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Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice.

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 (FK506_M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506_M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10 mg/kg FK506_M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506_M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506_M. In addition, minimal number of immune cells invaded inside the gel of the islet-FK506_M group. The single injection of FK506_M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model.

SUBMITTER: Pathak S

PROVIDER: S-EPMC8241191 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice.

Pathak Shiva S Regmi Shobha S Gupta Biki B Poudel Bijay K BK Pham Tung Thanh TT Yong Chul Soon CS Kim Jong Oh JO Kim Jae-Ryong JR Park Min Hui MH Bae Young Kyung YK Yook Simmyung S Ahn Cheol-Hee CH Jeong Jee-Heon JH

Drug delivery 20171101 1

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 m ...[more]

PMID: 28911248

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Project description:Discovering the function of an unknown protein, particularly one with neither structural nor functional correlates, is a daunting task. Interaction analyses determine binding partners, whereas DNA transfection, either transient or stable, leads to intracellular expression, though not necessarily at physiologically relevant levels. In theory, direct intracellular protein delivery (protein transduction) provides a conceptually simpler alternative, but in practice the approach is problematic. Domains such as HIV TAT protein are valuable, but their effectiveness is protein specific. Similarly, the delivery of intact proteins via endocytic pathways (e.g. using liposomes) is problematic for functional analysis because of the potential for protein degradation in the endosomes/lysosomes. Consequently, recent reports that microspheres can deliver bio-cargoes into cells via a non-endocytic, energy-independent pathway offer an exciting and promising alternative for in vitro delivery of functional protein. In order for such promise to be fully exploited, microspheres are required that (i) are stably linked to proteins, (ii) can deliver those proteins with good efficiency, (iii) release functional protein once inside the cells, and (iv) permit concomitant tracking. Herein, we report the application of microspheres to successfully address all of these criteria simultaneously, for the first time. After cellular uptake, protein release was autocatalyzed by the reducing cytoplasmic environment. Outside of cells, the covalent microsphere-protein linkage was stable for ≥90 h at 37 °C. Using conservative methods of estimation, 74.3% ± 5.6% of cells were shown to take up these microspheres after 24 h of incubation, with the whole process of delivery and intracellular protein release occurring within 36 h. Intended for in vitro functional protein research, this approach will enable study of the consequences of protein delivery at physiologically relevant levels, without recourse to nucleic acids, and offers a useful alternative to commercial protein transfection reagents such as Chariot™. We also provide clear immunostaining evidence to resolve residual controversy surrounding FACS-based assessment of microsphere uptake.

Dataset Information

Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice.

Publications

Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice.

Similar Datasets

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