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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.

Injectable hydrogels are a unique class of hydrogels that are formed upon injection into living bodies. They possess features of typical hydrogels such as softness, 3D network structures, large contents of water, the ability to load water-soluble substances, and so on. Furthermore, their injectability allows injectable hydrogels to be implanted into living bodies using a syringe in a minimally invasive way. After being loaded with different active substances (drugs, proteins, genes, viruses, cells, etc.), injectable hydrogels have been demonstrated to be potential in many different biomedical applications including controlled release and tissue engineering. However, biodegradability is also an important property of injectable hydrogels and allows removal of the hydrogels after accomplishment of their tasks. In this Perspective, we aim at introducing several different types of biodegradable and injectable hydrogels and compare their differences in properties and applications. Lastly, we also point out some remaining problems and future trends in the field of biodegradable and injectable hydrogels.

This paper presents the three-dimensional analysis of the stress distribution arising in an isotropic infinite slab with a triaxial ellipsoidal cavity, the surface of which is subjected to the thre...

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.

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.

To maintain the cellular functions of a stem cells for therapeutic tissue engineering, an advanced cell culture method for safe cell dissociation is necessary. We developed a novel cell dissociation method by applying pH-responsive bioreducible polymer on the surface of tissue culture plates (TCPs). We applied acid-responsive bioreducible poly (amino ester) (PAE) as a new candidate for surface coating method to develop alternative cell dissociation method against conventional enzyme (trypsin-ethylene diamine tetra acetic acid (EDTA)) treatment. Human adipose derived stem cells (hADSCs) were cultured on and dissociated from PAE-coated TCPs to compare cell adhesion, cell proliferation, cell viability, and functionality to those of the cells cultured on and dissociated with trypsin-EDTA from normal TCPs without PAE coating. To confirm the in vivo therapeutic efficacy of the hADSCs retrieved from PAE-coated TCPs compared to that of the cells retrieved from normal TCPs with trypsin-EDTA, we induced skin defects at the dorsal area of mice and injected the cells collected from both conditions. With the PAE coating method, cell adhesion, cell proliferation, cell viability, and functionality, especially the angiogenic efficacy, were well preserved when compared to those of the cells treated with trypsin-EDTA. In addition to in vitro results, injecting hADSCs retrieved from PAE-coated TCPs showed similar in vivo angiogenesis and wound closing efficiency compared to those of injecting hADSCs retrieved from normal TCPs with trypsin-EDTA treatment at 2 weeks after the transplantation into mouse skin wound models. We proposed the alternative method for the cell dissociation with pH-responsive bioreducible polymer, PAE. This PAE coating method may lead to the development of alternative cell dissociation method without using enzyme for future regenerative medicine and stem cell therapy.

Despite the advantages of stem cell injection to the skin wound site, this technique is limited in terms of the delivery of therapeutically functional stem cells to the wound site. Considering the abnormal microenvironment of a wound site, even a small damage or loss of cell function induced by severe trypsin treatment might lead to decrement of the therapeutic efficacy of stem cells. In this study, we have synthesized pH-responsive polymer mixed poly(amino ester) (mPAE), which can provide the appropriate cell culture condition for cell growth without cytotoxicity along with the maintenance of extracellular matrix after detachment using low pH (6.0) PBS. Human adipose derive stem cells (hADSCs) cultured on and detached from mPAE-coated tissue culture plates (TCPs) showed similar cell adhesion and angiogenic paracrine factor secretion, compared to hADSCs cultured on and detached from TCPs with trypsin. As a result, hADSCs detached with pH 6.0 PBS from mPAE-coated TCPs showed similar therapeutic angiogenesis and wound regeneration, compared to the hADSCs detached with trypsin from TCPs. In conclusion, our pH-responsive polymer, mPAE, might be utilized as an enzyme-free cell detachment system for future tissue engineering.

