Redox-responsive glycosylated combretastatin A-4 derivative as novel tubulin polymerization inhibitor for glioma and drug delivery.

Combretastatin A-4 (CA4), a tubulin inhibitor, binds to the colchicine site of tubulin, inhibits tubulin polymerization, and leads to the apoptosis of tumor cells. However, the poor hydrophilicity and blood-brain barrier (BBB) penetration ability of CA4 hampers its application in the treatment of glioma. In this study, a novel combretastatin A-4 derivative (CA4D) was designed and developed, which was further conjugated with glucose via disulfide-bond-bridged (CA4D-SS-Glu) to enhance the BBB penetration capacity. The obtained CA4D-SS-Glu conjugate displayed a suitable water partition coefficient and the superior ability across BBB in vitro and in vivo. In addition, the CA4D-SS-Glu exhibited rapid redox-responsive drug release in the presence of glutathione, enhanced in vitro cytotoxicity, and cell apoptosis. Our data further confirmed that CA4D-SS-Glu inhibited proliferation, and restrained migration via affecting microtubule stabilization. Additionally, the conjugate also showed the highest antiproliferative and antitumor action on glioma in vivo as compared to CA4D and CA4. Taken together, the novel CA4D-SS-Glu conjugate possess improved physicochemical property and BBB penetration ability, reduction triggered release of CA4D, and efficient antiproliferative activity. These results provided a novel and effective entry to the treatment of glioma.