Contact

  • Academic
    shobhar@stanford.edu
    University - Academic staff Department: Pediatrics - Gastroenterology Position: Research Scientist

Additional Info

  • Mail Code: 5483

All Publications

  • Enhanced viability and function of mesenchymal stromal cell spheroids is mediated via autophagy induction. Autophagy Regmi, S., Raut, P. K., Pathak, S., Shrestha, P., Park, P., Jeong, J. 2020

    Abstract

    Mesenchymal stromal cells (MSCs) have received attention as promising therapeutic agents for the treatment of various diseases. However, poor post-transplantation viability has been a major hurdle in MSC-based therapy, despite encouraging results in many inflammatory disorders and tissue repair. Recently, three dimensional (3D)-cultured MSCs (MSC3D) were shown to have higher cell survival and enhanced anti-inflammatory effects, although the underlying mechanisms have not yet been elucidated. In this study, we investigated the molecular mechanisms by which MSC3D gain the potential for enhanced cell viability. Herein, we found that macroautophagy/autophagy was highly induced and ROS production was suppressed in MSC3D as compared to 2D-cultured MSCs (MSC2D). Interestingly, inhibition of autophagy induction caused decreased cell viability and increased apoptotic activity in MSC3D. Furthermore, modulation of ROS production was closely related to the survival and apoptosis of MSC3D. We also observed that HMOX1 (heme oxygenase 1) was significantly up-regulated in MSC3D. In addition, gene silencing of HMOX1 caused upregulation of ROS production and suppression of the genes related to autophagy. Moreover, inhibition of HIF1A (hypoxia inducible factor 1 subunit alpha) caused suppression of HMOX1 expression in MSC3D, indicating that the HIF1A-HMOX1 axis plays a crucial role in the modulation of ROS production and autophagy induction in MSC3D. Finally, the critical role of autophagy induction on improved therapeutic effects of MSC3D was further verified in dextran sulfate sodium (DSS)-induced murine colitis. Taken together, these results indicated that autophagy activation and modulation of ROS production mediated via the HIF1A-HMOX1 axis play pivotal roles in enhancing the viability of MSC3D.

    View details for DOI 10.1080/15548627.2020.1850608

    View details for PubMedID 33206581

  • Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity. Stem cell research & therapy Regmi, S., Pathak, S., Thanh, T. P., Nguyen, T. T., Sung, J., Yook, S., Kim, J. O., Yong, C. S., Choi, I., Doh, K., Park, P., Park, J., Seo, Y., Kim, B., Lee, D., Moon, I., Kim, H., Jeong, J. 2019; 10 (1): 230

    Abstract

    BACKGROUND: Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20-50%) due to irreversible cerebral edema or sepsis. Stem cell-based treatment has emerged as a promising alternative therapeutic strategy to prolong the survival of patients suffering from FHF via theinhibition of SIRS due to their immunomodulatory effects.METHODS: 3D spheroids of adipose-derived mesenchymal stem cells (3D-ADSC) were prepared by the hanging drop method. The efficacy of the 3D-ADSC to rescue FHF was evaluated in a D-galactosamine/lipopolysaccharide (GalN/LPS)-induced mouse model of FHF via intraportal transplantation of the spheroids.RESULTS: Intraportally delivered 3D-ADSC better engrafted and localized into the damaged livers compared to 2D-cultured adipose-derived mesenchymal stem cells (2D-ADSC). Transplantation of 3D-ADSC rescued 50% of mice from FHF-induced lethality, whereas only 20% of mice survived when 2D-ADSC were transplanted. The improved transplantation outcomes correlated with the enhanced immunomodulatory effect of 3D-ADSC in the liver microenvironment.CONCLUSION: The study shows that the transplantation of optimized 3D-ADSC can efficiently ameliorate GalN/LPS-induced FHF due to improved viability, resistance to exogenous ROS, and enhanced immunomodulatory effects of 3D-ADSC.

    View details for DOI 10.1186/s13287-019-1337-3

    View details for PubMedID 31615539

  • Inflammation-triggered local drug release ameliorates colitis by inhibiting dendritic cell migration and Th1/Th17 differentiation. Journal of controlled release : official journal of the Controlled Release Society Regmi, S. n., Pathak, S. n., Nepal, M. R., Shrestha, P. n., Park, J. n., Kim, J. O., Yong, C. S., Choi, D. Y., Chang, J. H., Jeong, T. C., Orive, G. n., Yook, S. n., Jeong, J. H. 2019

    Abstract

    Enteric-coated formulations using Eudragit® polymers have been extensively used for delivering drugs to the lower gastrointestinal tract. However, these drug-delivery systems cannot accurately deliver the therapeutic cargoes to colon because of early degradation of the polymers at alkaline pH of the small intestine. Here, we describe a precise method of delivering drugs to inflammation sites in colon using an oral drug delivery system. Tacrolimus (FK506)-loaded microspheres were prepared using a thioketal-based polymer that releases drug in response to reactive oxygen species (ROS), which are abundantly produced at the sites of inflammation in acute colitis. Orally-administered FK506-loaded thioketal microspheres (FK506-TKM) led to substantial accumulation of FK506 in inflamed colon and effectively alleviated dextran-sulfate sodium (DSS)-induced murine colitis. At the molecular level, FK506-TKM significantly inhibited infiltration of CD4+ and CD8+ T lymphocytes in colon and differentiation of CD4+ T cells to Th1 and Th17 cells in colon-draining mesenteric lymph nodes via restricting dendritic cell migration from colon. Our findings indicate orally-administered thioketal-based drug delivery system as a promising means of treating acute inflammatory bowel diseases.

