(291) A development of monocarboxylate transporter 4 inhibitor/docetaxel-loaded smart layer-by-layer nanoparticles for prostate cancer therapy

Background: : Prostate cancer is the second leading cause of cancer death in the US, with advanced disease featuring increased anaerobic glycolysis and excessive lactic acid production. Monocarboxylate transporter 4 (MCT4) facilitates lactate export, maintaining the hyperglycolytic, acid-resistant phenotype typical in advanced prostate cancer cells. Docetaxel is one of the few current clinical treatment options for advanced cancer treatment when androgen deprivation has failed. However, the current clinical treatment has major side effects, such as neuropathy and alcohol intoxication.

Objective: : To develop and characterize smart layer-by-layer (LBL) nanoparticles loaded with an MCT4 inhibitor (AZD0095) and docetaxel (DTX) for targeted prostate cancer therapy, aiming to enhance drug efficacy and reduce the current clinical formulation-associated side effects.

Methods: : Nanoparticles were formulated from poly(lactide-co-glycolide) acid (PLGA) via nanoprecipitation, freeze-dried, and coated with sodium acetate and a prostate-specific membrane antigen (PSMA) ligand, generating both standard (F) and smart LBL (SF) nanoparticles. Physicochemical properties—particle mean diameter, zeta potential, percent weight, and surface chemistry—were measured using ZetaSizer, UV/VIS spectrophotometry, and FTIR. Cytotoxicity on C4-2 castration-resistant prostate cancer cells was quantified by MTS assay.

Results: : LBL smart nanoparticles (SF3) had a smaller mean diameter (260.4±38 nm) than standard PLGA nanoparticles (F3: 559.1±16 nm). Sodium acetate coating was confirmed by FTIR. Blank nanoparticles exhibited no cytotoxicity. Drug-loaded smart nanoparticles demonstrated strong, dose-dependent cytotoxicity, reducing C4-2 cell viability to 31.17±8.13% (SF3) and 34.78±7.74% (F3) after 48 hours at 0.1 µg/mL, indicating significant potency against prostate cancer cells.

Conclusions: : Smart LBL nanoparticles containing both MCT4 inhibitor and docetaxel were successfully developed and exhibited enhanced cytotoxicity toward prostate cancer cells. This targeted delivery platform may improve therapeutic efficacy and minimize current docetaxel clinical formulation vehicle-associated side effects. Planned future studies will examine the biodistribution and pharmacokinetics of the optimized nanoformulation.

Sponsorship:: The research reported was supported by Florida A&M University start-up Award #101, program 11, the RCMI Grant 5U54MD007582 from the National Institute on Minority Health and Health Disparities.