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- 저자 : Shiva Pathak (검색결과 24 건)
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Immunoisolation of pancreatic islets <i>via</i> thin-layer surface modification
Pathak, Shiva,Pham, Tung Thanh,Jeong, Jee-Heon,Byun, Youngro Elsevier 2019 Journal of controlled release Vol.305 No.-
<P><B>Abstract</B></P> <P>Islet transplantation is an alternative method of replacing exogenous insulin to treat type 1 diabetes. However, transplantation of allo- or xenograft islets causes the activation of host's immune reaction, which leads to the failure of the transplanted grafts. Immunosuppressive-sparing strategies have been introduced to avoid adverse effects associated with a long-term use of the immunosuppressive drugs. In this regard, macro/microencapsulation, surface camouflage, and surface modification with immune-privileged cells have been performed to protect the transplanted islets against instant blood-mediated inflammatory reactions or immune reactions. However, the increased size of the encapsulated islets after transplantation leads to insufficient oxygen and nutrients for the islets, causing most of them to undergo apoptosis. Therefore, recent studies have aimed at reducing the capsule thickness while maintaining immunoprotective ability of encapsulated islets. In this review, we discuss several techniques of thin-layer surface coating of pancreatic islets using a variety of polymers, therapeutic agents (TA), TA-loaded nano or microparticles, and living cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Islet transplantation is a promising method for treating type-1 diabetes. </LI> <LI> Physical and chemical methods have been introduced for surface modification. </LI> <LI> Small molecules, polymers, particles, and cells are used for surface modification. </LI> <LI> Surface modification prolongs islet graft survival in animal models. </LI> <LI> Long-term <I>in vivo</I> effects of surface modification need to be evaluated. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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( Shiva Pathak ),( Biki Gupta ),( Bijay Kumar Poudel ),( Tuan Hiep Tran ),( Shibha Regmi ),( Tung Thanh Pham ),( Raj Kumar Thapa ),( Min Soo Kim ),( Chul Soon Yong ),( Jong Oh Kim ),( Jee Heon Jeong ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
Tacrolimus-loaded poly(lactic-co-glycolic acid) micro spheres (TAC-PLGA-M) can be administered for the long-term survival of transplanted organs due to their immunosuppressive activity. The purpose of our study was to optimize the parameters of the clcctrospray method, and to prepare T AC-PLGA-M with a high payload and desirable release properties. TAC-PLGA-M were prepared using the electrospray method. III vitro characterization and evaluation were performed using scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy. Drug-loading efficiency was greater than 80% in all formulations with a maximum loading capacity of 16.81±0.37%. XRD and DSC studies suggested that the drug was incorporated in an amorphous state or was molecularly dispersed in the microspheres. The ill vitro release study showed prolonged release patterns. TAC-PLGA-M with enhanced drug loading and prolonged-release patterns were successfully prepared using the electro-spray method.
