Desarrollo y evaluación cinético-dinámica de sistemas poliméricos para la vehiculización de cisplatino

Résumé

Cisplatin, an antitumor agent used for the treatment of many solid tumours, shows significant side effects, which represent serious limitations for its use. Some previous data have reported that intermittent administrations of sub-therapeutic doses of cisplatin were able to induce apoptosis more effectively than a single high dose. This evidence supports the idea that sustained release formulations could be a good strategy to increase its therapeutic efficacy, reducing the toxicity. Cisplatin-PLGA micro- and nanoparticles were prepared using the solvent evaporation method with a double emulsion (w/o/w) to characterize their pharmacological properties in in-vitro and in-vivo studies. In-vitro studies showed a duality in the mechanism of action for cisplatin depending on the concentration. In fact, all treatments with the formulations were able to induce cell arrest in the G2/M phase of the cell-cycle followed by a progressive and slow activation of caspase-3, inducing an irreversible cell lost. However for free drug, the high concentrations caused an accumulation of cells in G0/G1 phase, followed by a rapid and intensive activation/deactivation of caspase-3, which is mainly associated with renal cells death and resistance phenomenon. In order to characterize the relationship between cisplatin concentration and its antiproliferative effect, a new semi-mechanistic biopharmaceutic-pharmacodynamic model has been developed. In-vitro release profiles from PLGA formulations were described using an empirical sigmoidal model based on the characterization of two drug release processes: diffusion and matrix degradation. All cytotoxicity data were simultaneously modeled under the Gomperzt framework incorporating the drug release model and where, two mechanisms of drug action were quantitatively identified: an inhibition of cell proliferation, where the formulations were mainly involved followed by a stimulation of cell death, mediated by the activation of a signal transduction process, associated with the apoptotic pathway. The model parameters were independent from the formulation, making this model a suitable tool to explore in silico, alternative in-vitro and in-vivo scenarios to optimize these delivery systems. Furthermore, intraperitoneal administration of cisplatin-nanoparticles exhibited a tumour inhibition similar to free cisplatin or oxaliplatin for the same dose, associated with a reduction of the toxicity and suggesting a more selective delivery of drug in the tumour.