    View details for DOI 10.1016/j.jconrel.2019.11.001

    View details for PubMedID 31689461

  • Controlled Nutrient Delivery to Pancreatic Islets Using Polydopamine-Coated Mesoporous Silica Nanoparticles. Nano letters Primavera, R., Wang, J., Buchwald, P., Ganguly, A., Patel, S., Bettencourt, L., Chetty, S., Yarani, R., Regmi, S., Levitte, S., Kevadiya, B., Guindani, M., Decuzzi, P., Thakor, A. S. 2025

    Abstract

    In this study, we designed a nanoscale platform for sustained amino acid delivery to support transplanted pancreatic islets. The platform features mesoporous silica nanoparticles (MSNPs) loaded with glutamine (G), an essential amino acid required for islet survival and function, and coated with polydopamine (PD). We investigated various PD concentrations (0.5-2 mg/mL) and incubation times (0.5-2 h) to optimize G release, identifying that a PD concentration of 0.5 mg/mL incubated for 0.5 h yielded the best results to support islet viability and functionality ex vivo, particularly under inflammatory conditions. In syngeneic islet transplantation in STZ-diabetic mice, G alone provided only temporary benefits; however, PD-G-MSNPs significantly improved islet engraftment and function, with animals maintaining glycemic control for 30 days due to controlled G release. Our findings support the use of this nanoscale platform to provide essential nutrients like G to transplanted islets until they can establish their own blood and nutrient supply.

    View details for DOI 10.1021/acs.nanolett.4c03613

    View details for PubMedID 39791700

  • Catechol-modified stabilizer facilitates impulsive ligand functionalization of particulates and membrane modification of cells JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY Shrestha, P., Pathak, S., Regmi, S., Youn, Y., Jeong, J., Lee, J., Ryu, D., Yook, S., Gwon, Y., Choi, J., Jiang, H., Kim, J., Jeong, J. 2024; 101

    View details for DOI 10.1016/j.jddst.2024.106161

    View details for Web of Science ID 001312402000001

  • Time-course analysis of cisplatin induced AKI in preclinical models: implications for testing different sources of MSCs. Journal of translational medicine Ganguly, A., Chetty, S., Primavera, R., Levitte, S., Regmi, S., Dulken, B. W., Sutherland, S. M., Angeles, W., Wang, J., Thakor, A. S. 2024; 22 (1): 789

    Abstract

    Kidneys are at risk from drug-induced toxicity, with a significant proportion of acute kidney injury (AKI) linked to medications, particularly cisplatin. Existing cytoprotective drugs for cisplatin-AKI carry side effects, prompting a search for better biological therapies. Mesenchymal Stem Cells (MSCs) are under consideration given their regenerative properties, yet their clinical application has not achieved their full potential, mainly due to variability in the source of MSC tested. In addition, translating treatments from rodent models to humans remains challenging due to a lack of standardized dosing and understanding potential differential responses to cisplatin between animal strains.In the current study, we performed a time-course analysis of the effect of cisplatin across different mouse strains and evaluated gender related differences to create a robust preclinical model that could then be used to explore the therapeutic efficacy of different sources of MSCs for their ability to reverse AKI.Our data indicated that different mouse strains produce differential responses to the same cisplatin dosing regimen. Despite this, we did not observe any gender-related bias towards cisplatin nephrotoxicity. Furthermore, our time-course analysis identified that cisplatin-induced inflammation was driven by a strong CXCL1 response, which was used as a putative biomarker to evaluate the comparative therapeutic efficacy of different MSC sources in reversing AKI. Our data indicates that UC-MSCs have a stronger anti-inflammatory effect compared to BM-MSCs and AD-MSCs, which helped to ameliorate cisplatin-AKI.Overall, our data underscores the importance of using an optimized preclinical model of cisplatin-AKI to test different therapies. We identified CXCL1 as a potential biomarker of cisplatin-AKI and identified the superior efficacy of UC-MSCs in mitigating cisplatin-AKI.

    View details for DOI 10.1186/s12967-024-05439-6

    View details for PubMedID 39192240

    View details for PubMedCentralID 4146684

  • Endogenous stem cell mobilization and localized immunosuppression synergistically ameliorate DSS-induced Colitis in mice. Stem cell research & therapy Regmi, S., Pathak, S., Chaudhary, D., Kim, J. O., Nam, J. W., Kim, H. S., Jiang, H. L., Ryu, D., Sung, J. H., Yook, S., Jeong, J. H. 2024; 15 (1): 167

    Abstract

    Stem cell therapy is a promising alternative for inflammatory diseases and tissue injury treatment. Exogenous delivery of mesenchymal stem cells is associated with instant blood-mediated inflammatory reactions, mechanical stress during administration, and replicative senescence or change in phenotype during long-term culture in vitro. In this study, we aimed to mobilize endogenous hematopoietic stem cells (HSCs) using AMD-3100 and provide local immune suppression using FK506, an immunosuppressive drug, for the treatment of inflammatory bowel diseases.Reactive oxygen species (ROS)-responsive FK506-loaded thioketal microspheres were prepared by emulsification solvent-evaporation method. Thioketal vehicle based FK506 microspheres and AMD3100 were co-administered into male C57BL6/J mice with dextran sulfate sodium (DSS) induced colitis. The effect of FK506-loaded thioketal microspheres in colitis mice were evaluated using disease severity index, myeloperoxidase activity, histology, flow cytometry, and gene expression by qRT-PCR.The delivery of AMD-3100 enhanced mobilization of HSCs from the bone marrow into the inflamed colon of mice. Furthermore, targeted oral delivery of FK506 in an inflamed colon inhibited the immune activation in the colon. In the DSS-induced colitis mouse model, the combination of AMD-3100 and FK506-loaded thioketal microspheres ameliorated the disease, decreased immune cell infiltration and activation, and improved body weight, colon length, and epithelial healing process.This study shows that the significant increase in the percentage of mobilized hematopoietic stem cells in the combination therapy of AMD and oral FK506 microspheres may contribute to a synergistic therapeutic effect. Thus, low-dose local delivery of FK506 combined with AMD3100 could be a promising alternative treatment for inflammatory bowel diseases.