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Pathak, Shiva,Regmi, Shobha,Pham, Tung Thanh,Yong, Chul Soon,Kim, Jong Oh,Yook, Simmyung,Park, Min-Hui,Bae, Yong Kyung,Jeong, Jee-Heon Wolters Kluwer Health, Inc. All rights reserved. 2018 Transplantation Vol.102 No.7
INTRODUCTION: Pancreatic islet transplantation is a promising technique to treat type 1 diabetes. Long-term survival of the graft is required for a successful islet transplantation. Repeated use of immunosuppressive drugs after organ/cell transplantation often leads to severe adverse effects including nephrotoxicity, hepatotoxicity, and opportunistic infections. Thus, development of a local immunosuppression protocol is necessary to improve the islet graft survival in clinics. MATERIALS AND METHODS: Pancreatic islets from Sprague-Dawley rats were transplanted into the subcutaneous space of B6 mice using injectable hydrogel. Briefly, 1000 islet equivalents were suspended in Matrigel premixed with FK506-loaded poly(lactic-co-glycolic acid) microspheres (10 mg/kg) and clodronate liposomes (6.25 mg/kg) and injected into the subcutaneous space over the flanks of streptozocin-induced diabetic mice. Blood glucose level was monitored using a potable glucometer. RESULTS: Islets transplanted without any immunosuppression were rejected within two weeks. In contrast, the islets transplanted with the immunosuppressive regimen of FK506 and clodronate survived indefinitely. Immunological studies revealed that the immunosuppressive cocktail inhibited the proliferation of immune cells residing at the peripheral lymph nodes. Interestingly, the systemic immune system of the transplanted mice remained unaffected. Furthermore, histochemical analysis revealed the intact morphology of the islets at the transplanted site when codelivered with the immunosuppressant. DISCUSSION: Antigen presenting cells and T-cells orchestrate the immune rejection cascade. Macrophage depletion by the liposomal clodronate and the inhibition of T-cell activation by FK506 completely blocked the immune rejection cascade in the immune competent mice. The inhibition of immune stimulation in the peripheral lymph nodes improved the islet grafted into the subcutaneous space. Thus, the use of local immune suppression is an effective approach to enhance the survival of the transplanted islets. CONCLUSION: We developed a protocol for the local codelivery of pancreatic islets and immune suppressive agents. Indefinite graft survival was obtained with the use of macrophage depleting agent and T-cell inhibitor. The single dose of local immune suppression during transplantation may avoid toxic effects associated with a long-term use of immune suppressive agents in clinics.
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Pathak, Shiva,Regmi, Shobha,Pham, Tung Thanh,Yong, Chul Soon,Kim, Jong Oh,Yook, Simmyung,Park, Min-Hui,Bae, Yong Kyung,Jeong, Jee-Heon Wolters Kluwer Health, Inc. All rights reserved. 2018 Transplantation Vol.102 No.7
INTRODUCTION: Pancreatic islet transplantation is a promising technique to treat type 1 diabetes. Long-term survival of the graft is required for a successful islet transplantation. Repeated use of immunosuppressive drugs after organ/cell transplantation often leads to severe adverse effects including nephrotoxicity, hepatotoxicity, and opportunistic infections. Thus, development of a local immunosuppression protocol is necessary to improve the islet graft survival in clinics. MATERIALS AND METHODS: Pancreatic islets from Sprague-Dawley rats were transplanted into the subcutaneous space of B6 mice using injectable hydrogel. Three major groups were prepared for transplantation. (1) Islets transplanted FK506-loaded poly(lactic-co-glycolic acid) microspheres (10 mg/kg), (2) Islets transplanted with clodronate liposomes (6.25 mg/kg), and (3) Islet transplanted with the combination of both immune suppressants. The suspension of islets and immune suppressants in Matrigel was then injected into the subcutaneous space over the flanks of streptozocin-induced diabetic mice. RESULTS: Islets transplanted without any immunosuppression were rejected within two weeks. In contrast, the islets transplanted with the single immunosuppressive regimen of FK506 or clodronate improved survival rate compared with that of the control mice. More interestingly, the graft transplanted using the combination of both immune suppressants survived indefinitely. Immunological studies revealed that the immunosuppressive cocktail inhibited the proliferation of immune cells residing at the peripheral lymph nodes. Interestingly, the systemic immune system of the transplanted mice remained unaffected. Furthermore, histochemical analysis revealed the intact morphology of the islets at the transplanted site when codelivered with the immunosuppressant. DISCUSSION: Antigen presenting cells and T-cells orchestrate the immune rejection cascade. Macrophage depletion by the liposomal clodronate and the inhibition of T-cell activation by FK506 completely blocked the immune rejection cascade in the immune competent mice. The inhibition of immune stimulation in the peripheral lymph nodes improved the islet grafted into the subcutaneous space. Thus, the use of local immune suppression is an effective approach to enhance the survival of the transplanted islets. CONCLUSION: We developed a protocol for the local codelivery of pancreatic islets and immune suppressive agents. Indefinite graft survival was obtained with the use of macrophage depleting agent and T-cell inhibitor. The single dose of local immune suppression during transplantation may avoid toxic effects associated with a long-term use of immune suppressive agents in clinics.National Research Foundation of Korea (NRF) Grant nos: 2015R1A5A2009124 and 2017R1D1A1B03027831. Korea Health Industry Development Institute (KHIDI) Grant no: HI16C1767.
