicity, while CC-loaded EPNGs exhibited higher killing efficiency to CD44-positive A549 cells than to CD44-negative HepG2 cells and free CC. Confocal images confirmed that CC-loaded EPNGs could effectively be internalized by CD44-mediated endocytosis pathway and rapidly escape from the endo/lysosomal compartment. Human lung tumor-bearing mice imaging assays further revealed that CC-loaded EPNGs actively target tumor locations. Remarkably, CC-loaded EPNGs also exhibited enhanced antitumor activity with negligible systemic toxicity. These results implied that these EPNGs have appeared as stable and promising nanocarriers for tumor-targeting protein delivery.

Recent Advances of pH-Induced Charge-Convertible Polymer-Mediated Inorganic Nanoparticles for Biomedical Applications.

The incorporation of functional polymers and inorganic nanoparticles into nanoplatforms has the potential to produce personalized nanomedicine systems for further biomedical applications. Polymers that endow inorganic nanoparticles with unique surface properties for prolonged blood circulation and improved tumor targeting and cellular uptake are especially desired. pH-induced charge-switchable polymers are sensitive to the pH of the tumor environment and maintain a negative or neutral charge in blood circulation, increasing their circulation time and enhancing tumor accumulation via the enhanced permeability and retention effect. This type of polymer further transforms its charge to positive in acidic tumor locations to promote cellular uptake. Furthermore, the combination of pH-induced charge-switchable polymers with various inorganic nanoparticles (e.g., magnetic nanoparticles, gold nanoparticles, quantum dots, and upconversion materials) activates their intrinsic functions in in situ diagnosis and disease therapy. This review briefly overviews the recent progress in the development and application of various pH-induced charge-convertible polymers functionalized with different types of inorganic nanoparticles for different biomedical applications. More importantly, future developments in this field are also discussed.

One-Step Preparation of pH-Responsive Polymeric Nanogels as Intelligent Drug Delivery Systems for Tumor Therapy.

In this work, pH-responsive polypeptide-based nanogels are reported as potential drug delivery systems. By the formation of pH-sensitive benzoic imine bonds, pH-responsive nanogels are constructed using hydrophilic methoxy poly(ethylene glycol)- b-poly[ N-[ N-(2-aminoethyl)-2-aminoethyl]-l-glutamate] (MPEG- b-PNLG) and hydrophobic terephthalaldehyde (TPA) as a cross-linker. At pH 7.4, MPEG- b-PNLG nanogels exhibit high stabilities with hydrophobic inner cores, which allow encapsulation of hydrophobic therapeutic agents. Under tumoral acidic environments (pH ∼6.4), the cleavage of benzoic imine bonds induces the destruction of MPEG- b-PNLG nanogels and leads to rapid release of their payloads. The formation and pH sensitivity of the nanogels are investigated by dynamic light scattering. These nanogels exhibit excellent stabilities in the presence of salt or against dilution. The globular morphologies of the nanogels are confirmed using transmission electron microscopy. Doxorubicin is used as a model drug to evaluate drug encapsulation and release. Finally, the anticancer activities of the drug-encapsulated nanogels are assessed in vitro.

Bioinspired pH- and Temperature-Responsive Injectable Adhesive Hydrogels with Polyplexes Promotes Skin Wound Healing.

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.

Polymer-Based and pH-Sensitive Nanobiosensors for Imaging and Therapy of Acidic Pathological Areas.

Nanobiosensors with high sensitivity and specificity have shown great potential in the detection of diseases. The incorporation of therapeutic agents with nanobiosensors allows the simultaneous diagnosis and therapy of diseases. The delivery of nanobiosensors and therapeutic agents using polymers is a common strategy to improve imaging and therapeutic efficacies. These polymers play important roles in several aspects during a successful delivery process, such as increasing the stability and biocompatibility of the nanobiosensors and improving their cell endocytosis. The pH-sensitivity of the nanobiosensors endows them with various capabilities, such as enabling the selective targeting of pathological areas, activation of imaging signals and controlled release of payloads. This review focuses on the design, preparation and characterization of polymer-based and pH-sensitive nanobiosensors and the in intro/in vivo assessment of their ability to serve as efficient agents for the diagnosis and therapy of acidic pathological areas.

Tuning Surface Charge and PEGylation of Biocompatible Polymers for Efficient Delivery of Nucleic Acid or Adenoviral Vector.

