1. Clickable, acid labile immunosuppressive prodrugs for in vivo targeting
- Author
-
Tracy K. Snyder, Hua Wang, Miguel C. Sobral, Vijay S. Gorantla, Yevgeny Brudno, and David J. Mooney
- Subjects
Drug ,Alginates ,medicine.medical_treatment ,media_common.quotation_subject ,Biomedical Engineering ,Hydrocarbons, Cyclic ,Context (language use) ,02 engineering and technology ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Tacrolimus ,Mice ,In vivo ,medicine ,Animals ,General Materials Science ,Prodrugs ,media_common ,Sirolimus ,Drug Carriers ,Mice, Inbred BALB C ,business.industry ,Immunosuppression ,Hydrogels ,Prodrug ,Hydrogen-Ion Concentration ,Mycophenolic Acid ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Drug Liberation ,Immunosuppressive drug ,Click Chemistry ,0210 nano-technology ,business ,Immunosuppressive Agents ,Allotransplantation ,Half-Life - 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.
- Published
- 2019