Redefining platinum(iv) chemotherapy: α-tocopherol succinate functionalization and nanoparticle encapsulation to improve cisplatin- and oxaliplatin-based therapies

Abstract

Platinum(IV) prodrugs offer a promising strategy to overcome the limitations of cisplatin and oxaliplatin, including systemic toxicity and acquired resistance. In this study, two novel α-tocopherol succinate-functionalized Pt(IV) complexes, [Pt(oxalato)(DACH)(OAc)(α-TOS)] (4) and [PtCl₂(NH₃)₂(OAc)(α-TOS)] (5), were synthesized and characterized to enhance the efficacy and selectivity of platinum-based chemotherapy. Functionalization with α-TOS (3) was designed to increase lipophilicity and enable selective intracellular reduction. Physicochemical characterization confirmed the chemical stability in aqueous solution and favorable lipophilicity (log P_o/w) of both complexes. Photoreduction studies demonstrated their efficient activation under biologically relevant conditions, leading to the release of active Pt(II) species and α-TOS. To enhance their pharmacokinetics and tumor selectivity, both prodrugs were encapsulated in biocompatible poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles, improving aqueous solubility and cellular uptake. Cytotoxicity assays in multiple cancer cell lines revealed that the nanoparticle formulations were generally more effective in exerting long-term cytotoxic activity compared to free cisplatin and oxaliplatin. These findings highlight the potential of α-TOS-functionalized Pt(IV) prodrugs as next-generation anticancer agents. The combination of strategic ligand modification and nanomedicine-based delivery provides a promising approach for improving the therapeutic profile of platinum-based chemotherapy.