As an effective and safe strategy to overcome the limits of therapeutic nucleic acid or adenovirus (Ad) vectors for in vivo application, various technologies to modify the surface of vectors with nonimmunogenic/biocompatible polymers have been emerging in the field of gene therapy. However, the transfection efficacy of the polymer to transfer genetic materials is still relatively weak. To develop more advanced and effective polymers to deliver not only Ad vectors, but also nucleic acids, 6 biocompatible polymers were newly designed and synthesized to different sizes (2k, 3.4k, or 5k) of poly(ethylene) glycol (PEG) and different numbers of amine groups (2 or 5) based on methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-l-glutamate (PNLG). We characterized size distribution and surface charge of 6 PNLGs after complexation with either nucleic acid or Ad. Among all 6 PNLGs, the 5 amine group PNLG showed the strongest efficacy in delivering nucleic acid as well as Ad vectors. Interestingly, cellular uptake results showed higher uptake ability in Ad complexed with 2 amine group PNLG than Ad/5 amine group PNLG, suggesting that the size of Ad/PNLGs is more essential than the surface charge for cellular uptake in polymers with charges greater than 30 mV. Moreover, the endosome escape ability of Ad/PNLGs increased depending on the number of amine groups, but decreased by PEG size. Cancer cell killing efficacy and immune response studies of oncolytic Ad/PNLGs showed 5 amine group PNLG to be a more effective and safe carrier for delivering Ad. Overall, these studies provide new insights into the functional mechanism of polymer-based approaches to either nucleic acid or Ad/nanocomplex. Furthermore, the identified ideal biocompatible PNLG polymer formulation (5 amine/2k PEG for nucleic acid, 5 amine/5k PEG for Ad) demonstrated high transduction efficiency as well as therapeutic value (efficacy and safety) and thus has strong potential for in vivo therapeutic use in the future.

Recent strategies to develop pH-sensitive injectable hydrogels.

"Smart" biomaterials that are responsive to pathological abnormalities are an appealing class of therapeutic platforms for the development of personalized medications. The development of such therapeutic platforms requires novel techniques that could precisely deliver therapeutic agents to the diseased tissues, resulting in enhanced therapeutic effects without harming normal tissues. Among various therapeutic platforms, injectable pH-responsive biomaterials are promising biomaterials that respond to the change in environmental pH. Aqueous solutions of injectable pH-responsive biomaterials exhibit a phase transition from sol-to-gel in response to environmental pH changes. The injectable pH-responsive hydrogel depot can provide spatially and temporally controlled release of various bioactive agents including chemotherapeutic drugs, peptides, and proteins. Therapeutic agents are imbibed into hydrogels by simple mixing without the use of toxic solvents and used for long-term storage or in situ injection using a syringe or catheter that could form a stable gel and acts as a controlled release depot in a minimally invasive manner. Tunable physicochemical properties of the hydrogels, such as biodegradability, ability to interact with drugs and mechanical properties, can control the release of the therapeutic agent. This review highlights the advances in the design and development of biodegradable and in situ forming injectable pH-responsive biomaterials that respond to the physiological conditions. Special attention has been paid to the development of amphoteric pH-responsive biomaterials and their utilization in biomedical applications. We also highlight key challenges and future directions of pH-responsive biomaterials in clinical translation.

Advances in biodegradable and injectable hydrogels for biomedical applications.

In situ-forming injectable hydrogels are smart biomaterials that can be implanted into living bodies with minimal invasion. Due to pioneer work of Prof. Sung Wan Kim in this field, injectable hydrogels have shown great potentials in many different biomedical applications. Biodegradable and injectable hydrogels can be administered at room temperature as viscous polymer sols. They will degrade after accomplishing their tasks. Before injecting into living bodies, active substances can be loaded into viscous polymer sols with a high loading efficiency by simple mixing. After injecting into living bodies, active substances-loaded hydrogels can be formed and active substances can be released in a controlled manner upon diffusion or polymer degradation. Due to their outstanding properties and unique features, injectable hydrogels are very promising in many biomedical applications including drug/protein/gene delivery, tissue engineering, and regenerative medicine. In this review, we briefly introduce recent development of several important types of in situ-forming injectable hydrogels reported by our group during the last three years. Important properties and potential applications (such as cancer therapy, insulin release and wound healing) of these injectable hydrogels are reviewed. Challenges and perspectives in this research field are also discussed.

Temperature and pH-responsive in situ hydrogels of gelatin derivatives to prevent the reoccurrence of brain tumor.

