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

Purpose: 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.
Methods: 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.
Results: 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 t _1/2 and AUC _0-∞ 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%).
Conclusion: The above results suggested that TPGS-Gly-TXA9 possessed better antitumor efficiency than TXA9 and could be further investigated as an anti-cancer agent.