Poly(methylmetacrylate) (PMMA) core–shell nanospheres act as efficient pharmacophores for the antiproliferative [PtCl3(NH3)]− complex by forming ionic couples

Polymer-based, covalently linked drug-delivery systems have been shown to improve the therapeutic index of effective but toxic anticancer agents, such as cisplatin, by exploiting the peculiar features of tumour blood and lymphatic circulation. In the present study, positively charged poly(methylmetacrylate) core–shell nanospheres (ZN2) were used as pharmacophores for anionic platinum-containing moieties (PtA). The antitumor effect of the resulting non-covalent adduct (PtA–ZN2) was assessed in C57BL/6 mice bearing B16 murine melanoma. PtA–ZN2 was significantly more effective than cisplatin in inhibiting B16 tumour growth when both agents were used at their respective maximum tolerated doses; importantly, mice receiving PtA–ZN2 exhibited no signs of significant general toxicity. Tumour growth in mice treated with unconjugated PtA did not significantly differ from that observed in control animals. As expected, the in vivo efficacy of PtA–ZN2, cisplatin and PtA was found to correlate with Pt intratumour accumulation. In vitro cytotoxicity assays on cultured B16 cells also evidenced a superior efficacy for PtA–ZN2 as compared with unconjugated PtA. This was associated with higher intracellular levels of Pt in cells treated with PtA–ZN2, suggesting that the pharmacophore may facilitate Pt accumulation in tumour cells, even when blood circulation and lymphatic drainage are not an issue.

The non-covalent adduct between the antiproliferative [PtCl3(NH3)]− complex and positively charged poly(methylmetacrylate) core–shell nanospheres showed higher in vivo efficacy on mice bearing B16 murine melanoma with respect to the complex alone and cisplatin. This was related to a higher Pt intratumour and cellular accumulation.Figure optionsDownload as PowerPoint slide