Glioblastoma multiforme (GBM) is a grade IV malignant brain tumor with a median survival time of approximately 12-16 months. Because of its highly aggressive and heterogeneous nature it is very difficult to remove by surgical resection. Herein we have reported dual stimuli-responsive and biodegradable in situ hydrogels of oligosulfamethazine-grafted gelatin and loaded with anticancer drug paclitaxel (PTX) for preventing the progress of Glioblastoma. The oligosulfamethazine (OSM) introduced to the gelatin backbone for the formation of definite and stable in situ hydrogel. The hydrogels transformed from a sol to a gel state upon changes in stimuli. pH and temperature and retained a distinct shape after subcutaneous administration in BALB/c mice. The viscosity of the sol state hydrogels was tuned by varying the feed molar ratio between gelatin and OSM. The porosity of the hydrogels was confirmed to be lower in higher degree OSM by SEM. Sustained release of PTX from hydrogels in physiological environments (pH 7.4) was further retarded up to 63% in 9th days in tumor environments (pH 6.5). While the empty hydrogels were non-toxic in cultured cells, the hydrogels loaded with PTX showed antitumor efficacy in orthotopic-GBM xenograft mice. Collectively, the gelatin-OSM formed porous hydrogels and released the cargo in a sustained manner in tumor environments efficiently suppressing the progress of GBM. Thus, gelatin-OSM hydrogels are a potential candidate for the direct delivery of therapeutics to the local areas in brain diseases.

Optimizing Active Tumor Targeting Biocompatible Polymers for Efficient Systemic Delivery of Adenovirus.

Adenovirus (Ad) has risen to be a promising alternative to conventional cancer therapy. However, systemic delivery of Ad, which is necessary for the treatment of metastatic cancer, remains a major challenge within the field, owing to poor tumor tropism and nonspecific hepatic tropism of the virus. To address this limitation of Ad, we have synthesized two variants of folic acid (FA)-conjugated methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-L-glutamate (P5N2LG-FA and P5N5LG-FA) using 5 kDa poly(ethylene glycol) (PEG) with a different level of protonation (N2 < N5 in terms of charge), along with a P5N5LG control polymer without FA. Our findings demonstrate that P5N5LG, P5N2LG-FA, and P5N5LG-FA exert a lower level of cytotoxicity compared to 25 kDa polyethyleneimine. Furthermore, green fluorescent protein (GFP)-expressing Ad complexed with P5N2LG-FA and P5N5LG-FA (Ad/P5N2LG-FA and Ad/P5N5LG-FA, respectively) exerted superior transduction efficiency compared to naked Ad or Ad complexed with P5N5LG (Ad/P5N5LG) in folate receptor (FR)-overexpressing cancer cells (KB and MCF7). All three nanocomplexes (Ad/P5N5LG, Ad/P5N2LG-FA, and Ad/P5N5LG-FA) internalized into cancer cells through coxsackie adenovirus receptor-independent endocytic mechanism and the cell uptake was more efficient than naked Ad. Importantly, the cell uptake of the two FA functionalized nanocomplexes (Ad/P5N2LG-FA and Ad/P5N5LG-FA) was dependent on the complementary interaction of FA-FR. Systemically administered Ad/P5N5LG, Ad/P5N2LG-FA, and Ad/P5N5LG-FA showed exponentially higher retainment of the virus in blood circulation up to 24 h post-administration compared with naked Ad. Both tumor-targeted nanocomplexes (Ad/P5N2LG-FA and Ad/P5N5LG-FA) showed significantly higher intratumoral accumulation than naked Ad or Ad/P5N5LG via systemic administration. Both tumor-targeted nanocomplexes accumulated at a lower level in liver tissues compared to naked Ad. Notably, the nonspecific accumulation of Ad/P5N2LG-FA was significantly lower than Ad/P5N5LG-FA in several normal organs, while exhibiting a significantly higher intratumoral accumulation level, showing that careful optimization of polyplex surface charge is critical to successful tumor-targeted systemic delivery of Ad nanocomplexes.

Tumor-targeting peptide conjugated pH-responsive micelles as a potential drug carrier for cancer therapy.

