Star-shape paclitaxel prodrug self-assembled nanomedicine: combining high drug loading and enhanced cytotoxicity

Abstract

Conventional nanoparticulate drug delivery systems of paclitaxel (PTX) are challenged with low drug loading efficiency and potential biomaterials-induced toxicity. In this work, novel star-shape PTX prodrugs modified by vitamin E succinate with a load of double PTX molecules via carbonate (PC) or succinate (PE) as the linkers at the 2′ position of PTX were synthesized, which were capable of self-assembling into nanoparticles (NPs) with high loading efficiency despite their remarkably hydrophobic character. The in vitro studies revealed that the prodrugs in the form of nanoparticles with high physical stability were little hydrolyzed in rat plasma. In addition, the carbonate bond in PC was more susceptible to hydrolysis than the ester bond in PE in PBS. Compared with PENPs, PCNPs exhibited comparably higher in vitro cytotoxicity against MCF-7 cells and A549 cells due to more conversion of PC to PTX. The in vivo fluorescence imaging demonstrated that PCNPs could passively accumulate in tumors by EPR effect. These results suggested that compared with the succinate conjugate of PTX, the self-assembled NPs of the double PTX loaded carbonate conjugate with extracellular stability can be a more suitable candidate for treatment of cancers after being internalized by cancer cells for its stronger cytotoxicity, and the carbonate linkage is more feasible to be linked with PTX molecules for the design of such type of prodrugs. Overall, the self-assembled nanotechnology of novel star-shape prodrugs with a load of double PTX molecules opens new perspectives for the development of nanomedicines with high loading efficiency and enhanced cytotoxicity.