The length of disulfide bond-containing linkages impacts the oral absorption and antitumor activity of paclitaxel prodrug-loaded nanoemulsions.

ABSTRACT

The rational design of oral paclitaxel (PTX) preparations is still a challenge. Many studies focus on developing PTX-loaded nanoemulsions (NEs) for oral administration. Unfortunately, PTX has poor affinity with the commonly used oil phases, leading to low encapsulation efficiency, poor colloidal stability, and premature drug leakage of PTX-loaded NEs. Herein, three lipophilic PTX prodrugs are synthesized by conjugating PTX with citronellol (CIT), using different lengths of disulfide bond-containing linkages. Interestingly, compared with PTX, the prodrugs exhibit higher affinity with the oil phase, effectively improving the encapsulation efficiency, colloidal stability, and sustained-release behavior of NEs. In addition, the disulfide bond-bridged prodrugs could specifically release PTX in tumor cells, reducing unnecessary systemic exposure of PTX. As a result, all three prodrug NEs exhibited improved oral bioavailability and antitumor effects compared to oral Taxol. Moreover, the length of disulfide bond-containing linkages exhibits great impacts on the oral absorption, drug release, and antitumor behaviors of NEs. It is found that the prodrug NEs with the shortest linkages show comparable antitumor effects with intravenous Taxol, but with less systemic and gastrointestinal toxicity.