Deuterated colchicine liposomes based on oligomeric hyaluronic acid modification enhance anti-tumor effect and reduce systemic toxicity

Abstract

Deuterated drugs are produced by substituting hydrogen atoms with deuterium atoms at specific sites in a drug molecule to prolong its metabolic cycle and reduce the production of toxic metabolites. Deuterated drugs have recently attracted increasing attention from the pharmaceutical industry. Colchicine exhibits a strong anti-tumor activity but has a short half-life, rapid attenuated drug concentration, narrow treatment window, and lack of tumor-specific targeting in vivo, resulting in toxicity and side effects. In this study, we explored whether deuteration could reduce the toxicity of colchicine. We prepared deuterated colchicine liposomes coated with oligo-hyaluronic acid, which can bind to the tumor-specific CD44 receptor and reduce the clearance of immune cells from the blood, resulting in a long blood circulation time and active targeting. We observed that deuteration of the colchicine B ring reduced drug toxicity and improved the anti-tumor response in 4 T1 breast cancer. Liposomes modified with oligo-hyaluronic acid exhibited increased tumor accumulation, further improving the anti-tumor effect of the drugs. Our results provide a basis for the development and application of deuterated drugs in the field of nano-preparations.