    View details for DOI 10.1186/s13287-024-03777-2

    View details for PubMedID 38872206

    View details for PubMedCentralID 6557461

  • Precision Delivery of Human Bone Marrow-Derived Mesenchymal Stem Cells Into the Pancreas Via Intra-arterial Injection Prevents the Onset of Diabetes. Stem cells translational medicine Primavera, R., Regmi, S., Yarani, R., Levitte, S., Wang, J., Ganguly, A., Chetty, S., Guindani, M., Ricordi, C., Meyer, E., Thakor, A. S. 2024

    Abstract

    Mesenchymal stem cells (MSCs) are a promising therapy to potentially treat diabetes given their potent anti-inflammatory and immune-modulatory properties. While these regenerative cells have shown considerable promise in cell culture, their clinical translation has been challenging. In part, this can be attributed to these cells not reaching the pancreas to exert their regenerative effects following conventional intravenous (IV) injection, with the majority of cells being trapped in the lungs in the pulmonary first-pass effect. In the present study, we will therefore examine whether direct delivery of MSCs to the pancreas via an intra-arterial (IA) injection can improve their therapeutic efficacy. Using a mouse model, in which repetitive low doses of STZ induced a gentle, but progressive, hyperglycemia, we tested bone marrow-derived MSCs (BM-MSCs) which we have shown are enriched with pro-angiogenic and immunomodulatory factors. In cell culture studies, BM-MSCs were shown to preserve islet viability and function following exposure to proinflammatory cytokines (IFN-gamma, IL-1beta, and TNF-alpha) through an increase in pAkt. When tested in our animal model, mice receiving IV BM-MSCs were not able to mitigate the effects of STZ, however those which received the same dose and batch of cells via IA injection were able to maintain basal and dynamic glycemic control, to similar levels as seen in healthy control animals, over 10 days. This study shows the importance of considering precision delivery approaches to ensure cell-based therapies reach their intended targets to enable them to exert their therapeutic effects.

    View details for DOI 10.1093/stcltm/szae020

    View details for PubMedID 38530131

  • β Cell and Autophagy: What Do We Know? Biomolecules Mohammadi-Motlagh, H. R., Sadeghalvad, M., Yavari, N., Primavera, R., Soltani, S., Chetty, S., Ganguly, A., Regmi, S., Fløyel, T., Kaur, S., Mirza, A. H., Thakor, A. S., Pociot, F., Yarani, R. 2023; 13 (4)

    Abstract

    Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure.

    View details for DOI 10.3390/biom13040649

    View details for PubMedID 37189396

    View details for PubMedCentralID PMC10136307

  • Integrated transcriptome-proteome analyses of human stem cells reveal source-dependent differences in their regenerative signature. Stem cell reports Ganguly, A., Swaminathan, G., Garcia-Marques, F., Regmi, S., Yarani, R., Primavera, R., Chetty, S., Bermudez, A., Pitteri, S. J., Thakor, A. S. 2022

    Abstract

    Mesenchymal stem cells (MSCs) are gaining increasing prominence as an effective regenerative cellular therapy. However, ensuring consistent and reliable effects across clinical populations has proved to be challenging. In part, this can be attributed to heterogeneity in the intrinsic molecular and regenerative signature of MSCs, which is dependent on their source of origin. The present work uses integrated omics-based profiling, at different functional levels, to compare the anti-inflammatory, immunomodulatory, and angiogenic properties between MSCs from neonatal (umbilical cord MSC [UC-MSC]) and adult (adipose tissue MSC [AD-MSC], and bone marrow MSC [BM-MSC]) sources. Using multi-parametric analyses, we identified that UC-MSCs promote a more robust host innate immune response; in contrast, adult-MSCs appear to facilitate remodeling of the extracellular matrix (ECM) with stronger activation of angiogenic cascades. These data should help facilitate the standardization of source-specific MSCs, such that their regenerative signatures can be confidently used to target specific disease processes.

    View details for DOI 10.1016/j.stemcr.2022.11.006

    View details for PubMedID 36493779

  • Curcumin-laden ECM-mimicking microfibers assemble with mesenchymal stem cells to generate heterospheroids and enhance cell viability and function JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY Shrestha, P., Pathak, S., Regmi, S., Narayanan, K., Nguyen, T., Yook, S., Kim, J., Jeong, J. 2022; 115: 500-509

    View details for DOI 10.1016/j.jiec.2022.08.036

    View details for Web of Science ID 000869743800007

  • Umbilical cord mesenchymal stromal cells-from bench to bedside. Frontiers in cell and developmental biology Chetty, S., Yarani, R., Swaminathan, G., Primavera, R., Regmi, S., Rai, S., Zhong, J., Ganguly, A., Thakor, A. S. 2022; 10: 1006295

    Abstract

    In recent years, mesenchymal stromal cells (MSCs) have generated a lot of attention due to their paracrine and immuno-modulatory properties. mesenchymal stromal cells derived from the umbilical cord (UC) are becoming increasingly recognized as having increased therapeutic potential when compared to mesenchymal stromal cells from other sources. The purpose of this review is to provide an overview of the various compartments of umbilical cord tissue from which mesenchymal stromal cells can be isolated, the differences and similarities with respect to their regenerative and immuno-modulatory properties, as well as the single cell transcriptomic profiles of in vitro expanded and freshly isolated umbilical cord-mesenchymal stromal cells. In addition, we discuss the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). The clinical applications of umbilical cord-mesenchymal stromal cells are also discussed, especially in relation to obstacles and potential solutions for their effective translation from bench to bedside.

