Abstract
This study aimed to evaluate the anticancer efficacy of a newly developed HER2-targeting small-molecule inhibitor, MKH066, and to overcome its limited aqueous solubility through encapsulation in polymeric micelles for HER2-positive breast cancer therapy. MKH066 exhibited significantly higher cytotoxicity in HER2-overexpressing BT-474 and SK-BR-3 cells than in MCF-7 and MDA-MB-231 cells. The mPEG2K-PLLA3K micelle (M4) was selected based on its particle size below 200 nm, low polydispersity index (0.08), and the highest drug loading content (9.1%). M4 exhibited a reduced critical micelle concentration (~ 38 µg/mL) after drug encapsulation, sustained drug release over 96 h, and significantly improved apoptosis induction in BT-474 cells. The in vivo biodistribution demonstrated greater and prolonged tumor accumulation after intravenous injection in MCF-7 and BT-474 tumor models. In vivo studies demonstrated that intravenously administered M4 significantly inhibited tumor growth and increased apoptosis in tumor tissues without noticeable systemic toxicity. These findings provide proof-of-concept that polymeric micelle formulation enables the translation of the preferential in vitro anticancer activity of poorly water-soluble MKH066 into systemic in vivo application.