An amphiphilic graft copolymer, composed of poly(β-amino ester)-graft-poly(ethylene glycol) (PAE-g-PEG), was prepared as the drug carrier for treatment of rheumatoid arthritis (RA). PAE-g-PEG was synthesized through Michael addition polymerization and analyzed by 1H nuclear magnetic resonance (1H NMR). Owing to its amphiphilic property, PAE-g-PEG was self-assembled into spherical micelles (23 nm in diameter) in an aqueous environment Methotrexate, a hydrophobic drug for the treatment of RA, was physically loaded into the hydrophobic core of micelles by the dialysis method, resulting in high encapsulation efficiency (85.36%). Dynamic light scattering and transmission electron microscopy revealed that the micellar structure at pH 7.4 rapidly disassociated under the mildly acidic environment (pH < 6.5), mimicking the pathological condition of RA. Owing to the rapid disassociation of PAE-g-PEG micelles, methotrexate in the micelles was rapidly released under the mildly acidic condition. The micelles were non-toxic to and readily taken up by RAW 264.7 cells. When systemically administered into collagen-induced arthritis mice models, the pH-sensitive micelles effectively accumulated in inflamed joints, implying their high targetability to RA. Overall, PAE-g-PEG micelles might be useful as the carrier for targeting RA.

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.

The activation and maturation of dendritic cells are critical in immunotherapy, and the potency of DCs is associated with high levels of antigen presentation on major histocompatibility complex (MHC) class I and II and the expression of costimulatory signals. Graphene oxide (GO) and its derivatives have many excellent physicochemical properties, including large and hydrophobic surface available for interacting with hydrophobic or aromatic drugs via π–π stacking forces, flexibility of the chemical modification on the surfaces, and capacity of DC activation. In this study, we designed a simple strategy to achieve the co-delivery of a DNA vaccine and hydrophobic immune adjuvant (R848) and to enhance the adjuvanticity of R848 via the synergistic effect of GO and R848. Thiolated low-molecular-weight polyethylenimine (TPEI1.8) was crosslinked with 4-aminothiophenol-modified GO (TGO) via the formation of disulfide bonds. Thus, TGO with its assembled TPEI1.8 could not only load R848 but also electrostatically interact with the DNA vaccine. Owing to the reducibility of the disulfide bond in the cellular environment, the DNA vaccine could be readily released. This system can significantly enhance the DNA transfection, the expression of the costimulatory signal, and the level of antigen presentation to MHC class I DCs for their activation and maturation.

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.

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.

In this paper, scattering of plane compressional waves by two rigid inclusions in an infinite poroelastic medium is investigated. Laplace transform and Erdelyi's formula are used to satisfy the pla...

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.

The singular stress problem of a penny-shaped crack situated symmetrically on an off-diametral plane of a sphere is presented in this paper when the surface of the crack is subjected to a known pre...

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.

The problem of light scattering by a homogeneous sphere above a plane boundary is considered in this paper. Hankel transformation and Erdelyi's formula are used to satisfy the boundary conditions o...

Since delivering drugs to an entire tumoral region leads to high therapeutic efficacy and good prognosis, achieving deep tumoral penetration of drugs is a major issue in cancer treatment. In this regard, conventional nanomedicines (50 nm) have shown limitations in cancer therapy, primarily attributed to the heterogeneous distribution of drugs because of the physiological barrier of the tumor interstitial space. To address this issue, we prepared transformable hybrid nanoparticles (TNPs) consisting of a pH-responsive nanocarrier (PEG-PBAE) and doxorubicin (DOX)-conjugated ultrasmall (3 nm) gold nanoparticles (nanosatellites). It has been shown that PEG-PBAE can serve as a reservoir for nanosatellites and release them in mildly acidic conditions (pH 6.5), mimicking the tumor microenvironment. When DOX-loaded TNPs (DOX-TNPs) were intravenously injected into tumor-bearing mice, they successfully accumulated and dissociated at the extracellular level of the tumor, leading to the disclosure of nanosatellites and free DOX. While the free DOX accumulated in tumor tissue near blood vessels, the deeply diffused nanosatellites were taken up by the tumor cell, followed by the release of DOX via cleavage of pH-responsive ester linkages in the nanosatellites at the intracellular level. Consequently, the DOX-TNPs effectively suppressed tumor growth through improved tumor penetration of DOX, suggesting their promising potential as a cancer nanomedicine.Deep tumor penetration of anticancer drug is an important issue for high therapeutic efficacy. If the drugs cannot reach cancer cells in a sufficient concentration, their effectiveness will be limited. In this regard, conventional nanomedicine showed only modest therapeutic efficacy since they cannot deliver their payloads to the deep site of tumor tissue. This heterogeneous distribution of the drug is primarily attributed to the physiological barriers of the tumor microenvironment, including a dense extracellular matrix. To surmount this challenge, we developed tumor acidity-triggered transformable nanoparticles. By encapsulating doxorubicin-conjugated ultrasmall gold nanosatellites into the nanoparticles, the drug was not significantly bound to genetic materials, resulting in its minimal sequestration near the vasculature and deep tumor penetration. Our strategy could resolve not only the poor penetration issue of the drug but also its restricted tumor accumulation, suggesting the potential as an effective nanotherapeutics.