    View details for DOI 10.3389/fcell.2022.1006295

    View details for PubMedID 36313578

    View details for PubMedCentralID PMC9597686

  • Mesenchymal stromal cells for the treatment of Alzheimer's disease: Strategies and limitations. Frontiers in molecular neuroscience Regmi, S., Liu, D. D., Shen, M., Kevadiya, B. D., Ganguly, A., Primavera, R., Chetty, S., Yarani, R., Thakor, A. S. 2022; 15: 1011225

    Abstract

    Alzheimer's disease (AD) is a major cause of age-related dementia and is characterized by progressive brain damage that gradually destroys memory and the ability to learn, which ultimately leads to the decline of a patient's ability to perform daily activities. Although some of the pharmacological treatments of AD are available for symptomatic relief, they are not able to limit the progression of AD and have several side effects. Mesenchymal stem/stromal cells (MSCs) could be a potential therapeutic option for treating AD due to their immunomodulatory, anti-inflammatory, regenerative, antioxidant, anti-apoptotic, and neuroprotective effects. MSCs not only secret neuroprotective and anti-inflammatory factors to promote the survival of neurons, but they also transfer functional mitochondria and miRNAs to boost their bioenergetic profile as well as improve microglial clearance of accumulated protein aggregates. This review focuses on different clinical and preclinical studies using MSC as a therapy for treating AD, their outcomes, limitations and the strategies to potentiate their clinical translation.

    View details for DOI 10.3389/fnmol.2022.1011225

    View details for PubMedID 36277497

  • Heterospheroid formation improves therapeutic efficacy of mesenchymal stem cells in murine colitis through immunomodulation and epithelial regeneration. Biomaterials Regmi, S. n., Seo, Y. n., Ahn, J. S., Pathak, S. n., Acharya, S. n., Nguyen, T. T., Yook, S. n., Sung, J. H., Park, J. B., Kim, J. O., Young, C. S., Kim, H. S., Jeong, J. H. 2021; 271: 120752

    Abstract

    Tissue repairing capacity and immunomodulatory effects of mesenchymal stem cells (MSCs) have been extensively utilized for treating various inflammatory disorders; however, inconsistent efficacy and therapeutic outcomes due to low survival rate after transplantation often restrain their clinical potential. To overcome these limitations, 3-dimensional culture (3D-culture) was established to augment stemness and paracrine functions of MSCs, although hypoxic stress at the core often leads to unexpected cell death. Thus, we designed a novel strategy to improve the microenvironment of MSCs by creating heterospheroids (HS) consisting of MSCs and quercetin (QUR)-loaded microspheres (MSCHS), to achieve local drug delivery to the cells. Notably, MSCHS exhibited resistance for senescence-associated phenotype and oxidative stress-induced apoptosis compared to 3D-cultured MSCs (MSC3D), as well as to 2D-cultured cells (MSC2D) in vitro. In a murine model of colitis, MSC3D and MSCHS exhibited enhanced anti-inflammatory impact than MSC2Dvia attenuating neutrophil infiltration and regulating helper T cell (Th) polarization into Th1 and Th17 cells. Interestingly, MSCHS provided better therapeutic outcomes compared to MSC3D, partially due to their enhanced survival capacity in vivo. Moreover, we found that MSC-derived paracrine factor, prostaglandin E2 (PGE2), can directly drive the epithelial regeneration process by inducing specialized tissue-repairing cell generation using the intestinal organoid culture. Importantly, MSC3D and MSCHS displayed an outstanding regeneration-inducing potency compared to MSC2D owing to their superior PGE2 secretion. Taken together, we suggest a convergent strategy of MSCHS formation with reactive oxygen species (ROS) scavenger, QUR, which can maximize the inflammation-attenuating and tissue-repairing capacity of MSCs, as well as the engraftment efficiency after transplantation.

    View details for DOI 10.1016/j.biomaterials.2021.120752

    View details for PubMedID 33730631

  • Particulate-Based Single-Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation. Advanced healthcare materials Pathak, S., Acharya, S., Regmi, S., Shrestha, P., You, Z., Bae, Y. K., Park, M. H., Yook, S., Kim, J., Park, S. Y., Jeong, D., Yong, C. S., Kim, J. O., Chang, J. H., Jeong, J. 2020: e2001157

    Abstract

    Recent studies emphasize on developing immune tolerance by an interim administration of various immunosuppressive drugs. In this study, a robust protocol is reported for local immunomodulation using a single-dose of FK506 microspheres and clodronate liposomes (mFK+CLO) in a xenogeneic model of islet transplantation. Surprisingly, the single-dose treatment with mFK+CLO induce tolerance to the islet xenograft. The recipient mice display tolerogenic dendritic cells (tDCs) with decreased antigen presenting ability and T cell activation capacity. Furthermore, a reduced percentage of CD4+ and CD8+ T cells and an impaired differentiation of naive CD4+ T cells into interferon-gamma producing Th1 and interleukin-17 producing Th17 cells are observed. In addition, the immunosuppressive protocol leads to the generation of Foxp3+ regulatory T cells (Tregs) which are required for the long-term graft survival. The enhanced generation of tDCs and Tregs by the single treatment of mFK+CLO cause xenograft tolerance, suggesting a possible clinical strategy which may pave the way towards improving therapeutic outcomes of clinical islet transplantation.

    View details for DOI 10.1002/adhm.202001157

    View details for PubMedID 33251762

  • Single-dose intraperitoneal delivery of FK506-encapsulated polymeric microspheres for the alleviation of murine colitis JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY Pathak, S., Regmi, S., Nepal, M., Shrestha, P., Choi, J., Yook, S., Jeong, J. 2020; 91: 121–28

    View details for DOI 10.1016/j.jiec.2020.07.041

    View details for Web of Science ID 000573546300011

  • Local release of NECA (5'-(N-ethylcarboxamido)adenosine) from implantable polymeric sheets for enhanced islet revascularization in extrahepatic transplantation site. Journal of controlled release : official journal of the Controlled Release Society Nguyen, T. T., Emami, F., Yook, S., Nguyen, H. T., Pham, T. T., Pathak, S., Regmi, S., Kim, J. O., Yong, C. S., Kim, J., Jeong, J. 2020

