PACLITAXEL-LOADED PCL-TPGS NANOPARTICLES: IN VITRO AND IN VIVO PERFORMANCE

BERNABEU E.; HELGUERA G.; LEGASPI M.J.; GONZALEZ L.; HOCHT C.; TAIRA C.; CHIAPPETTA D.A.

Viña del Mar

Taller; OBI 2013; 2013

Sociedad Latinoamericana de órganos artificiales, biomateriales e ingeniería de tejidos

Breast cancer is now the most frequent cancer in women both in the developed and the developing world. The largest number of cases occurs in low- and middle-income countries where breast cancer is diagnosed in very late stages. Nowadays, the main practice for breast cancer treatment is surgery followed by radiotherapy and/or chemotherapy. Despite advances on treatment, approximately one third of patients will eventually develop metastatic breast cancer. They have bad prognosis with a median survival time between 18 to 24 months. The use of the adjuvant chemotherapy is increasingly important in the breast cancer treatment. Therefore, is paramount developing novel anticancer drug formulations to improve the drug biodistribution and the therapeutic efficacy. In this work, we developed Cremophor® EL-free nanoparticles (NPs) loaded with Paclitaxel (PTX) to improve the drug i.v. pharmacokinetic profile and to evaluate its activity against commercially available formulation Taxol®. PTX-loaded poly(ε-caprolactone)?alpha tocopheryl polyethylene glycol 1000 succinate (PCL-TPGS) NPs were prepared using three different techniques: i) by nanoprecipitation (NPr-method), ii) by emulsion-solvent evaporation homogenized with an Ultra-Turrax® (UT-method) and iii) by emulsion using an ultrasonicator as homogenizer (US-method). The size, size distribution, and zeta potential of the NPs were measured with a Zetasizer Nano-Zs. Drug loading and in vitro drug release profiles were measured by HPLC-UV. In vitro release studies were performed in phosphate buffer (pH 7.4) USP 30 with 0.5% tween-80 using dialysis bag diffusion technique. The in vitro anti-tumoral activity was assessed using two human breast cancer cell lines (MCF-7 and MDA-MB-231) with the WTS assay. In addition, this novel NP formulation was evaluated in vivo versus Taxol®. The NPs prepared by US-method showed the smallest size and the highest drug content. The NPs exhibited a slow and continuous release of PTX. Cytotoxicity studies with both cell lines showed that PTX-loaded PCL-TPGS NPs presented higher cytotoxicity than PTX solution at different concentrations. Importantly, in the case of triple negative MDA-MB-231 breast cancer cells we observed an increase of up to 3.5 fold higher mortality rate comparing PTX-loaded PCL-TPGS NPs vs. Taxol®. Finally, in vivo studies demonstrated that PTX-loaded PCL-TPGS NPs had longer systemic circulation time and slower plasma elimination rate than Taxol®. These results showed that the US-method is advantageous to prepare a controlled release particulate system. In vitro studies showed that the PTX-loaded PCL-TPGS NPs prepared with the US-method presented better anticancer activity compared to PTX solution at different concentrations assayed on MCF-7 and MDA-MB-231 breast cancer cells. Also, PTX-loaded NPs showed better pharmacokinetic parameters in rats compared to Taxol®. Therefore, the novel NPs presented here might be an interesting alternative drug delivery system for PTX in cancer chemotherapy.