Oral targeted delivery by nanoparticles enhances efficacy of an Hsp90 inhibitor by reducing systemic exposure in murine models of colitis and colitis-associated cancer.
J Crohns Colitis. 2019 Jun 05;:
Authors: Yang M, Zhang F, Yang C, Wang L, Sung J, Garg P, Zhang M, Merlin D
BACKGROUND AND AIMS: Heat shock protein 90 (Hsp90)-targeted therapy has been proposed as a promising strategy for the treatment of ulcerative colitis (UC) and colitis-associated cancer (CAC). The systemic administration of the Hsp90 inhibitor, 17-AAG, was found to be profoundly protective in preclinical mouse models of inflammatory bowel disease (IBD). However, the therapeutic potential of 17-AAG is limited by potential side effects associated with its systemic exposure and the modest bioavailability afforded by its oral administration.
METHODS: In an effort to address these issues, we herein used a versatile single-step surface-functionalizing technique to prepare a 17-AAG oral delivery system using PLGA/PLA-PEG-FA nanoparticles (NP-PEG-FA/17-AAG).
RESULTS: NP-PEG-FA could be efficiently taken up by mouse Colon-26 cells and activated Raw 264.7 cells in vitro and by inflamed mouse colitis tissues in vivo. The therapeutic efficacy of orally administrated NP-PEG-FA/17-AAG was evaluated in in vivo models using dextran sulfate sodium (DSS)-induced UC and azoxymethane (AOM)/DSS-induced CAC, and results indicated that NP-PEG-FA/17-AAG significantly alleviated the symptoms of UC and CAC. More importantly, our inflamed colitis-targeted 17-AAG nano-formulation reduced systemic exposure and provided a degree of therapeutic response similar to that obtained by systemic administration (intraperitoneal, IP) of 17-AAG, but at a 10-fold lower dose.
CONCLUSIONS: We therefore describe a convenient, orally administrated 17-AAG delivery system that exhibits enhanced efficacy in UC and CAC therapy while reducing systemic exposure. This system may represent a promising therapeutic approach for treating UC and CAC.
PMID: 31168612 [PubMed – as supplied by publisher]