    Abstract

    Clinical intraportal pancreatic islet infusion is popular for treating type I diabetes. However, multiple doses of islets and anti-rejection protocols are needed to compensate for early large cell losses post-infusion due to the harsh hepatic environment. Thus, extrahepatic sites are utilized to enable efficient islet engraftment and reduce islet mass. Here, we reported an effective islet revascularization protocol that was based on the co-implantation of islet/fibrin gel construct with poly(lactic-co-glycolic) acid sheet releasing NECA (5'-(N-ethylcarboxamido) adenosine; a potent agonist of adenosine) into mouse epididymal fat pad. Thin, flexible sheets (d = 4 mm) prepared by simple casting exhibited sustained NECA release for up to 21 days, which effectively improved early islet engraftment with a median diabetic reversal time of 18.5 days. Western blotting revealed the facilitative effect of NECA on VEGF expression from islets in vitro and from grafts in vivo. In addition, NECA directly promoted the angiogenic activities of islet-derived endothelial cells by enhancing their proliferation and vessel-like tube formation. As a result, neovasculatures were effectively formed in the engrafted islet vicinity, as evidenced by vasculature imaging and immunofluorescence. Taken together, we suggest NECA-releasing PLGA sheets offer a safe and effective drug delivery system that enhances islet engraftment while reducing islet mass at extrahepatic sites for clinical relevance.

    View details for DOI 10.1016/j.jconrel.2020.02.029

    View details for PubMedID 32087300

  • Injectable hydrogels for islet transplantation: a concise review JOURNAL OF PHARMACEUTICAL INVESTIGATION Shrestha, P., Regmi, S., Jeong, J. 2020; 50 (1): 29-45

    View details for DOI 10.1007/s40005-019-00433-3

    View details for Web of Science ID 000511684600003

  • Targeted delivery of doxorubicin for the treatment of bone metastasis from breast cancer using alendronate-functionalized graphene oxide nanosheets JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY Tung Thanh Pham, Hanh Thuy Nguyen, Cao Dai Phung, Pathak, S., Regmi, S., Ha, D., Kim, J., Yong, C., Kim, S., Choi, J., Yook, S., Park, J., Jeong, J. 2019; 76: 310–17

    View details for DOI 10.1016/j.jiec.2019.03.055

    View details for Web of Science ID 000470939700027

  • Mesenchymal Stem Cell Capping on ECM-Anchored Caspase Inhibitor-Loaded PLGA Microspheres for Intraperitoneal Injection in DSS-Induced Murine Colitis SMALL Pathak, S., Regmi, S., Shrestha, P., Choi, I., Doh, K., Jeong, J. 2019; 15 (23): e1901269

    Abstract

    Mesenchymal stem cells (MSCs) are considered as a promising alternative for the treatment of various inflammatory disorders. However, poor viability and engraftment of MSCs after transplantation are major hurdles in mesenchymal stem cell therapy. Extracellular matrix (ECM)-coated scaffolds provide better cell attachment and mechanical support for MSCs after transplantation. A single-step method for ECM functionalization on poly(lactic-co-glycolic acid) (PLGA) microspheres using a novel compound, dopamine-conjugated poly(ethylene-alt-maleic acid), as a stabilizer during the preparation of microspheres is reported. The dopamine molecules on the surface of microspheres provide active sites for the conjugation of ECM in an aqueous solution. The results reveal that the viability of MSCs improves when they are coated over the ECM-functionalized PLGA microspheres (eMs). In addition, the incorporation of a broad-spectrum caspase inhibitor (IDN6556) into the eMs synergistically increases the viability of MSCs under in vitro conditions. Intraperitoneal injection of the MSC-microsphere hybrid alleviates experimental colitis in a murine model via inhibiting Th1 and Th17 differentiation of CD4+ T cells in colon-draining mesenteric lymph nodes. Therefore, drug-loaded ECM-coated surfaces may be considered as attractive tools for improving viability, proliferation, and functionality of MSCs following transplantation.

    View details for DOI 10.1002/smll.201901269

    View details for Web of Science ID 000485484800013

    View details for PubMedID 31018047

  • Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. European journal of cell biology Regmi, S. n., Pathak, S. n., Kim, J. O., Yong, C. S., Jeong, J. H. 2019

    Abstract

    Mesenchymal stem cells (MSCs) are promising alternative agents for the treatment of inflammatory disorders due to their immunomodulatory functions, and several clinical trials on mesenchymal stem cell (MSC)-based products are currently being conducted. In this review, we discuss recent progress made on the use of MSCs as immunomodulatory agents, developmental challenges posed by MSC-based therapy, and the strategies being used to overcome these challenges. In this context, current understanding of the mechanisms responsible for MSC interactions with the immune system and the molecular responses of MSCs to inflammatory signals are discussed. The immunosuppressive activities of MSCs are initiated by cell-to-cell contact and the release of immuno-regulatory molecules. By doing so, MSCs can inhibit the proliferation and function of T cells, natural killer cells, B cells, and dendritic cells, and can also increase the proliferation of regulatory T cells. However, various problems, such as low transplanted cell viability, poor homing and engraftment into injured tissues, MSC heterogeneity, and lack of adequate information on optimum MSC doses impede clinical applications. On the other hand, it has been shown that the immunomodulatory activities and viabilities of MSCs might be enhanced by 3D-cultured systems, genetic modifications, preconditioning, and targeted-delivery.

    View details for DOI 10.1016/j.ejcb.2019.04.002

    View details for PubMedID 31023504

  • Hyaluronic acid-capped compact silica-supported mesoporous titania nanoparticles for ligand-directed delivery of doxorubicin ACTA BIOMATERIALIA Gupta, B., Poudel, B., Ruttala, H., Regmi, S., Pathak, S., Gautam, M., Jin, S., Jeong, J., Choi, H., Ku, S., Yong, C., Kim, J. 2018; 80: 364–77

