Polymeric microsphere-facilitated site-specific delivery of quercetin prevents senescence of pancreatic islets <i>in vivo</i> and improves transplantation outcomes in mouse model of diabetes

다국어 초록 (Multilingual Abstract)

<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>