Drug Delivery Systems Based on Trimethyl Lock Lactonization:  Poly(ethylene glycol) Prodrugs of Amino-Containing Compounds

A novel methodology for the synthesis of poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed which is based on the trimethyl lock lactonization reaction. These PEG-modified double prodrugs are water soluble, and by selective modification of the specifier or trigger,...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2000-02, Vol.43 (3), p.475-487
Main Authors: Greenwald, Richard B, Choe, Yun H, Conover, Charles D, Shum, Kwok, Wu, Dechun, Royzen, Maksim
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - administration & dosage
Antibiotics, Antineoplastic - chemistry
Antineoplastic agents
Biological and medical sciences
Daunorubicin - administration & dosage
Daunorubicin - chemistry
Drug Delivery Systems
Drug Screening Assays, Antitumor
Female
General aspects
Humans
Lactones - chemical synthesis
Lactones - chemistry
Lactones - pharmacokinetics
Lactones - pharmacology
Medical sciences
Mice
Mice, Inbred BALB C
Neoplasm Transplantation
Pharmacology. Drug treatments
Polyethylene Glycols - chemistry
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacokinetics
Prodrugs - pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:A novel methodology for the synthesis of poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed which is based on the trimethyl lock lactonization reaction. These PEG-modified double prodrugs are water soluble, and by selective modification of the specifier or trigger, plasma half-lives can be adjusted at will to result in a wide range of values. Facile syntheses of ester, carbonate, and carbamate functionalities were accomplished and combined with greater or lesser degrees of steric hindrance in the spacer group, or on the aromatic framework, to achieve predictable ranges of drug concentration in plasma. In vivo screening of PEG prodrugs was done using a M109 syngeneic solid mouse tumor model. One of the PEG−daunorubicin prodrugs, with a half-life of 2 h, was evaluated in an in vivo solid tumor panel and found to be more efficacious against ovarian tumors (SKOV3) than equivalent amounts of daunorubicin.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990498j