    Abstract

    Mesoporous titania nanoparticles (MTN), owing to their high surface area to volume ratio and tunable pore sizes, appear capable of delivering sizable amounts of drug payloads, and hence, show considerable promise as drug delivery candidates in cancer therapy. We designed silica-supported MTN (MTNst) coated with hyaluronic acid (HA) to effectively deliver doxorubicin (DOX) for breast cancer therapy. The HA coating served a dual purpose of stabilizing the payload in the carriers as well as actively targeting the nanodevices to CD44 receptors. The so-formed HA-coated MTNst carrying DOX (HA/DOX-MTNst) had spheroid particles with a considerable drug-loading capacity and showed significantly superior in vitro cytotoxicity against MDA-MB-231 cells as compared to free DOX. HA/DOX-MTNst markedly improved the cellular uptake of DOX in an apparently CD44 receptor-dependent manner, and increased the number of apoptotic cells as compared to free DOX. These nanoplatforms accumulated in large quantities in the tumors of MDA-MB-231 xenograft tumor-bearing mice, where they significantly enhanced the inhibition of tumor growth compared to that observed with free DOX with no signs of acute toxicity. Based on these excellent results, we deduced that HA/DOX-MTNst could be successfully used for targeted breast cancer therapy. STATEMENT OF SIGNIFICANCE: This is the first study to use silica-supported mesoporous titania nanoparticles (MTNst) for doxorubicin (DOX) delivery to treat breast cancer, which exhibited effective and enhanced in vitro and in vivo apoptosis and tumor growth inhibition. Solid silica was used to support the mesoporous TiO2 resulting in MTNst, which efficiently incorporated a high DOX payload. The hyaluronic acid (HA) coating over the MTNst surface served a dual purpose of first, stabilizing DOX inside the MTNst (capping agent), and second, directing the nanoplatform device to CD44 receptors that are highly expressed in MDA-MB-231 cells (targeting ligand). The NPs exhibited highly efficacious in vitro tumor-cell killing and excellent in vivo tumor regression, highlighting the enormous promise of this system for breast cancer therapy.

    View details for DOI 10.1016/j.actbio.2018.09.006

    View details for Web of Science ID 000449133400030

    View details for PubMedID 30201431

  • Polyamino Acid Layer-by-Layer (LbL) Constructed Silica-Supported Mesoporous Titania Nanocarriers for Stimuli-Responsive Delivery of microRNA 708 and Paclitaxel for Combined Chemotherapy ACS APPLIED MATERIALS & INTERFACES Gupta, B., Ruttala, H., Poudel, B., Pathak, S., Regmi, S., Gautam, M., Poudel, K., Sung, M., Ou, W., Jin, S., Jeong, J., Ku, S., Choi, H., Yong, C., Kim, J. 2018; 10 (29): 24392–405

    Abstract

    Cellular Fas-associated protein with death domain-like interleukin-1β-converting enzyme-inhibitory protein (c-FLIP), often strongly expressed in numerous cancers, plays a pivotal role in thwarting apoptosis and inducing chemotherapy resistance in cancer. An integrated approach combining chemotherapy with suppression of c-FLIP levels could prove paramount in the treatment of cancers with c-FLIP overexpression. In this study, we utilized a polymeric layer-by-layer (LbL) assembly of silica-supported mesoporous titania nanoparticles (MTNst) to co-deliver paclitaxel (PTX) and microRNA 708 (miR708) for simultaneous chemotherapy and c-FLIP suppression in colorectal carcinoma. The resulting LbL miR708/PTX-MTNst showed dose-dependent cytotoxicity in HCT-116 and DLD-1 colorectal carcinoma cell lines, which was remarkably superior to that of free PTX or LbL PTX-MTNst. LbL miR708/PTX-MTNst strongly inhibited c-FLIP expression and resulted in increased expression of proapoptotic proteins. In DLD-1 xenograft tumor-bearing mice, the nanoparticles accumulated in the tumor, resulting in remarkable tumor regression, with the PTX and miR708-loaded nanoparticles showing significantly greater inhibitory effects than the free PTX or PTX-loaded nanoparticles. Immunohistochemical analyses of the tumors further confirmed the remarkable apoptotic and antiproliferative effects of the nanoparticles, whereas organ histology reinforced the biocompatibility of the system. Therefore, the LbL miR708/PTX-MTNst system, owing to its ability to deliver both chemotherapeutic drug and inhibitory miRNA to the tumor site, shows great potential to treat colorectal carcinoma in clinical settings.

    View details for DOI 10.1021/acsami.8b06642

    View details for Web of Science ID 000440511900009

    View details for PubMedID 29978708

  • Polymeric microsphere-facilitated site-specific delivery of quercetin prevents senescence of pancreatic islets in vivo and improves transplantation outcomes in mouse model of diabetes ACTA BIOMATERIALIA Pathak, S., Regmi, S., Nguyen, T., Gupta, B., Gautam, M., Yong, C., Kim, J., Son, Y., Kim, J., Park, M., Bae, Y., Park, S., Jeong, D., Yook, S., Jeong, J. 2018; 75: 287–99

    Abstract

    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 in vitro 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-1). 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 in vivo transplanted HC sample showed lower intensity compared to that of the control islets or the islet cell clusters. Thus, in situ delivery of therapeutic agent may be a promising approach to improve therapeutic outcomes in cell therapy.In this study, we aimed to improve outcomes in islet transplantation using in situ 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 in vitro 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 in vivo transplantation. Thus, local delivery of antioxidants like quercetin may be an attractive way to improve outcomes in cell therapy.

    View details for DOI 10.1016/j.actbio.2018.06.006

    View details for Web of Science ID 000440125600024

    View details for PubMedID 29883808

  • Paclitaxel and Erlotinib-co-loaded Solid Lipid Core Nanocapsules: Assessment of Physicochemical Characteristics and Cytotoxicity in Non-small Cell Lung Cancer PHARMACEUTICAL RESEARCH Gupta, B., Poudel, B., Regmi, S., Pathak, S., Ruttala, H., Gautam, M., An, G., Jeong, J., Choi, H., Yong, C., Kim, J. 2018; 35 (5): 96

