Clickable, acid labile immunosuppressive prodrugs for in vivo targeting. (6th November 2019)

• Record Type: Journal Article
• Authors: Wang, Hua; Sobral, Miguel C.; Snyder, Tracy; Brudno, Yevgeny; Gorantla, Vijay S.; Mooney, David J.
• Is Part Of: Biomaterials science. Volume 8:Number 1(2020)
• Page Start: 266
• Page End: 277
• Publication Date: 2019-11-06
• Subjects: Biomedical materials -- Periodicals; 610.28
• DOI: 10.1039/c9bm01487j
• Languages: English
• ISSNs: 2047-4830

Abstract

Abstract : Clickable immunosuppressive prodrugs enable in vivo replenishment of drugs in biomaterial depots to maintain long-term immunosuppression in tissue/organ transplantation. Abstract : Allotransplantation offers the potential to restore the anatomy and function of injured tissues and organs, but typically requires life-long, systemic administration of immunosuppressive drugs to prevent rejection, which can result in serious complications. Targeting the immunosuppressive drug to the graft favors local tissue concentration versus systemic drug exposure and end-organ toxicity. This could reduce the overall dose and dosing frequency of immunosuppressive drugs, and improve the safety and efficacy of treatment. Here, we developed dibenzocyclooctyne (DBCO)-modified prodrugs of the immunosuppressive drugs tacrolimus, rapamycin and mycophenolic acid, and demonstrated their targeted conjugation both in vitro and in vivo to azido-modified hydrogels via Click chemistry. Such azido-modified hydrogels placed in transplanted tissues enable sustained local release of drugs, and could be repeatedly refilled with systemically administered acid-labile prodrugs after drug exhaustion. Thus, clickable prodrugs with degradable linkers provide new possibilities for graft targeted immunosuppression in the context of allotransplantation.