B-cell maturation antigen -targeted Tirapazamine-loaded liposomes overcome hypoxia-induced drug resistance and metastasis in multiple myeloma.

Abstract

Multiple myeloma (MM) is a highly fatal disease, particularly in the relapsed-refractory stage, due to drug resistance associated with tumor hypoxia. TPZ, a hypoxia-activated pro-drug, effectively kills hypoxic tumor cells; however, its severe side effects have limited its therapeutic use. This study investigates BCMA-targeted liposomes loaded with TPZ to enhance their therapeutic efficacy while reducing toxicity. TPZ inhibits cell proliferation, induces apoptosis, and reverses the metastasis driven by hypoxia in MM cells. Encapsulation into liposomes maintained its cytotoxic effects in hypoxic MM cells. BCMA-targeting increased specific delivery in MM cells and enhanced biodistribution to MM cells within the bone marrow. In a relapsed/refractory MM mouse model, BCMA-targeted TPZ-loaded liposomes significantly reduced tumor progression while minimizing body weight loss in mice and reducing cytotoxicity in PBMCs, achieving a Efficacy-to-Body-Weight Toxicity Ratio of 8.3 compared to 1 for free TPZ. This study provides preclinical proof-of-concept for using BCMA-targeted TPZ-loaded liposomes as a promising and safer therapeutic option for relapsed/refractory MM.