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Phan, V.H. Giang,Thambi, Thavasyappan,Gil, Moon Soo,Lee, Doo Sung Elsevier 2017 Polymer Vol.109 No.-
<P><B>Abstract</B></P> <P>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 <I>in vivo</I>, 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 <I>in vitro</I> 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 <I>in vivo</I> 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 <I>in vivo</I> 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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Temperature- and pH-sensitive PEG-PSMCU copolymer was synthesized and characterized. </LI> <LI> PEG-PSMCU copolymers could form in situ hydrogel in SD rats. </LI> <LI> PEG-PSMCU hydrogels exhibited sustained biodegradation <I>in vivo.</I> </LI> <LI> Lysozyme-loaded PEG-PSMCU hydrogels exhibit sustained protein release <I>in vivo.</I> </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>An anionic injectable hydrogel based on temperature- and pH-sensitive poly(ethylene glycol)-poly(sulfamethazine carbonate urethane) copolymers has been developed for the sustained delivery of cationic model protein, lysozyme.</P> <P>[DISPLAY OMISSION]</P>
Giang Phan, V.H.,Duong, Huu Thuy Trang,Thambi, Thavasyappan,Nguyen, Thanh Loc,Turabee, Md. Hasan,Yin, Yue,Kim, Seong Han,Kim, Jaeyun,Jeong, Ji Hoon,Lee, Doo Sung IPC Science and Technology Press 2019 Biomaterials Vol.195 No.-
<P><B>Abstract</B></P> <P>Lymphoid organs, which are populated by dendritic cells (DCs), are highly specialized tissues and provide an ideal microenvironment for T-cell priming. However, intramuscular or subcutaneous delivery of vaccine to DCs, a subset of antigen-presenting cells, has failed to stimulate optimal immune response for effective vaccination and need for adjuvants to induce immune response. To address this issue, we developed an in situ-forming injectable hybrid hydrogel that spontaneously assemble into microporous network upon subcutaneous administration, which provide a cellular niche to host immune cells, including DCs. In situ-forming injectable hybrid hydrogelators, composed of protein-polymer conjugates, formed a hydrogel depot at the close proximity to the dermis, resulting in a rapid migration of immune cells to the hydrogel boundary and infiltration to the microporous network. The biocompatibility of the watery microporous network allows recruitment of DCs without a DC enhancement factor, which was significantly higher than that of traditional hydrogel releasing chemoattractants, granulocyte-macrophage colony-stimulating factor. Owing to the sustained degradation of microporous hydrogel network, DNA vaccine release can be sustained, and the recruitment of DCs and their homing to lymph node can be modulated. Furthermore, immunization of a vaccine encoding amyloid-β fusion proteinbearing microporous network induced a robust antigen-specific immune response in vivo and strong recall immune response was exhibited due to immunogenic memory. These hybrid hydrogels can be administered in a minimally invasive manner using hypodermic needle, bypassing the need for cytokine or DC enhancement factor and provide niche to host immune cells. These findings highlight the potential of hybrid hydrogels that may serve as a simple, yet multifunctional, platform for DNA vaccine delivery to modulate immune response.</P>
V. H. Giang Phan,Thai Minh Duy Le,고피나단 자나르다난,Phuong-Khanh Thi Ngo,이두성,Thavasyappan Thambi 한국공업화학회 2021 Journal of Industrial and Engineering Chemistry Vol.96 No.-
One of the major challenges in wound healing is the development of suitable hydrogels that areinjectable, biocompatible with multiple functionalities and properties such as high mechanical, tissueadhesiveness, and swelling properties. However, these hydrogels should not elicit any immunologicalresponse and synthesis steps should be easier and tunable according to the requirements. Consideringthese properties, we synthesized a thermo-sensitive triblock copolymer consisting of bovine serumalbumin (BSA) protein capable of leveraging the needs for a proper wound closure and tissueregeneration on excisional injuries. Firstly, the triblock copolymer consisting of poly(e-caprolactone-colactide)-b-poly(ethylene glycol)-b-poly(e-caprolactone-co-lactide (PCLA) was synthesized and then thecopolymer was grafted with BSA to yield BSA-PCLA bioconjugates. Aqueous solutions of free-flowingbioconjugate sol at room temperature can transform to gel at physiological temperature with highviscoelastic 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 significanttoxicity at implantation sites. BSA-PCLA bioconjugate gel exhibited good adhesive property to majororgans including liver, heart, and spleen when compared with control PCLA gel. When tested for in vivowound closure trials, the BSA-PCLA gels showed rapid wound contraction compared to the PCLA and thecontrol. The increased angiogenesis and collagen deposition were confirmed from the histological studiesof the samples. These highly adhesive, biocompatible, biodegradable, thermos-sensitive bioconjugategels show promising potential in wound healing and tissue regeneration without any additionalbiofactors or inorganic nanoparticles.
Bioengineered robust hybrid hydrogels enrich the stability and efficacy of biological drugs
Gil, Moon Soo,Cho, Jinhwan,Thambi, Thavasyappan,Giang Phan, V.H.,Kwon, Inchan,Lee, Doo Sung Elsevier Science Publishers 2017 Journal of controlled release Vol.267 No.-
<P><B>Abstract</B></P> <P>Biological drugs are exquisitely tailored components offering the advantages of high specificity and efficacy that are considered safe for treating diseases. Nevertheless, the effectiveness of biological drugs is limited by their inherent short biological half-life and poor stability in vivo. Herein, we engineered a novel delivery platform based on hybrid injectable hydrogels, in which pH- and temperature-responsive biodegradable copolymers were site-specifically coupled to the sulfhydryl group of human serum albumin, which effectively enhances the stability and circulation half-life of the biological drug, recombinant uricase enzyme (Uox). The albumin ligand conjugated to the Uox allowed specific-binding of the enzyme within the protein shell, and the synthetic polymers effectively shield the protein-enzyme complex. Such close confinement exhibits strong resistance towards various physical, chemical and therapeutically relevant stressors such as temperature, pH and proteases. Subcutaneous administration of Uox-loaded bioengineered hybrid hydrogel improved the pharmacokinetics by prolonging its circulation half-life. As a consequence, the bioengineered hybrid hydrogel normalized the serum uric acid level in hypoxanthine/potassium oxonate-induced hyperuricemia mice, and no obvious side effects were observed in the major organs. The characteristic of the bioengineered hydrogel networks applicable to a variety of biological drugs by simple mixing that unlock the possibility of adapting biological drugs to therapeutic applications.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Gil, Moon Soo,Thambi, Thavasyappan,Phan, V. H. Giang,Kim, Seong Han,Lee, Doo Sung The Royal Society of Chemistry 2017 Journal of materials chemistry. B, Materials for b Vol.5 No.34
<P>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 <I>in vitro</I> 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.</P>