Drug delivery systems: water soluble taxol 2'-poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness.
Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(circulation) > t1/2(hydrolysis). When PEG derivatives of molecular weight approximately 40 kDa were employed with paclitaxel, ca. 4% by weight of paclitaxel was carried by the water soluble prodrug form, and equivalent in vivo toxicity and increased life expectancy in the P388-treated mouse was observed. An effective method for prescreening prodrugs was found to be the acute murine lethality, which reflects the equivalency of the solubilized transport form and the native drug.
Greenwald
R B
RB
Enzon Inc, Piscataway, New Jersey 08854-3969, USA.
Gilbert
C W
CW
Pendri
A
A
Conover
C D
CD
Xia
J
J
Martinez
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D016503:Drug Delivery Systems; D006207:Half-Life; D006868:Hydrolysis; D007928:Lethal Dose 50; D007939:Leukemia L1210 / Q000473:pathology; D007941:Leukemia P388 / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011355:Prodrugs; D011092:Polyethylene Glycols; D017239:Paclitaxel