Herein, we prepared tumor-targeting peptide (AP peptide; CRKRLDRN) conjugated pH-responsive polymeric micelles (pH-PMs) in cancer therapy by active and pH-responsive tumor targeting delivery systems, simultaneously. The active tumor targeting and tumoral pH-responsive polymeric micelles were prepared by mixing AP peptide conjugated PEG-poly(d,l-lactic acid) block copolymer (AP-PEG-PLA) into the pH-responsive micelles of methyl ether poly(ethylene glycol) (MPEG)-poly(beta-amino ester) (PAE) block copolymer (MPEG-PAE). These mixed amphiphilic block copolymers were self-assembled to form stable AP peptide-conjugated and pH-responsive AP-PEG-PLA/MPEG-PAE micelles (AP-pH-PMs) with an average size of 150 nm. The AP-pH-PMs containing 10 wt % of AP-PEG-PLA showed a sharp pH-dependent micellization/demicellization transition at the tumoral acid pH. Also, they presented the pH-dependent drug release profile at the acidic pH of 6.4. The fluorescence dye, TRITC, encapsulated AP-pH-PMs (TRITC-AP-pH-PMs) presented the higher tumor-specific targeting ability in vitro cancer cell culture system and in vivo tumor-bearing mice, compared to control pH-responsive micelles of MPEG-PAE. For the cancer therapy, the anticancer drug, doxorubicin (DOX), was efficiently encapsulated into the AP-pH-PMs (DOX-AP-pH-PMs) with a higher loading efficiency. DOX-AP-pH-PMs efficiently deliver anticancer drugs in MDA-MB231 human breast tumor-bearing mice, resulted in excellent anticancer therapeutic efficacy, compared to free DOX and DOX encapsulated MEG-PAE micelles, indicating the excellent tumor targeting ability of AP-pH-PMs. Therefore, these tumor-targeting peptide-conjugated and pH-responsive polymeric micelles have great potential application in cancer therapy.

Effect of hydrophobic octadecyl groups on pH-sensitive aggregation behavior of imidazole-containing polyaspartammide derivatives.

The effect of hydrophobic octadecyl groups on pH-dependent aggregation behavior of polyaspartammide derivatives was studied. A series of pH-sensitive amphiphilic polymers with different degrees of octaceylamine (C18) substitution were synthesized through a successive graft reaction of octaceylamine, O-(2-aminoethyl)-O'-methylpolyethylene glycol, and 1-(3-aminopropyl)imidazole on polysuccinimide. Micelle-like nano-aggregates were formed in aqueous solution at pH > 6.8 and they showed different pH dependent aggregation behavior according to degree of substitution (DS) of the hydrophobic C18 chains. These polymers will have a potential application as carriers for pH-sensitive drug release in anticancer or intracellular delivery systems.

Modularly engineered alginate bioconjugate hydrogel as biocompatible injectable scaffold for in situ biomineralization.

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.

Albumin affibody-outfitted injectable gel enabling extended release of urate oxidase-albumin conjugates for hyperuricemia treatment.

Therapeutic proteins are attractive candidates for the treatment of human diseases. However, their short half-life often limits their clinical application. To overcome this problem, injectable hydrogels have been developed as depots for controlled release of therapeutic proteins, but these systems have not yet achieved the desired extended, sustained drug release profile. Our strategy herein was to implement selective and strong interactions between the hydrogels and therapeutic proteins. Specifically, we investigated whether strong and specific interactions between human serum albumin (HSA) and albumin-binding peptide (ABP) can be used to achieve extended release of urate oxidase (Uox), a therapeutic protein for hyperuricemia treatment, from pH- and temperature-sensitive injectable hydrogels consisting of poly(ethylene glycol)-poly(ß-amino ester urethane) (PEG-PAEU) copolymer. Thus, HSA was conjugated to Uox (Uox-HSA) and ABP was introduced in PEG-PAEU (PEG-PAEU-ABP). Polymers, conjugates, and hydrogels were extensively characterized for their physicochemical characteristics and in vivo efficacy in a hyperuricemia mouse model. Briefly, the hydrogels exhibited good injectability, in vitro biocompatibility and extended drug release, and in vivo gel formation and degradability. The serum half-life of the Uox-HSA loaded in PEG-PAEU-ABP hydrogels was ~96 h in mice, which was ~88, ~5.5, and ~2 times longer than that of free native Uox, free Uox-HSA, and Uox-HSA loaded in PEG-PAEU hydrogels, respectively. In the hyperuricemia mouse model, Uox-HSA loaded in PEG-PAEU-ABP hydrogels exhibited a substantially extended period of uric acid-lowering efficacy. These results clearly show that by applying ABP-HSA strong interaction to injectable hydrogels and therapeutic protein, the concentration of the therapeutic protein can be maintained for a long period in vivo, prolonging its therapeutic effect. Further, our approach can be tailored to accommodate other therapeutic proteins, which potentially expands the clinical applicability range of these systems.

A novel injectable pH-temperature sensitive hydrogel containing chitosan-insulin electrosprayed nanosphere composite for an insulin delivery system in type I diabetes treatment.

