Abstract
The possibility of spontaneous self-assembly of dicarboxylato Pt(IV) prodrugs and the consequences on their uptake in cancer cells have been evaluated in different aqueous solutions. Four Pt(IV) complexes, namely, (OC-6-33)-diacetatodiamminedichloridoplatinum(IV), Ace, (OC-6-33)-diamminedibutanoatodichloridoplatinum(IV), But, (OC-6-33)-diamminedichloridodihexanoatoplatinum(IV), Hex, and (OC-6-33)-diamminedichloridodioctanoatoplatinum(IV), Oct, have been dispersed in i) milliQ water, ii) phosphate buffered saline, and iii) complete cell culture media (RPMI 1640 or DMEM) containing fetal bovine serum (FBS). The samples have been analyzed by dynamic light scattering (DLS) to measure the size and distribution of the nanoparticles possibly present. The zeta potential offered an indication of the 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.
Highlights
Targeted- and immuno-therapy represent a new roadmap in cancer treatment to obtain high therapeutic effects with low systemic toxicity [1]
We investigated whether the simple dicarboxylato cisplatin-based Ace, But, Hex, and Oct (Figure 4), originally tested as single-molecule antiproliferative prodrugs [12], are able to self-assemble in aqueous solution to generate carrier-free nanostructure and whether this possible phenomenon could have any significance in the experimental conditions employed in the preclinical tests
Dynamic light scattering (DLS) and zeta potential analyses were performed in 10 mM KNO3 at 37°C with a Malvern Zetasizer Nano ZS (Malvern Instruments Ltd., Malvern, UK) at a fixed scattering angle of 173°, using a He–Ne laser and DLS software for Windows. e preparation of the solutions and corresponding DLS measurements were performed at least in triplicate by two independent operators to mediate the effect of the manipulation procedures on the results
Summary
Targeted- and immuno-therapy represent a new roadmap in cancer treatment to obtain high therapeutic effects with low systemic toxicity [1]. We investigated whether the simple dicarboxylato cisplatin-based Ace, But, Hex, and Oct (Figure 4), originally tested as single-molecule antiproliferative prodrugs [12], are able to self-assemble in aqueous solution to generate carrier-free nanostructure and whether this possible phenomenon could have any significance in the experimental conditions employed in the preclinical tests.
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