New chemotherapy approaches based on mucus-penetrating nanoparticles as carriers for paclitaxel

Abstract

Paclitaxel is a natural cytotoxic agent widely used in clinics against breast, ovarian and non-small cell lung cancers. It is classified as class IV by the Biopharmaceutical Classification System presenting a very low oral bioavailability limiting its oral administration. Recently, poly(anhydride) nanoparticles combined with cyclodextrins and poly(ethylene glycol) have been described to increase the oral uptake of paclitaxel when orally administered to rats. Poly(anhydride) nanoparticles were prepared by the solvent displacement method with rather homogeneous size distribution and with a yield of 60-70%. The drug loading achieved varied between 4.5-15% (w/w). Poly(anhydride) nanoparticles containing paclitaxel orally administered to C57BL/6J mice displayed sustained drug levels in plasma for at least 24 hours, with longer residence time for pegylated nanoparticles, and a wide organ distribution similar to Taxol®. This resulted in an increase in the oral bioavailability of paclitaxel up to 60-80%. Besides, the developed poly(anhydride) nanoparticles were evaluated in a syngenic tumor model of mouse Lewis lung carcinoma. Mice were treated orally with the different poly(anhydride) nanoparticles or intravenously with the commercially available formulation Taxol®. Results showed that oral paclitaxel loaded in poly(anhydride) nanoparticles was able to slow down tumor growth in this tumor model in C57BL/6J mice. Moreover, the combination of these poly(anhydride) nanoparticles encapsulating paclitaxel with a selective IDO inhibitor, such as 1-methyl-tryptophan, was a more effective strategy than the single chemotherapy based on paclitaxel loaded in poly(anhydride) nanoparticles. In conclusion, these nanocarriers appear to be promising systems for the future development in oral chemotherapy even in combination with immunotherapy treatment.