Resumen de Cyclodextrin-poly (anhydride) nanoparticles for oral delivery of paclitaxel
Paclitaxel is a potent anticancer agent approved for the treatment of a large number of solid tumors, including refractory ovarian and breast cancer, non-small-cell lung carcinoma, head and neck carcinoma and leukemia. However, till now, no commercial formulations for the oral administration of this drug are available. This fact can be related with the low oral bioavailability of paclitaxel (less than 10%), mainly due to its low aqueous solubility, p-glycoprotein efflux and first pass metabolism by cytochrome P450 located in the gut and the liver (CYP2C8 and CYP3A4).%&/The aim of this work was to develop new formulations and strategies for the oral delivery of paclitaxel. For this purpose, the association between cyclodextrins and bioadhesive nanoparticles have been studied. On one hand, bioadhesive nanoparticles would permit to stablish adhesive interactions with the gut mucosa inducing their immobilisation at the gut surface and thus increase the residence time of the pharmaceutical device in close contact with the absorptive membrane. On the other hand, the use of cyclodextrins would increase the loading capability of the nanoparticles and inhibit or decrease the activity of cytochrome P450 and p-glycoprotein. %&/In accordance with this strategy, after the oral administration of paclitaxel loaded in cyclodextrin-poly(anhydride) nanoparticles in rats, sustained plasmatic levels of paclitaxel for at least 24 h were observed. Interestingly, the results obtained in this thesis showed that the oral bioavailability of paclitaxel, increases up to 80% when paclitaxel was complexed with native ß-cyclodextrin or hydroxypropyl-ß-cyclodextrin derivative and, then, loaded in bioadhesive nanoparticles. This observation has been related with a synergistic effect of bioadhesive capability of the nanoparticles and the inhibitory effect induced by cyclodextrins in the first pass metabolism (CYP450) and P-glycoprotein efflux. %&/In summary, this thesis reveals that the association between the cyclodextrins and bioadhesive poly(anhydride) nanoparticles was a good strategy to permit the oral administration of paclitaxel.
