Encapsulation of Islets with Matrigel in Cldrosome in a Xenograft Murine Model

Abstract

The purpose of this study is to develop a potent immunosuppressive system to prevent islet rejection after transplantation for the treatment of type 1 diabetes. This strategy is to encapsulate islets in matrigel containing liposomal clodronate Clodrosome® to inhibit activation of macrophages and immune cells in the early stage of transplantation. Liposomal clodronate, clodronate-encapsulated liposomes, can deplete macrophages, thereby preventing macrophage activation. The molecular imaging of Cy5.5 labeled liposome in matrigel demonstrated that liposomal clodronate remained in the matrigel for over 7 days. To evaluate the therapeutic efficacy of transplanted islets, four groups of islet transplanted mice (n=6 in each group) were prepared, such as below 1) Islet group, 2) Islet-Matrigel group, 3) Islet-Clodrosome group, and 4) Islet-Matrigel-Clodrosome group, where 2000 IEQ islets were subcutaneously transplanted and the dose of clodronate was 6.25 mg/kg. When islets were transplanted in matrigel containing liposomal clodronate (Islet-Matrigel-Clorosome group), the median survival time (MST) of transplanted islets was significantly increased (> 60 days) when compared to other groups. Immunohistochemical staining of islet-grafted tissues in matrigel demonstrated that locally delivered liposomal clodronate in matrigel effectively inhibited the activation of macrophage after islet transplantation. In addition, liposomal clodronate was effective on inhibiting immune cell migration and activation, and pro-inflammatory cytokine secretion was significantly down-regulated. In conclusion, locally delivered liposomal clodronate in matrigel effectively improved the grafted survival time of grafted islets.