A novel insulin composite delivery system was prepared and characterized. The composite consisted of a pH- and temperature-sensitive hydrogel, which is an oligomer serine-b-poly(lactide)-b-poly(ethylene glycol)-b-poly(lactide)-b-oligomer serine (OS-PLA-PEG-PLA-OS) pentablock copolymer, as matrix and chitosan-insulin electrosprayed nanospheres (CIN) as constituent materials. The properties of the OS-PLA-PEG-PLA-OS pentablock copolymer and the chitosan-insulin nanoparticles were characterized. The chitosan-insulin nanospheres uniformly distributed in the matrix had a reinforcing effect on the mechanical properties and prolonged the degradation time of the hydrogel depot under body conditions. The composite solutions accommodating different concentrations of the chitosan-insulin nanospheres were subcutaneously injected into induced diabetic BALB/c mice to study the in vivo insulin-release profile. The result showed that insulin concentrations in blood plasma were maintained at a steady-state level. Furthermore, the bio-properties of the insulin were retained and it showed a blood glucose level reducing effect for more than 60 hours after injection to a streptozotocin (STZ)-induced diabetic mouse model. The results suggested that this injectable pH-temperature sensitive hydrogel containing chitosan-insulin electrosprayed nanosphere composites has promising potential applications for type 1 diabetes treatment.

Injectable poly(amidoamine)-poly(ethylene glycol)-poly(amidoamine) triblock copolymer hydrogel with dual sensitivities: pH and temperature.

A novel triblock copolymer for use in an injectable pH- and temperature-sensitive hydrogel is synthesized by conjugating poly(amidoamine) (PAA) to poly(ethylene glycol): poly(amidoamine)-poly(ethylene glycol)-poly(amidoamine) (PAA-PEG-PAA). The polymer was characterized with (1)H NMR and gel permeation chromatography in the diluents CDCl(3) and CHCl(3), respectively. The PAA block acts as a pH- and temperature-sensitive block. The PAA-PEG-PAA copolymer in aqueous solution (12.5 wt %) underwent a sol-gel transition as a function of pH and temperature. After injection into a rat, the copolymer solution (12.5 wt %) was immediately changed to a gel.

Charge-convertible polymers for improved tumor targeting and enhanced therapy.

Charge-convertible polymers are a class of intelligent polymers that can convert their charges in response to a certain stimulus in their environment. This unique property endows charge-convertible polymer-based biomaterials with great advantages in the treatment of disease. Drug-loaded charge-convertible polymeric nanoparticles have the ability to target tumor cells by converting their surface charges from negative or neutral to positive at the tumor site. In addition, charge-convertible polymeric biomaterials can form complexes with negatively charged therapeutic agents and release them through charge conversion at the desired time and site. In this review, the properties of charge-convertible polymers and their applications in the treatment of cancer and stroke are covered. More importantly, the limitations and perspectives of charge-convertible polymeric biomaterials in future clinical applications are discussed.

Hierarchical tumor acidity-responsive self-assembled magnetic nanotheranostics for bimodal bioimaging and photodynamic therapy.

Nanosized self-assemblies built from inorganic nanoparticles and polymer ligands have the potential to generate personalized theranostics systems for diagnostic imaging and cancer therapy. However, most of the theranostics systems suffer from poor targeting activity, insensitive diagnosis and drug leakage, leading to poor treatment results. In this study, a hierarchical tumor acidity-responsive magnetic nanobomb (termed HTAMN) was developed for photodynamic therapy and diagnostic imaging. The HTAMNs were formed through the self-assembly of chlorin e6 (Ce6)-functionalized polypeptide ligand, methoxy poly (ethyleneglycol)-block-poly (dopamine-ethylenediamine-2,3-dimethylmaleic anhydride)-L-glutamate-Ce6 [mPEG-b-P (Dopa-Ethy-DMMA)LG-Ce6] and superparamagnetic iron oxide nanoparticles (SPIONs). Negatively charged HTAMNs circulate in the blood for prolonged periods and promote tumor retention by passive targeting to the tumor. Once the HTAMNs arrive at the tumor location, the acidic extracellular tumor environment reverses the surface charge of the HTAMNs, resulting in tumor accumulation and cellular uptake. Moreover, in response to the more acidic environment inside cells, the photosensitizers are activated resulted in enhanced diagnostic imaging and cancer treatment. The in vitro and in vivo results indicate the effective tumor accumulation, internalization, diagnostic sensitivity and superior photodynamic therapy effect of the HTAMNs. Therefore, designing smart HTAMNs can promote the rapid development of cancer theranostics for clinical implementation.

Smart injectable biogels based on hyaluronic acid bioconjugates finely substituted with poly(ß-amino ester urethane) for cancer therapy.

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(ß-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.