Redox-responsive prodrug for improving oral bioavailability of paclitaxel through bile acid transporter-mediated pathway

Most anticancer drugs are not orally bioavailable due to their undesirable physicochemical properties and inherent physiological barriers. In this study, a polymeric prodrug strategy was presented to enhance the oral bioavailability of BCS class IV drugs using paclitaxel (PTX) as the model drug. PTX was covalently conjugated with cholic acid-functionalized PEG by a redox-sensitive disulfide bond. Cholic acid-functionalized PEGylated PTX (CPP) achieved remarkably improved PTX solubility (>30,000-fold), as well as favorable stability under the physiological environment and controlled drug release in the tumor. Meanwhile, CPP could self-assemble into nanoparticles with an average size of 56.18 +/- 2.06 nm and drug loading up to 17.6% (w/w). Then, permeability study on Caco-2 cell monolayers demonstrated that CPP obtained an approximately 4-fold increase by apical sodium-dependent bile acid transporter (ASBT) mediated transport, compared with Taxol (R). Pharmacokinetic studies carried out in rats confirmed that the oral bioavailability of CPP was 10-fold higher than that of Taxol (R). Finally, significant improvement in the antitumor efficacy of CPP against breast cancer was confirmed on MDAMB-231 cells. In summary, this prodrug-based cascade strategy offers new ways for chemotherapeutic drugs whose oral delivery is limited by solubility and permeability, also endows drugs with the capacity of tumorspecific release.

Automated summary

This study successfully enhanced the oral bioavailability of BCS class IV drug PTX using a polymeric prodrug strategy, improving drug release and permeability in vivo, and ultimately enhancing the antitumor efficacy against breast cancer.