    Abstract

    Lung cancer is the leading cause of cancer-related deaths. The aim of this study was to design solid lipid core nanocapsules (SLCN) comprising a solid lipid core and a PEGylated polymeric corona for paclitaxel (PTX) and erlotinib (ERL) co-delivery to non-small cell lung cancer (NSCLC), and evaluate their physicochemical characteristics and in vitro activity in NCI-H23 cells.PTX/ERL-SLCN were prepared by nanoprecipitation and sonication and physicochemically characterized by dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier-transform infrared spectroscopy. In vitro release profiles at pH 7.4 and pH 5.0 were studied and analyzed. In vitro cytotoxicity and cellular uptake and apoptosis assays were performed in NCI-H23 cells.PTX/ERL-SLCN exhibited appropriately-sized spherical particles with a high payload. Both PTX and ERL showed pH-dependent and sustained release in vitro profiles. PTX/ERL-SLCN demonstrated concentration- and time-dependent uptake by NCI-H23 cells and caused dose-dependent cytotoxicity in the cells, which was remarkably greater than that of not only the free individual drugs but also the free drug cocktail. Moreover, well-defined early and late apoptosis were observed with clearly visible signs of apoptotic nuclei.PTX/ERL-SLCN could be employed as an optimal approach for combination chemotherapy of NSCLC.

    View details for DOI 10.1007/s11095-017-2337-6

    View details for Web of Science ID 000428687800002

    View details for PubMedID 29536182

  • Tissue adhesive FK506-loaded polymeric nanoparticles for multi-layered nano-shielding of pancreatic islets to enhance xenograft survival in a diabetic mouse model BIOMATERIALS Tung Thanh Pham, Tiep Tien Nguyen, Pathak, S., Regmi, S., Hanh Thuy Nguyen, Tuan Hiep Tran, Yong, C., Kim, J., Park, P., Park, M., Bae, Y., Choi, J., Byun, Y., Ahn, C., Yook, S., Jeong, J. 2018; 154: 182–96

    Abstract

    This study aims to develop a novel surface modification technology to prolong the survival time of pancreatic islets in a xenogenic transplantation model, using 3,4-dihydroxyphenethylamine (DOPA) conjugated poly(lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (DOPA-NPs) carrying immunosuppressant FK506 (FK506/DOPA-NPs). The functionalized DOPA-NPs formed a versatile coating layer for antigen camouflage without interfering the viability and functionality of islets. The coating layer effectively preserved the morphology and viability of islets in a co-culture condition with xenogenic lymphocytes for 7 days. Interestingly, the mean survival time of islets coated with FK506/DOPA-NPs was significantly higher as compared with that of islets coated with DOPA-NPs (without FK506) and control. This study demonstrated that the combination of surface camouflage and localized low dose of immunosuppressant could be an effective approach in prolonging the survival of transplanted islets. This newly developed platform might be useful for immobilizing various types of small molecules on therapeutic cells and biomaterial surface to improve the therapeutic efficacy in cell therapy and regenerative medicine.

    View details for DOI 10.1016/j.biomaterials.2017.10.049

    View details for Web of Science ID 000419538900015

    View details for PubMedID 29128846

  • Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes FASEB JOURNAL Pathak, S., Regmi, S., Gupta, B., Tung Thanh Pham, Yong, C., Kim, J., Yook, S., Kim, J., Park, M., Bae, Y., Jeong, J. 2017; 31 (11): 5111–21

    Abstract

    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 from the transplanted area revealed significantly reduced apoptosis in ICCs. Transplantation of ICCs may 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. Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes.

    View details for DOI 10.1096/fj.201700490R

    View details for Web of Science ID 000413398500038

    View details for PubMedID 28754712

  • Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice DRUG DELIVERY Pathak, S., Regmi, S., Gupta, B., Poudel, B. K., Tung Thanh Pham, Yong, C., Kim, J., Kim, J., Park, M., Bae, Y., Yook, S., Ahn, C., Jeong, J. 2017; 24 (1): 1350–59

    Abstract

    Immune rejection after transplantation is common, which leads to prompt failure of the graft. Therefore, to prolong the survival time of the graft, immunosuppressive therapy is the norm. Here, we report a robust immune protection protocol using FK506-loaded microspheres (FK506M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10 mg/kg FK506M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506M. In addition, minimal number of immune cells invaded inside the gel of the islet-FK506M group. The single injection of FK506M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model.

    View details for DOI 10.1080/10717544.2017.1377317

    View details for Web of Science ID 000410914100002

    View details for PubMedID 28911248

  • Folate receptor-targeted hybrid lipid-core nanocapsules for sequential delivery of doxorubicin and tanespimycin COLLOIDS AND SURFACES B-BIOINTERFACES Gupta, B., Pathak, S., Poudel, B., Regmi, S., Ruttala, H., Gautam, M., Lee, J., Jeong, J., Choi, H., Yong, C., Kim, J. 2017; 155: 83–92

    Abstract

    When exposed to cancer cells, cytotoxic drugs such as doxorubicin (DOX) can lead to the induction of heat shock protein 90 (Hsp90), a molecular chaperone associated with a number of cancer-related client proteins, and result in cell survival. Co-administration of DOX with tanespimycin (TNP), an Hsp90 inhibitor, can sensitize the cancer cells to the cytotoxic effects of DOX. The effect of such a combination has been found to depend on the schedule of administration. Sequential administration of DOX and TNP has been linked to highly synergistic combination effects. Therefore, we aimed to develop folate-receptor targeted hybrid lipid-core nanocapsules comprising a hybrid lipid core lodging TNP and a polymeric corona lodging DOX (F-DTN). These nanocarriers were capable of delivering DOX and TNP sequentially, which was well demonstrated by an in vitro release study. The in vitro release profiles displayed pH-dependent and sustained release features. F-DTN exhibited excellent morphological characteristics with highly monodispersed particles. In vitro tests with F-DTN in MCF-7 cell line demonstrated exceptional cytotoxicity, with high cellular uptake and apoptosis. These findings were appreciably more assertive than tests with free individual drugs (DOX, TNP), free drug combination (DOX/TNP), or non-folate receptor-targeted hybrid lipid-core nanocapsules (DTN). In vivo pharmacokinetic study revealed noticeable enhancement of bioavailability and plasma circulation time of the drugs when encapsulated in the carrier system. Therefore, hybrid lipid-core nanocapsules have the potential to be utilized for application in folate receptor-targeted combination chemotherapy.

