Design and Synthesis of Polymer Prodrugs for Improving Water-Solubility, Pharmacokinetic Behavior and Antitumor Efficacy of TXA9.

Abstract

TXA9, a novel cardiac glycoside, has a potent anti-proliferative effect against A549 human lung cancer cells, however, possesses a poor water-solubility and a rapid metabolic rate in vivo which limited the further development of TXA9. To overcome the shortcomings of TXA9, four polymer prodrugs of TXA9 were designed and synthesized. Poly (ethylene glycol) monomethyl ether (mPEG) and α-tocopherol polyethylene glycol succinate (TPGS) were applied to modify TXA9 via carbonate ester and glycine linkers respectively to obtain four polymer prodrugs. The water-solubility and stability of prodrugs were studied in vitro while their pharmacokinetic behaviors and antitumor activity were investigated in vivo. The water-solubility of TXA9 was obviously increased and prodrugs with glycine linkers showed a better stability in rat plasma. Their pharmacokinetic investigation found that the t1/2 and AUC0-∞ of TPGS-Gly-TXA9 was increased by 80- and 9.6-fold compared with that of TXA9, which was more superior than the other three prodrugs. More importantly, the tumor inhibition rate of TPGS-Gly-TXA9 (43.81%) on A549 xenograft nude mice was significantly increased compared with that of TXA9 (25.26%). The above results suggested that TPGS-Gly-TXA9 possessed better antitumor efficiency than TXA9 and could be further investigated as an anti-cancer agent.