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Shiva Pathak,Shobha Regmi,Mahesh Raj Nepal,Prakash Shrestha,Jeong Uk Choi,Simmyung Yook,Jee-Heon Jeong 한국공업화학회 2020 Journal of Industrial and Engineering Chemistry Vol.91 No.-
Based on the severity of the disease progression, the treatment of ulcerative colitis involvesadministration of single or multiple therapeutic agents. In refractory cases of ulcerative colitis, FK506(FK) is the drug of choice in clinics. To maintain a long-term stable blood concentration of FK and toreduce its dosing frequency, we propose single-dose injection of FK-loaded biodegradable microspheres(FK-Ms). FK-Ms were intraperitoneally-injected into mice fed with dextran-sulfate sodium (DSS). Pharmacokinetics study revealed presence of FK in blood for over 20 days. The single intraperitonealinjection of the drug-loaded microspheres effectively alleviated DSS-induced murine colitis. Mechanistically, the single injection of FK-Ms inhibited the infiltration of T cells into colon andattenuated differentiation of T cells into interferon-g secreting Th1 and interleukin-17A secreting Th17cells in colon-draining mesenteric lymph nodes. Therefore, administration of prolonged-release typemicrospheres can be considered as an alternative for the effective treatment of inflammatory boweldiseases.
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Pathak, Shiva,Regmi, Shobha,Gupta, Biki,Pham, Tung Thanh,Yong, Chul Soon,Kim, Jong Oh,Yook, Simmyung,Kim, Jae-Ryong,Park, Min Hui,Bae, Young Kyung,Jeong, Jee-Heon Federation of American Societies for Experimental 2017 The FASEB Journal Vol. No.
<P>An alternative route for pancreatic islet transplantation is the subcutaneous space; however, inadequate vascularization in the subcutaneous space limits the availability of oxygen and nutrients to the subcutaneously transplanted islets, which leads to the development of a necrotic core in the islets, thereby causing islet dysfunction. Thus, we aimed to prevent the early apoptosis of pancreatic islets after transplantation into subcutaneous space by preparing islet clusters of appropriate size. We prepared fully functional islet cell clusters (ICCs) by using the hanging-drop technique. We optimized the size of ICCs on the basis of viability and functionality after culture in an hypoxic environment. We transplanted ICCs into the subcutaneous space of diabetic mice and evaluated the viability of the islets at the transplantation site. In an hypoxic environment, ICCs exhibited improved viability and functionality compared with control islets. ICCs, upon transplantation into the hypoxic subcutaneous space of diabetic mice, showed better glycemic control compared with control islets. Live/dead imaging of the islets after retrieval fromthe transplanted area revealed significantly reduced apoptosis in ICCs. Transplantation of ICCsmay be an attractive strategy to prevent islet cell apoptosis that results from nonimmune-mediated physiologic stress at the transplantation site.-Pathak, S., Regmi, S., Gupta, B., Pham, T. T., Yong, C. S., Kim, J. O., Yook, S., Kim, J.-R., Park, M. H., Bae, Y. K., Jeong, J.-H. Engineeredislet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes.</P>
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Pathak, Shiva,Regmi, Shobha,Nguyen, Tiep Tien,Gupta, Biki,Gautam, Milan,Yong, Chul Soon,Kim, Jong Oh,Son, Youlim,Kim, Jae-Ryong,Park, Min Hui,Bae, Young Kyung,Park, So Young,Jeong, Daewon,Yook, Simmyu Elsevier 2018 ACTA BIOMATERIALIA Vol.75 No.-
