Lopinavir Derivative as Potent P-gp Inhibitor Enables Delivery through HPMA Copolymer Conjugates and Overcoming Tumor Chemoresistance to Conventional Cytostatic Drugs.

Tumor chemoresistance caused by P-glycoprotein (P-gp) expression in cancer cells remains a significant challenge in cancer chemotherapy. Herein, a novel P-gp-inhibiting lopinavir derivative (LD) was synthesized via esterification of protease inhibitor lopinavir with 5-methyl-4-oxohexanoic acid. LD proved to be a potent P-gp inhibitor with EC50 ∼ 1 μM, capable of considerable sensitization of P-gp-expressing cancer cells to conventional cytostatic drugs in vitro. The oxo functional group introduced in LD allowed its covalent linkage with the N-(2-hydroxypropyl)methacrylamide copolymer carrier via a pH-sensitive hydrazone bond (P-LD). Polymer conjugation enhanced the pharmacological properties of LD in vivo, increasing its half-life in the bloodstream, protecting it from metabolic degradation, and promoting its accumulation in tumors via the enhanced permeability and retention effect. P-LD exhibited P-gp-inhibitory activity and sensitized cells to polymer-bound cytostatic drugs in vitro. Importantly, P-LD remarkably improved the antitumor efficacy of a polymer-bound doxorubicin in two P-gp-expressing mouse tumor models without exhibiting any systemic toxicity.