title: Turning low-molecular-weight drugs into prolonged acting prodrugs by reversible pegylation: a study with gentamicin.
abstract: Pegylation is a powerful technology to prolong the action of proteins in vivo, but it is impractical for low-molecular-weight (LMW) drugs, which are usually inactivated upon such modification. Here, we have applied a recently developed strategy of reversible pegylation to gentamicin, a LMW antibiotic. Variable length polyethyleneglycol (PEG-SH) chains were covalently linked to gentamicin using two heterobifunctional agents, each containing a spontaneously hydrolyzable bond. The inactive derivatives regained full antibacterial potency upon incubation under physiological conditions in vitro, and following systemic administration to rats, they released native active gentamicin with half-lives 7- to 15-fold greater than those of systemically administered nonderivatized gentamicin. In conclusion, reversibly pegylated prodrug derivatives of gentamicin were found to be capable of releasing gentamicin for prolonged periods in vivo. Most importantly, the major drawback of conventional pegylation, namely, the loss of pharmacological potency following irreversible derivatization, has been overcome.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yonit
authors.initials: Y
authors.lastname: Marcus
authors.forename: Keren
authors.initials: K
authors.lastname: Sasson
authors.forename: Mati
authors.initials: M
authors.lastname: Fridkin
authors.forename: Yoram
authors.initials: Y
authors.lastname: Shechter
mesh_terms: D000818:Animals; D004926:Escherichia coli / Q000187:drug effects; D005839:Gentamicins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006868:Hydrolysis; D008297:Male; D008826:Microbial Sensitivity Tests; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005839:Gentamicins; D011355:Prodrugs; D011092:Polyethylene Glycols