PEG Prodrugs of 6-Mercaptopurine for Parenteral Administration Using Benzyl Elimination of Thiols

Authors: Yun H. Choe; Richard B. Greenwald; Charles D. Conover; Hong Zhao; Clifford B. Longley; Shuiyun Guan; Qiuxia Zhao; Jing Xia

Source: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, Volume 14, Number 9, 2004 , pp. 455-468(14)

Publisher: Cognizant Communication Corporation

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Abstract:

6-Mercaptopurine (6-MP) is an orally administered, water-insoluble purine analog that is effective against acute lymphatic leukemia. Oral absorption of 6-MP, however, is quite erratic, with only 16–50% of the administered dose reaching the blood. In this report, water-soluble parenterally administered poly(ethylene glycol) (PEG) prodrugs of 6-MP were synthesized using several chemical approaches that enabled the protection of the thiol group through a modification of the benzyl elimination (BE) system. In our earlier work on antimetabolites, it was found that branching of the PEG allowed greater loading of the active drug. This approach was also utilized within this work to give multiloaded systems. The resulting conjugates were stable in pH 7.4 PBS buffer as well as in rat plasma for extended periods. However, these conjugates did act as prodrugs in vivo and a number of PEG–6-MP constructs had significant (P < 0.05) activity in murine leukemia, as well as certain solid tumors, compared with unconjugated 6-MP in a solubilizing vehicle. The fact that some PEG–6-MP conjugates were stable during in vitro plasma dissociation assays, but demonstrated in vivo anticancer activity, suggests extravascular cleavage of the linking group. This work demonstrates that PEG conjugation is an effective means of solubilizing 6-MP for parenteral administration.

Keywords: 6-Mercaptopurine; Poly(ethylene glycol); Prodrug; Parenteral administration; enzyl elimination

Document Type: Research article

Affiliations: 1: Enzon Pharmaceuticals, Inc., 20 Kingsbridge Road, Piscataway, NJ 08854

Publication date: 2004-01-01

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Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.

PEG Prodrugs of 6-Mercaptopurine for Parenteral Administration Using Benzyl Elimination of Thiols

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