Cisplatin(IV)-fatty acid prodrug-bound albumin nanoparticles: In vitro, in silico, and in vivo evaluation in breast cancer therapy.

The therapeutic outcome of cisplatin (CP) in triple-negative breast cancer (TNBC) is hindered by irreversible protein binding, systemic toxicities, and resistance development. Therefore, we synthesized three CP(IV) prodrugs of fatty acids (FAs) possessing reversible albumin binding to overcome these shortcomings. Among these, CP-OA depicted the most cytotoxicity in MDA-MB-231 and 4T1 cells, showing synergistic effect and potential dose reduction. Albumin nanoparticles of CP-OA (CP-OA NPs) were optimized using a Design of Experiments (DoE) approach, yielding a particle size of 189.6 nm, PDI 0.23, and 77.47% entrapment efficiency. CP-OA NPs showed improved drug loading, sustained release, enhanced apoptosis (∼5 folds), ROS generation (∼2 folds), and mitochondrial depolarization (∼6 folds). The in vivo studies portrayed reduction in tumor volume (5.64-folds), organ toxicities and hemolysis (6.18-folds) compared to marketed formulation. Overall, this study highlights the therapeutic potential of CP(IV) prodrug bound albumin nanoparticles in improving therapeutic efficacy and safety of CP in TNBC.