Evaluation of PolyMPC–Dox Prodrugs in a Human Ovarian Tumor Model

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• 作者：Kaitlyn E. Wong ; Maria C. Mora ; Matthew Skinner ; Samantha McRae Page ; Giovanna M. Crisi ; Richard B. Arenas ; Sallie S. Schneider ; Todd Emrick
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：May 2, 2016
• 年：2016
• 卷：13
• 期：5
• 页码：1679-1687
• 全文大小：497K
• 年卷期：0
• ISSN：1543-8392

文摘

A polymer prodrug, composed of doxorubicin (Dox) conjugated covalently to poly(methacryloyloxyethyl phosphorylcholine) (polyMPC), was evaluated for the treatment of human ovarian tumors in animals. PolyMPC–Dox prodrugs were prepared using facile conjugation chemistry to yield conjugates soluble in water and injectable saline, with a Dox loading of ∼19 weight percent. Toxicity evaluation showed that polyMPC was well-tolerated in mice at doses up to 800 mg/kg, confirming the biocompatibility of the polymer carrier at a high concentration. Additionally, the polyMPC–Dox prodrug was well-tolerated in animals at a Dox equivalent dose of 10 mg/kg, greater than twice the maximum tolerated dose of free Dox (∼4 mg/kg) in the same mouse strain. In a human ovarian tumor model (SKOV-3), polyMPC–Dox accumulated in tumors at twice the level of free Dox, with no additional off-target organ uptake, a result of improved pharmacokinetics afforded by the prodrug and passive targeting attributed to an enhanced permeability and retention effect. When administered to human ovarian tumor-bearing mice using a recurring dosing regimen comparable to that used clinically, polyMPC–Dox significantly retarded tumor growth relative to treatment with free Dox. Moreover, animals treated with multiple doses of polyMPC–Dox (eight total doses) exhibited enhanced survival, with a notably reduced incidence of toxicity or adverse events relative to mice treated with free Dox. These in vivo results demonstrate advantages of treating human ovarian tumors with polyMPC–Dox, including reduced systemic toxicity, improved drug accumulation in tumors, and enhanced therapeutic efficacy.