<P><B>Abstract</B></P> <P>Attenuation of senescence progression may be attractive way to preserve the functionality of pancreatic islets (PI) after transplantation. In this study, we developed a model for <I>in vitro</I> induction of premature senescence in rat PI and showed the effectiveness of quercetin (QU) to prevent the senescence. To provide targeted-delivery of QU to the PI after transplantation, we prepared the hybrid clusters (HC) of islet single cells (ISC) and QU-loaded polymeric microspheres (QU; ∼7.55 ng HC<SUP>−1</SUP>). Long-term culture of the HC revealed reduced levels of reactive oxygen species and decreased expression of senescence-associated beta galactosidase, Rb, p53, p16, and p21 compared to that of the control islets. Transplantation of HC into subcutaneous space of the immune-deficient mice produced better glycemic control compared to the control islets or the ICC-transplanted mice. SA-β-Gal staining of the <I>in vivo</I> transplanted HC sample showed lower intensity compared to that of the control islets or the islet cell clusters. Thus, <I>in situ</I> delivery of therapeutic agent may be a promising approach to improve therapeutic outcomes in cell therapy.</P> <P><B>Statement of Significance</B></P> <P>In this study, we aimed to improve outcomes in islet transplantation using <I>in situ</I> delivery of quercetin to pancreatic islets, using polymeric microspheres. We prepared prolonged release-type microspheres and constructed hybrid clusters of pancreatic islets and the microspheres using hanging drop method. The presence of quercetin in the cellular microenvironment attenuated the progression of senescence in the pancreatic islets in a long-term <I>in vitro</I> culture. Moreover, transplantation of the hybrid clusters in the diabetic mice produced better glycemic control compared to that of the control islets. In addition, quercetin delayed the progression of senescence in the pancreatic islets after <I>in vivo</I> transplantation. Thus, local delivery of antioxidants like quercetin may be an attractive way to improve outcomes in cell therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Quercetin prevents senescence of pancreatic islets <I>in vitro</I>. </LI> <LI> PLGA microspheres provide quercetin into the cellular microenvironment. </LI> <LI> Transplantation of the hybrid clusters produces better glycemic control. </LI> <LI> Hybrid clusters of cells and microspheres exhibit reduction of senescence. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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Pathak, Shiva,Regmi, Shobha,Gupta, Biki,Poudel, Bijay K.,Pham, Tung Thanh,Kim, Jae-Ryong,Park, Pil-Hoon,Yong, Chul Soon,Kim, Jong Oh,Bae, Young Kyung,Kim, Sang Kyoon,Jeong, Jee-Heon American Chemical Society 2016 ACS APPLIED MATERIALS & INTERFACES Vol.8 No.39
<P>Hypoxic or near-anoxic conditions that occur in the core of transplanted islets induce necrosis and apoptosis during the early stages after transplantation, primarily due to loss of vascularization during the isolation process. Moreover, secretion of various cytokines from pancreatic islets is detrimental to the viability of islet cells in vitro. In this study, we aimed to protect pancreatic islet cells against apoptosis by establishing a method for in situ delivery of curcumin to the pancreatic islets. Self-assembled heterospheroids composed of pancreatic islet cells and curcumin-loaded polymeric micro spheres were prepared by the three-dimensional cell culture technique. Release of curcumin in the microenvironment of pancreatic islets promoted survival of the islets. In hypoxic culture conditions, which mimic the in vivo conditions after transplantation, viability of the islets was significantly improved, as indicated by a decreased expression of pro-apoptotic protein and an increased expression of anti-apoptotic protein. Additionally, oxidative stress-induced cell death was suppressed. Thus, unlike co-transplantation of pancreatic islets and free microspheres, which provided a wide distribution of microspheres throughout the transplanted area, the heterospheroid transplantation resulted in colocalization of pancreatic islet cells and microspheres, thereby exerting beneficial effects on the cells.</P>
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