Abstract
The development of synthetic polymer drug-delivery systems is a promising strategy to improve the therapeutic index of effective but highly toxic anticancer agents, such as cisplatin, by taking advantage of the peculiar characteristics of tumor blood and lymphatic circulation, often referred to as the enhanced perme ability and retention (EPR) effect. In the present study, water-soluble, biocompatible core-shell nanospheres (ZN2) obtained from polymethylmethacrylate (PMMA), with a shell featuring positively charged quaternary ammonium groups, were used as noncovalently linked pharmacophores for the anionic platinum-containing moiety, [PtCl3NH3]- (PtA). The resulting adduct (PtA-ZN2), at the estimated maximum tolerated dose (MTD) of 25 mg Pt/kg/day for 5 consecutive days was significantly more effective than cisplatin, also at the MTD of 3.25 mg Pt/kg/day ×5, in inhibiting the growth of B16 murine melanoma in mice, in the absence of signs of general toxicity. In contrast, treatment with free PtA did not significantly affect tumor growth as compared to control mice. In vivo efficacy of the three Pt-containing species was found to correlate with Pt intratumor accumulation, as evaluated by ICP-MS following tumor tissue mineralization. PtA-ZN2 was also found to be superior to PtA in the in vitro cytotoxicity assays on cultured B16 cells (IC50 values at 5 days: 1.78 ± 0.79 |Lμg Pt/ml for PtA-ZN2 and 10.47 |Lμg Pt/ml for PtA), where the EPR effect is not an issue. This suggests that polymer conjugation can also enhance Pt efficacy at the single-cell level, possibly by facilitating Pt uptake; determinations of intracellular Pt levels following in vitro incubation of B16 cells with PtA and PtAZN2 and of internalization of fluorescent ZN2 nanospheres seem to support this hypothesis.
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Monti, E. et al. (2009). Assessment of the In Vivo Antiproliferative Activity of a Novel Platinum Particulate Pharmacophore. In: Bonetti, A., Leone, R., Muggia, F.M., Howell, S.B. (eds) Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-459-3_3
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DOI: https://doi.org/10.1007/978-1-60327-459-3_3
Publisher Name: Humana Press, Totowa, NJ
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