The therapeutic efficacy and safety improvements of crizotinib prodrug micelles on breast cancer treatment

Abstract

Nowadays, breast cancer has become a major killer threatening women's health. MET is a receptor tyrosine kinase that upon binding of its ligand, hepatocyte growth factor, activates downstream pathways with diverse cellular functions which are important in the occurrence and development of breast cancer. Crizotinib (Cro) is a multi-target tyrosine kinase inhibitor targeting ALK gene recombination, MET gene amplification and ROS gene. Although Cro has the ideal treatment for breast cancer, Cro has stronger hepatotoxicity and lacks targeting capacity to the tumor cell, which limited Cro to effectively therapy breast cancer. In this study, we develop a novel prodrug micelle through polymerization reaction polymerizing Cro onto the chain to form POEG-b-PCro prodrug micelles, in which the drug loading capacity of Cro was significantly increased to improve the cumulant of the tumor. Pharmacokinetic and biodistribution studies illustrated that POEG-b-PCro prodrug micelles had a significant effect by improving Cro content in the tumor. Meanwhile, the antitumor mechanism of POEG-b-PCro prodrug micelles proved that POEG-b-PCro prodrug micelles had a stronger effect by reducing negative regulatory proteins. POEG-b-PCro prodrug micelles had splendid safety through safety study in vivo to account for POEG-b-PCro prodrug micelles. Therefore, POEG-b-PCro prodrug micelles are a promising drug delivery strategy for reducing toxicity and enhancing the efficacy of Cro.