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

Abstract

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 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%).

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.

• Authors: Yiwen Li, Chun Ye, Chengcheng Cai, Meng Zhao, Na Han, Zhihui Liu, Jianxiu Zhai, Jun Yin
• Journal: Pharmaceutical research (Pharm Res) Vol. 37 Issue 3 Pg. 66 (Mar 12 2020) ISSN: 1573-904X [Electronic] United States
• PMID: 32166420 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cardiac Glycosides
• Polymers
• Prodrugs
• Water

Topics

• A549 Cells
• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Cardiac Glycosides (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Drug Design
• Esterification
• Humans
• Lung Neoplasms (drug therapy)
• Mice, Inbred BALB C
• Mice, Nude
• Polymers (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Prodrugs (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Solubility
• Water (chemistry)