*Purpose: To utilize a novel technology involving siRNA conjugated iron oxide nanoparticles to protect against ischemic damage to islet cells before transplant, therefore minimizing the amount of excised pancreas needed to allow for living donor islet cell transplantation to be a much more clinically feasible option in the treatment of diabetes mellitus (DM).

*Methods: After donor pancreatectomy, the islets were cultured for 2 days with siRNA conjugated nanoparticles that targeted the pro-apoptotic genes Caspase 3, Caspase 8 and Fas. In Study 1, the protective effects on the islets were assessed in vitro by direct islet counts before and after culture. Apoptosis was also directly analyzed via DNA apoptotic ladder assays. In Study 2, the insulin secreting effects of the islets were assessed in vivo by transplanting a marginal number of islets into diabetic recipients in a non-human primate model. After culture the harvested islet cells were transplanted via direct infusion into the recipient’s portal circulation in a similar manner to current clinical practice. The animals were maintained on a standard immunosuppressive protocol, and their blood glucose levels were analyzed and tracked.

*Results: It is generally accepted that greater than 10K/IEQ is required to maintain stable blood glucose levels in human and non-human primates. We have shown a dramatic reduction in insulin requirements by utilizing a marginal number of islet cells (4,400 – 7,800IEQ) compared to control cases without siRNA. Also, we have demonstrated the anti-apoptotic effects of the SiRNA conjugated islets in vitro with apoptotic ladder assays, as well as directly with minimal loss of islets after 2 day culture when compared to controls. We have also shown histologic evidence of positive insulin staining cells from the liver in recipients of direct portal infusion.

*Conclusions: It has been theorized that the reason for failure of islet transplantation has been due to ischemic injury of the islets after transplant. Our data have demonstrated for the first time ever the protective effects of magnetic nanoparticles as carriers for siRNA that targets pro-apoptotic genes in pancreatic islet cells before transplant. The use of siRNA conjugated iron oxide islets will further minimize the amount of islets needed for transplant, as well as decrease the amount of pancreas required to normalize blood glucose levels in the treatment of DM.

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