Doxorubicin conjugated to D-α-tocopheryl polyethylene glycol succinate and folic acid as a prodrug for targeted chemotherapy

This research developed a prodrug strategy to conjugate doxorubicin (DOX) to D‐α‐tocopheryl polyethylene glycol succinate (TPGS) and folic acid (FOL) for targeted chemotherapy to enhance the therapeutic effects and reduce the side effects of the drug. We synthesized two conjugates, TPGS–DOX and TPGS–DOX–FOL, to quantitatively evaluate the advantages of TPGS conjugation and FOL conjugation through passive and active targeting effects. The successful conjugation was confirmed by 1H nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy. The in vitro drug release was found pH dependent, which is in favor of cancer treatment. The in vitro cellular uptake and cytotoxicity were evaluated with MCF‐7 breast cancer cells. It was found that the cellular uptake of DOX increased 15.2% by TPGS conjugation and further 6.3% by FOL conjugation after 0.5‐h cell culture. The IC50 after 24‐h cell culture with MCF‐7 cancer cells showed that TPGS–DOX conjugate could be 1.19‐fold effective versus DOX and that TPGS–DOX–FOL could be 38.6‐fold effective than TPGS–DOX and thus 45.0‐fold more effective versus DOX. In vivo experiment showed that the half‐life of TPGS–DOX and TPGS–DOX–FOL were increased 3.79‐ and 3.9‐fold than the free DOX, and the area under the curve were increased 19.2‐ and 14.5‐fold than the DOX, respectively. The biodistribution data showed that TPGS–DOX and TPGS–DOX–FOL significantly lowered drug accumulation in the heart, thereby reducing the cardiotoxicity, which is the main side effect of the DOX. Furthermore, TPGS–DOX can limit, and TPGS–DOX–FOL can further deduce, the gastrointestinal side effect of the drug. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010