Albumin Nanoparticle-Based Delivery of Oxaliplatin-Oleic Acid Prodrug for Enhanced Breast Cancer Therapy

Triple-negative breast cancer (TNBC) remains a therapeutic outlier, with limited targeted options and frequent relapse despite chemotherapy. While platinum therapy can benefit some TNBC cases, including BRCA1/2-mutant tumors, toxicity and limited tumor-selective exposure often restrict its impact. To address these barriers, we applied a lipid-metallodrug prodrug approach and synthesized an oxaliplatin-oleic acid (OXA-OA) conjugate that coupled OXA's cytotoxicity with OA-associated anticancer activity. The prodrug was encapsulated into genipin-crosslinked albumin nanoparticles (OXA-OA Alb NPs) to improve tumor targeting, yielding a uniform size of 140.52 ± 4.35 nm, a PDI of 0.25 ± 0.05, and an encapsulation efficiency of 84.55 ± 4.49%. Spectrometric analysis confirmed successful OXA-OA conjugation. The nanoparticles demonstrated enhanced cellular uptake and tumor targeting. In vitro, OXA-OA Alb NPs reduced the IC₅₀ to 0.19 ± 0.36 µg/mL (4T1) and 0.20 ± 0.16 µg/mL (MDA-MB-231). This corresponded to 25 to 30-fold higher cytotoxicity than free OXA and > 50-fold than OA. Furthermore, apoptosis indices reached 1.47 (4T1) and 1.42 (MDA-MB-231), which were 4.19- and 4.50-fold higher than OA and 2.43- and 2.53-fold higher than OXA. In vivo, OXA-OA Alb NPs achieved ~ 90% tumor inhibition in a TNBC mouse model, with minimal systemic toxicity, stable liver and kidney function, and reduced organ damage compared with other treatment groups. These findings suggest that OXA-OA Alb NPs offer a promising and safer approach for TNBC, with potential for further exploration in preventing metastasis and recurrence.