Pretransplant Bioconjugation of Renal Endothelial Surfaces for TAK-242 Drug Delivery

Abstract Transplantation provides a unique opportunity wherein donor tissue is isolated ex vivo and available for tissue-specific manipulation prior to implantation. We previously demonstrated improved graft performance with covalently modified drug-eluting islets. In this work we provide preliminary studies extending the concept of covalent tissue modification for drug delivery to renal transplantation and demonstrate that the perfusion of reactive N-hydroxysuccinimide (NHS) esters through the renal artery affords the covalent modification of kidney vascular surfaces. The fluorescent labeling of vascular surface proteins has minimal impact on clinical markers of kidney function and host immune responses in murine isografts and allografts over 5 weeks. Additionally, histological analysis of modified graft tissue resected on day 35 reveals no gross abnormalities, with some covalent label still detectable. In a preliminary study, bioconjugation of renal vasculature with a slow-release prodrug of TAK-242 (a potent inhibitor of toll-like receptor 4) modulated the expression of inflammatory cytokines and reduced T-cell infiltration into graft tissue 48 h posttransplant.