Improving the efficacy of platinum-chemotherapy with the smart polymer poly(sodium acrylate)

Cisplatin and its derivatives are widely used in cancer chemotherapy; however, their clinical efficacy is hampered by instability, inherent reactivity and a poor pharmacokinetic profile. The “smart” polymer poly(sodium acrylate) (PNaA) may overcome these issues by ensuring the delivery of high cisplatin concentrations to the tumour site. PNaA is predicted to release drug cargo in a pH-dependent manner and is available in multiple branching topologies. Native (drug free) PNaA exhibited minimal impact on cell cycle progression and induced negligible levels of apoptosis, highlighting its inherent safety profile. In contrast, cisplatin delivered by PNaA, in all three branching topologies, displayed markedly improved cytotoxicity to colon adenocarcinoma and ovarian cancer cell lines. Surprisingly, there was no pH-dependency in the cytotoxic potency of the cisplatin-PNaA complex, which implies an alternative mechanism of action. Analysis by capillary electrophoresis demonstrated that cisplatin release from PNaA occurred over an extended 12-24 h period, whereas the cell cytotoxicity of loaded polymer occurred over 1 h. To further investigate the mechanism, a fluorescent derivative of PNaA was generated and it revealed a rapid cellular uptake and punctate localisation in the perinuclear region. Our data indicate that PNaA is an inert polymer capable of delivering cisplatin to cells using a mechanism that involves rapid intracellular accumulation of the drug-polymer complex. The mechanism was highly successful in improving the anticancer efficacy of cisplatin and can overcome a drug resistant phenotype, thereby rendering it a promising tool to improve chemotherapy.