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

TL;DR

A new lopinavir-based drug was developed to block P-gp in cancer cells, improving chemotherapy effectiveness and reducing tumor resistance.

Contribution

A novel lopinavir derivative was synthesized and conjugated to a copolymer to overcome tumor chemoresistance.

Findings

The lopinavir derivative inhibited P-gp with an EC50 of ~1 μM and sensitized cancer cells to chemotherapy drugs.

Conjugation with a copolymer improved the drug's pharmacological properties and tumor targeting.

The conjugate enhanced doxorubicin's antitumor efficacy in mouse models without toxicity.

Abstract

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.

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