Lopinavir Derivative as Potent P-gp Inhibitor Enables Delivery through HPMA Copolymer Conjugates and Overcoming Tumor...

Area of Science:

• Oncology
• Pharmacology
• Materials Science

Background:

• P-glycoprotein (P-gp) expression in cancer cells causes chemoresistance, limiting chemotherapy effectiveness.
• Developing effective P-gp inhibitors is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To synthesize and evaluate a novel P-gp-inhibiting lopinavir derivative (LD).
• To develop a polymer-conjugated form (P-LD) to enhance drug delivery and efficacy.
• To assess the in vitro and in vivo efficacy and toxicity of P-LD in combination with chemotherapy.

Main Methods:

• Synthesized a lopinavir derivative (LD) via esterification and conjugated it to a copolymer carrier (P-LD) using a pH-sensitive hydrazone bond.
• Evaluated P-gp inhibitory activity and chemosensitization of LD and P-LD in vitro.
• Assessed the in vivo pharmacokinetic properties, tumor accumulation, antitumor efficacy, and systemic toxicity of P-LD in combination with polymer-bound doxorubicin in mouse tumor models.

Main Results:

• LD demonstrated potent P-gp inhibition (EC50 ~ 1 μM) and sensitized P-gp-expressing cancer cells to cytostatic drugs in vitro.
• Polymer conjugation (P-LD) improved LD's half-life, metabolic stability, and tumor accumulation via the EPR effect.
• P-LD significantly enhanced the antitumor efficacy of polymer-bound doxorubicin in P-gp-expressing mouse tumor models without observable systemic toxicity.

Conclusions:

• The novel lopinavir derivative (LD) and its polymer conjugate (P-LD) are effective P-gp inhibitors.
• P-LD shows promise for overcoming chemoresistance and enhancing chemotherapy efficacy, particularly in combination with targeted drug delivery systems.
• P-LD represents a potential strategy to improve cancer treatment outcomes by mitigating P-gp-mediated multidrug resistance.