Colon-adhesive poly(maleic anhydride)-sirolimus conjugate alleviates local colitis inflammation

Abstract

Ulcerative colitis (UC) is a chronic, recurring inflammatory condition triggered by immunological imbalances in the digestive tract, leading to weight loss, diarrhea, rectal bleeding, and an increased risk of colon cancer. Existing UC treatments encounter significant limitations, such as primary non-responsiveness, secondary loss of efficacy, and adverse effects. This necessitates the development of drugs and drug formulations to broaden UC treatment options. This study describes the extended retention of poly(maleic anhydride)-drug conjugates in the large intestine of a DSS-induced acute colitis mouse model and highlights their potential for treating UC. Anti-inflammatory sirolimus (Siro) is considered an alternative drug for UC treatment, which however also has side effects due to nonspecific systemic delivery. Accordingly, poly(malic anhydride)-sirolimus (pSiro) is synthesized by linking Siro, a representative immunosuppressant and anti-inflammatory drug used in clinical practice, to anhydride groups of poly(maleic anhydride) via ester bonds. In a biodistribution study, poly(maleic anhydride) increases drug retention in the large intestine. Histochemical staining reveals the reduced inflammation degree in the treatment of pSiro, which leads to the decline of systemic inflammatory markers such as plasma TNF-α, NO, and LPS levels. These results suggest pSiro as a potential therapeutic option for the treatment of UC.