Carboplatin-loaded SMNDs to reduce GSH-mediated platinum resistance for prostate cancer therapy

Glutathione (GSH)-mediated drug resistance can strongly weaken the therapeutic efficiency of platinum(ii). Therapeutic platforms developed based on small-molecule-based nanodrugs (SMNDs) have gained great attention due to their unique properties. Herein, a novel SMND of carboplatin-lauric acid nanoparticles (CBP-LA NPs) was developed for the first time to reduce GSH-mediated platinum resistance and improve the antitumor efficiency of platinum(ii). A CBP-LA conjugate was synthesized and CBP-LA NPs were prepared. Intracellular glutathione determination and intracellular Pt-DNA adduct assay were performed. Then the cellular cytotoxicity, cellular uptake, targeted biodistribution and in vivo antitumor efficacy of CBP-LA NPs were investigated. The CBP-LA conjugate could self-assemble into nanoparticles with small, uniform size and high drug loading (48%). The CBP-LA NPs exhibited a low critical aggregation concentration of 1.4 μg mL^-1 and outstanding plasma stability in vitro. Under reduced conditions, the CBP-LA NPs showed redox-responsive behavior. The intracellular glutathione determination and the Pt-DNA adduct assay revealed that CBP-LA NPs could reduce the intracellular GSH levels and improve the efficiency of platinum chelating with DNA, which would overcome GSH-mediated platinum(ii) resistance. The cellular uptake study revealed that CBP-LA NPs were internalized by tumor cells, which was very beneficial for improving the therapeutic efficiency. Furthermore, an in vivo study demonstrated that CBP-LA NPs significantly enhanced drug accumulation at tumor sites and improved antitumor efficiency (p < 0.05) compared to the CBP solution group. This study suggests that CBP-LA NPs are a potential formulation to enhance prostate cancer therapy.