Cell therapy usually accompanies cell detachment as an essential process in cell culture and cell collection for transplantation. However, conventional methods based on enzymatic cell detachment can cause cellular damage including cell death and senescence during the routine cell detaching step due to an inappropriate handing. The aim of the current study is to apply the pH-responsive degradation property of poly (amino ester) to the surface of a cell culture dish to provide a simple and easy alternative method for cell detachment that can substitute the conventional enzyme treatment. In this study, poly (amino ester) was modified (cell detachable polymer, CDP) to show appropriate pH-responsive degradation under mild acidic conditions (0.05% (w/v) CDP, pH 6.0) to detach stem cells (human adipose tissue-derived stem cells (hADSCs)) perfectly within a short period (less than 10 min). Compared to conventional enzymatic cell detachment, hADSCs cultured on and detached from a CDP-coated cell culture dish showed similar cellular properties. We further performed in vivo experiments on a mouse hindlimb ischemia model (1.0 × 106 cells per limb). The in vivo results indicated that hADSCs retrieved from normal cell culture dishes and CDP-coated cell culture dishes showed analogous therapeutic angiogenesis. In conclusion, CDP could be applied to a pH-responsive cell detachment system as a simple and easy nonenzymatic method for stem cell culture and various cell therapies.

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.

Multifunctional nanosystems that can transport therapeutic and diagnostic agents into tumor sites and activate their respective functions via tumor-microenvironment recognition are highly desirable for clinical applications. We fabricated pH and redox dual-activatable self-assembled nanotheranostics (named as DA-SNs) via coordination-driven self-assembly of chlorin e6 (Ce6) disulfide-linked pH sensitive polymer ligand, poly (isobutylene-alt-maleic anhydride-graft-methoxy-poly (ethyleneglycol)-graft-imidazole-graft-Cystamine-Ce6) [PIMA-mPEG-API-SS-Ce6], and gadolinium ions (Gd3+). DA-SNs exhibited uniform particle size of ~48 nm, excellent stability, and inherent biosafety. Negatively charged DA-SNs could prolong blood circulation time (t1/2 = 2.91 h) and improve tumor accumulation. Moreover, DA-SNs could undergo surface charge switch from negative charge to positive one in a slightly acidic tumor extracellular environment (pH 6.8), thus enhancing cellular uptake. After entering tumor cells, fluorescence, photodynamic therapeutic activity, and T1MR contrast from DA-SNs could be activated within this intracellular environment with lowered pH and high level of GSH. Importantly, human tumors implanted in mice could be successfully visualized via distinct pH and redox dual-sensitive T1MR contrast and fluorescence imaging, indicating that DA-SNs could serve as a dual-modal MR/fluorescence imaging probe for tumor-targeting diagnosis. In addition, DA-SNs exhibited superior photodynamic therapeutic efficiency with negligible side effects. Therefore, this DA-SN shows great promise for synergistic photodynamic therapy and diagnostic imaging.

