Self-assembling Prodrug:Synthesis,Characterization And Anticancer Studies

Paclitaxel (PTX) and all-trans retinoic acid (ATRA) are both clinical anti-tumor drugs, and oleanolic acid (OA) is also proved to be anti-tumor active. But these drugs are extreme hydrophobic, which limits their clinical application. For synthesizing low-toxic and high-effective prodrugs of PTX, ATRA and OA with application prospect, we did research in two aspects.In the first section, we conjugated PEG monomethyl ether (mPEG) short chains to PTX via p-aminophenylacetic (APA) or hexamethylene diisocyanate (HDI) as linkers and prepared two amphiphilic prodrugs:mPEG-APA-PTX and mPEG-HDI-PTX, in order to get new PTX agent with high drug-loading and high water-solubility. The capability of self-assembling, the PTX release kinetics, the cytotoxicity and the life-time in plasma of them were characterized. As shown in results, the prodrugs self-assembled into stable nanoparticles in aqueous solution with high drug loading content (28wt%). MPEG-HDI-PTX nanoparticles stayed stable in aqueous solution, but completely lost their cytotoxicity and were eliminated rapidly in plasma. While mPEG-APA-PTX nanoparticles released PTX slowly at pH=7.4, their cytotoxicity was similar to Taxol(?) and the nanoparticles had a remarkable longer blood circulation time than Taxol(?). In summary, the mPEG-APA-PTX is capable of self-assembly into high drug-loaded and long plasma circulating polymeric nanoparticles.Section two is about obtaining of Dextran-ATRA and Dextran-OA amphiphilic prodrugs by esterification reaction between the carboxyl groups of All-trans retinoic acid or oleanolic acid and the hydroxyl groups of dextran. Both Dextran-ATRA and Dextran-OA had high drug loading content. The grafting rate of Dextran-ATRA was98%and its drug loading content was up to75.7%. While Dextran-OA only with a grafting rate of45%also had a drug loading content of57.2%. Either of these two prodrugs had the capability of self-assembling into stable nanoparticles in aqueous solution, with proper sizes suitable for targeting tumor tissue by the EPR effect. Dextran-ATRA and Dextran-OA had comparable anti-tumor activity with the free ATRA and OA against Bcap37breast cancer cells. In conclusion, we obtained Dextran-ATRA and Dextran-OA prodrug conjugates which had self-assembly capability and high drug loading content, which make them worth of further study.