Coordination self-assembly of platinum–bisphosphonate polymer–metal complex nanoparticles for cisplatin delivery and effective cancer therapy

Abstract

Cisplatin (CDDP) is a potent anti-carcinogen that is widely used for various solid tumors; however, its clinical application is limited by its severe nephrotoxicity. Novel platinum–bisphosphonate polymer–metal complex nanoparticles (Pt–bp NPs), based on platinum–bisphosphonate coordination, have been established. Three polymer carriers bearing alendronate (ALN) ligands, while containing different lengths of alkyl hydrophobic chains, were synthesized. Their structures were characterized by ¹H NMR, ³¹P NMR and FTIR. The ALN was used to coordinate to the CDDP precursor [Pt(NH₃)₂(OSO₃)(OH₂)], and the Pt–bp NPs were formed spontaneously. The Pt–bp NPs formed by the polymer carrier, ALN-PEG_2k-ASA_C18, which contained the poly(ethylene glycol) chain with ALN on one side and the octadecyl hydrophobic chain on the other side, was denoted as ALN-ASA_C18-CDDP; its diameter was within 200 nm. CDDP was released in a Cl⁻ or pH-dependent manner. The cytotoxic effects to the HeLa, A549 and MCF-7 cell lines were relatively weak, compared to CDDP. However, ALN-ASA_C18-CDDP showed significantly prolonged blood circulation time and tumor accumulation of platinum of 2.5-fold, compared to CDDP at 8 h. Besides, ALN-ASA_C18-CDDP was demonstrated to remarkably reduce systemic toxicity without compromising in vivo antitumor activity. These results indicate that the facilely prepared ALN-ASA_C18-CDDP has great utilization potential for CDDP delivery in a clinical setting.