Abstract
A systematic study of N(4) amino PEG-prodrugs of ara-C (1) was conducted and provided a series of disubstituted amides, as well as a carbamate derivative. These conjugates showed hydrolysis half lives in rat plasma from about 1 h to 3 days, but were stable for >24 h in phosphate buffer, pH 7.4. In an LX-1 solid lung tumor model some of the PEG prodrugs exhibited superior activity to ara-C when compared on a molar basis. One problematic issue that was identified in this investigation was the need to increase the loading of ara-C onto PEG in order to avoid highly viscous solutions.
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / administration & dosage*
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Antimetabolites, Antineoplastic / chemistry
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Cytarabine / administration & dosage*
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Cytarabine / chemistry
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Drug Delivery Systems / methods*
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Drug Delivery Systems / statistics & numerical data
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Drug Evaluation, Preclinical / methods
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Drug Evaluation, Preclinical / statistics & numerical data
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Female
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Humans
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Leukemia P388 / drug therapy
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Mice
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Mice, Nude
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Neoplasms / drug therapy
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Polyethylene Glycols / administration & dosage*
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Polyethylene Glycols / chemistry
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Prodrugs / administration & dosage*
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Prodrugs / chemistry
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Solvents / administration & dosage
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Solvents / chemistry
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays* / methods
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Xenograft Model Antitumor Assays* / statistics & numerical data
Substances
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Antimetabolites, Antineoplastic
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Prodrugs
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Solvents
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Cytarabine
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Polyethylene Glycols