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Will the self-assembly of platinum dicarboxylate (IV) precursor drugs affect their cellular uptake?

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Document pages: 8 pages

Abstract: The possibility of self-assembly of platinum dicarboxylate (IV) precursor drugs and their effect on the uptake of cancer cells were evaluated in different aqueous solutions. Four Pt (IV) complexes, namely, (oc-6-33) - diethylamine dichloroplatinum (IV), ACE, (oc-6-33) - dibutylamine dichloroplatinum (IV), but, (oc-6-33) - diethylamine dichlorohexadecane platinum (IV), cetane and (oc-6-33) - diethylamine dichlorotetrachloroplatinum (IV), Oct, have been dispersed in I) nanograms of water and II) phosphate buffered saline, And III) intact cell culture medium (RPMI 1640 or DMEM) containing fetal bovine serum (FBS). The samples were analyzed by dynamic light scattering (DLS) to measure the size and distribution of possible nanoparticles. Zeta potential provides an indication of th stability of the resulting aggregates. In the case of the most lipophilic compounds of the series, namely, Oct and to a lesser extent Hex, the formation of nanosized aggregates has been observed, in particular at the highest concentration tested (10 μM). The cell culture media had the effect to disaggregate these nanoparticles, mainly by virtue of their albumin content, able to interact with the organic chains via noncovalent (hydrophobic) interactions. For Oct, at the highest concentration employed for the uptake tests (10 μM), the combination between passive diffusion and endocytosis of the self-assembled nanoparticles makes the cellular uptake higher than in the presence of passive diffusion only. During the study of cellular uptake on A2780 ovarian cancer cells pretreated with cytochalasin D, a statistically significant inhibition of endocytosis was observed for Oct. In these experimental conditions, the relationship between uptake and lipophilicity becomes almost linear instead of exponential. Since Oct anticancer prodrug is active at nanomolar concentrations, where the aggregation in culture media is almost abolished, this phenomenon should not significantly impact its antiproliferative activity.

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