Pegylated nanoparticles to facilitate the intravenous-to-oral switch in docetaxel cancer chemotherapy

Resum

Docetaxel (DTX) is a semisynthetic taxoid, analogue of paclitaxel, derived from the European yew tree (Taxus bacata sp.) and is one of the most effective drugs in chemotherapy. It has proven to be useful against several types of cancers such as breast, ovarian, prostate, head and neck, gastric and non-small lung cancers. The oral bioavailability of DTX is hampered by their both high lipophilic character and low permeability related to their affinity for the P-glycoprotein and cytochrome P450 enzymatic complex. In order to solve these problems and, thus, enhance the oral absorption of these drugs, one possible solution may be the encapsulation of these drugs into polymeric nanoparticles with both mucus-penetrating properties and inhibitory abilities of the efflux pump activity and cythocrome P450 metabolism. In this way, in a first step, these nanoparticles would be capable to cross the mucus layer that covers the surface of the enterocytes and, thus, conduct the drug till the absorptive membrane. Once there, in a second step, the carriers would release the cargo and, in parallel, disturb the activity of enzymes and pumps involved in the presystemic metabolism of the loaded drug. The pegylation of nanoparticles from the copolymer of methyl vinyl ether and maleic anhydride (Gantrez® AN) yields submicronic carriers with these specific properties. In the present work, our aim was to explore the potential of these pegylated nanoparticles as delivery systems for docetaxel. In summary, pegylated nanoparticles provide an adequate device for the oral delivery of docetaxel. When orally administered, these nanoparticles offered prolonged and sustained plasma levels of the anticancer drug for 3 days. In addition, the relative oral bioavailability was calculated to be up 56% and around 12-times higher than for ¿naked¿ nanoparticles. Interestingly, the elimination and distribution of docetaxel in vivo from pegylated nanoparticles and intravenous Taxotere® was found to be similar, suggesting that these nanoparticles after reaching the surface of the enterocytes would remain within the gut and did not enter into the circulation. Finally, toxicity study revealed a reduced toxicity profile for nanoparticles orally administered compared to Taxotere®.