Pegylated nanoparticles for the oral delevery of paclitaxel

Resumo

Paclitaxel (PTX) is one of the most important anticancer drugs approved for the treatment of a broad range of human cancers, including refractory ovarian and breast cancer, non-small-cell lung carcinoma, head and neck carcinoma and leukemia. However, paclitaxel shows a very low oral absorption and bioavailability (less than 10%) due to its low aqueous solubility and an important intestinal pre-systemic metabolism. In fact, paclitaxel is a substrate of both the efflux multidrug transporter P-glycoprotein (P-gp) and the cytochrome P450 located in the gut and the liver (CYP2C8 and CYP3A4). The final aim of this work was the development of a bioadhesive nanoparticle formulation able to entrap a low bioavailable anticancer drug for oral administration. For this purpose, the association between polyethyleneglycols and bioadhesive nanoparticles would allow the higher encapsulation efficiency of paclitaxel, the modification of the bioadhesive properties of the nanoparticles, drug release and transport of the drug at the mucosal surface and enhancement of drug absorption due to the inhibitory effect of polyethyleneglycols on the activity of P-glycoprotein and cytochrome P450. In accordance with this strategy, after the oral administration of paclitaxel loaded in pegylated poly(anhydride) nanoparticles in rats, sustained plasmatic levels of paclitaxel for at least 48 h were observed. In the case of mice, plasmatic levels of the drug remained high and almost constant for at least 72 h post-administration. Interestingly, the results obtained in this thesis showed that the oral bioavailability of paclitaxel in rats increases up to 70% when paclitaxel was included in nanoparticles pegylated with polyethyleneglycol 2000 and until 90% after the oral administration of the same formulation in mice. In addition, the antitumor study in mice inoculated Lewis lung carcinoma (3LL) cells revealed that paclitaxel orally administered included in pegylated nanoparticles at a dose of 25 mg/kg, seems to be effective to reduce tumor growth in mice. These observations have been related with a synergistic effect of bioadhesive capability of the nanoparticles and the inhibitory effect induced by polyethyleneglycols in the first pass metabolism (CYP450) and P-glycoprotein efflux. In summary, this thesis reveals that the association between the polyethyleneglycols and bioadhesive poly(anhydride) nanoparticles was a good strategy to permit the oral administration of paclitaxel.