    View details for DOI 10.1016/j.colsurfb.2017.04.010

    View details for Web of Science ID 000403738000010

    View details for PubMedID 28410515

  • A three-dimensional assemblage of gingiva-derived mesenchymal stem cells and NO-releasing microspheres for improved differentiation INTERNATIONAL JOURNAL OF PHARMACEUTICS Regmi, S., Cao, J., Pathak, S., Gupta, B., Poudel, B., Pham Thanh Tung, Yook, S., Park, J., Yong, C., Kim, J., Yoo, J., Jeong, J. 2017; 520 (1-2): 163–72

    Abstract

    Stem cell therapy is an attractive approach to bone tissue regeneration. Nitric oxide (NO) has been reported to facilitate osteogenic differentiation of stem cells. To enhance osteogenic differentiation of gingiva-derived mesenchymal stem cells (GMSCs), we designed a method for in situ delivery of exogenous NO to these cells. A NO donor, polyethylenimine/NONOate, was incorporated into poly(lactic-co-glycolic acid) microspheres to deliver NO to the cells for an extended period of time under in vitro culture conditions. A hybrid aggregate of GMSCs and NO-releasing microspheres was prepared by the hanging drop technique. Confocal microscopy revealed homogeneous arrangement of the stem cells and microspheres in heterospheroids. Western blot analysis and live-dead imaging showed no significant change in cell viability. Importantly, the in situ delivery of NO within the heterospheroids enhanced osteogenic differentiation indicated by a 1.2-fold increase in alkaline phosphatase activity and an approximately 10% increase in alizarin red staining. In addition, a low dose of NO promoted proliferation of the GMSCs in this 3D system. Thus, delivery of the NO-releasing microsphers to induce differentiation of stem cells within this three dimensional system may be one of possible strategies to direct differentiation of a stem cell-based therapeutic agent toward a specific lineage.

    View details for DOI 10.1016/j.ijpharm.2017.02.014

    View details for Web of Science ID 000396948400018

    View details for PubMedID 28185957

  • Development of Bioactive PEGylated Nanostructured Platforms for Sequential Delivery of Doxorubicin and Imatinib to Overcome Drug Resistance in Metastatic Tumors ACS APPLIED MATERIALS & INTERFACES Gupta, B., Ramasamy, T., Poudel, B., Pathak, S., Regmi, S., Choi, J., Son, Y., Thapa, R., Jeong, J., Kim, J., Choi, H., Yong, C., Kim, J. 2017; 9 (11): 9280–90

    Abstract

    Metastasis of cancers accounts for almost all cancer-related deaths. In this study, we report a PEGylated nanostructured platform for coadministration of doxorubicin (DOX) and imatinib (IMT) intended to effectively inhibit metastatic tumors. The DOX and IMT coloaded nanostructured system (DOX/IMT-N) is characterized by an excellent encapsulation potential for both drugs and shows sequential and sustained drug release in vitro. DOX/IMT-N significantly inhibited the in vitro proliferation of MDA-MB-231 and SK-MEL-28 cells. The inhibitory effect on in vitro proliferation of the cells was significantly greater than the effect of free DOX, DOX/IMT cocktail, or the nanostructured system housing DOX only (DOX-N). DOX/IMT-N remarkably enhanced cellular drug uptake, resulting in enhanced apoptosis, caused by significant increases in the expression levels of apoptotic marker proteins. Intravenous administration of DOX/IMT-N to MBA-MB-231 xenograft tumor-bearing mice resulted in significantly improved inhibition of tumor progression compared to that with DOX, DOX/IMT, or DOX-N. Therefore, the nanostructured DOX/IMT-N system could potentially aid in overcoming drug resistance in metastatic tumors and improve the effectiveness of metastatic tumor therapeutics.

    View details for DOI 10.1021/acsami.6b09163

    View details for Web of Science ID 000397478100012

    View details for PubMedID 28240860

  • Superiority of three-dimensional stem cell clusters over monolayer culture: An archetype to biological application MACROMOLECULAR RESEARCH Regmi, S., Jeong, J. 2016; 24 (12): 1037–46

    View details for DOI 10.1007/s13233-016-4107-4

    View details for Web of Science ID 000391354900001

  • Hybrid Congregation of Islet Single Cells and Curcumin-Loaded Polymeric Microspheres as an Interventional Strategy to Overcome Apoptosis Associated with Pancreatic Islets Transplantation ACS APPLIED MATERIALS & INTERFACES Pathak, S., Regmi, S., Gupta, B., Poudel, B. K., Tung Thanh Pham, Kim, J., Park, P., Yong, C., Kim, J., Bae, Y., Kim, S., Jeong, J. 2016; 8 (39): 25702–13

    Abstract

    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 microspheres 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.

    View details for DOI 10.1021/acsami.6b07897

    View details for Web of Science ID 000384951800009

    View details for PubMedID 27666317

  • Preparation of High-Payload, Prolonged-Release Biodegradable Poly(lactic-co-glycolic acid)-Based Tacrolimus Microspheres Using the Single-Jet Electrospray Method CHEMICAL & PHARMACEUTICAL BULLETIN Pathak, S., Gupta, B., Poudel, B., Tuan Hiep Tran, Regmi, S., Tung Thanh Pham, Thapa, R., Kim, M., Yong, C., Kim, J., Jeong, J. 2016; 64 (2): 171–78

    Abstract

    Tacrolimus-loaded poly(lactic-co-glycolic acid) microspheres (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 electrospray method, and to prepare TAC-PLGA-M with a high payload and desirable release properties. TAC-PLGA-M were prepared using the electrospray method. In 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 in vitro release study showed prolonged release patterns. TAC-PLGA-M with enhanced drug loading and prolonged-release patterns were successfully prepared using the electrospray method.

    View details for DOI 10.1248/cpb.c15-00799

    View details for Web of Science ID 000369124300012

    View details for PubMedID 26833445