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.

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.

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.

For rapid detection of carbaryl pesticides, we developed a simple colorimetric detection method based on azo-coupling reaction. Pretreating carbaryl pesticides with an organic base yielded 1-naphthol, which readily reacted with a diazonium salt with a dramatic color change. Since the resulting azo dye can further change color with the organic base used in the pretreatment, phosphoric acid was added to suppress the confounding colorimetric response. We report that this new colorimetric method can selectively detect carbaryl pesticides from other carbamate pesticides within a minute. Moreover, carbaryl can be detected below 10 parts per million (ppm), which is below its permissible exposure limit (∼15 ppm). Finally, we successfully estimated the concentrations of carbaryl pesticides on fruit samples in the presence of natural interferences.

The singular stress problem of aperipheral edge crack around a cavity of spherical portion in an infinite elastic medium whenthe crack is subjected to a known pressure is investigated. The problem is solved byusing integral transforms and is reduced to the solution of a singularintegral equation of the first kind. The solution of this equation is obtainednumerically by the method due to Erdogan, Gupta , and Cook, and thestress intensity factors are displayed graphically.Also investigated in this paper is the penny shaped crack situated symmetrically on the central plane of a convex lens shaped elastic material. Doo-Sung Lee "Crack problems concerning boundaries of convex lens like forms" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-2 | Issue-3 , April 2018, URL: https://www.ijtsrd.com/papers/ijtsrd11106.pdf

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.

Paclitaxel (PTX) is used as a major antitumor agent for the treatment of recurrent and metastatic breast cancer. For the clinical application of PTX, it needs to be dissolved in an oil/detergent-based solvent due to its poor solubility in an aqueous medium. However, the formulation often causes undesirable complications including hypersensitivity reactions and limited tumor distribution, resulting in a lower dose-dependent antitumor effect. Herein, we introduce a facile and oil-free method to prepare albumin-based PTX nanoparticles for efficient systemic cancer therapy using a conjugate of human serum albumin (HSA) and poly(ethyleneglycol) (PEG). PTX were efficiently incorporated in the self-assembled HSA-PEG nanoparticles (HSA-PEG/PTX) using a simple film casting and re-hydration procedure without additional processes such as application of high pressure/shear or chemical crosslinking. The spherical HSA-PEG nanoparticle with a hydrodynamic diameter of ca. 280 nm mediates efficient cellular delivery, leading to comparable or even higher cytotoxicity in various breast cancer cells than that of the commercially available Abraxane®. When systemically administered in a mouse xenograft model for human breast cancer, the HSA-PEG-based nanoparticle formulation exhibited an extended systemic circulation for more than 96 h and enhanced intratumoral accumulation, resulting in a remarkable anticancer effect and prolonged survival of the animals.

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.

Multifunctional nanoplatforms that can combine diagnostic functions and therapeutic capabilities are highly required for the construction of novel cancer diagnosis-therapy integrative systems. In this work, we developed multifunctional and tumor redox-responsive magnetic nanoclusters (RMNs) by the self-assembly of iron oxide nanoparticles with a chlorin e6 (Ce6)-disulfide-linked polymer ligand. The core of RMNs could enhance the T2-weighted MR contrast capability, and the surface ligand could improve the system stability and load Ce6. In addition, the obtained RMNs also exhibited excellent biocompatibility and higher cytotoxicity upon near infrared (NIR)-irradiation. These RMNs with a size of ∼90 nm can effectively facilitate their accumulation in tumor sites through the enhanced permeability and retention (EPR) effect and subsequently are endocytosed into a highly reductive intracellular environment that activates fluorescence and photodynamic therapeutic antitumor activity. Furthermore, the in vivo imaging and therapy results not only confirmed that RMNs can as bimodal imaging probes for the early-stage diagnosis of cancer but also demonstrated the superior photodynamic therapeutic efficiency of RMNs in suppressing tumor growth. These results indicated that RMNs show great potential for simultaneous diagnostic imaging and photodynamic therapy.

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.

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.