title: Controlled release of proteins from their poly(ethylene glycol) conjugates: drug delivery systems employing 1,6-elimination.
abstract: Several tripartate releasable PEG linkers (rPEG) that can provide anchimeric assistance to hydrolysis (cyclization prodrugs) were prepared and, after conjugation to lysozyme demonstrated rapid cleavage in rat plasma compared to nonassisted, permanently bound PEG. By varying the chemical structure and adding steric hindrance, the half-life of the protein conjugates can be adjusted from slow to very fast. The pharmacokinetics (PK) of regeneration of native protein, from various rPEG conjugates can, for the first time, be easily followed in the rat using green fluorescent protein. The PK in mice was also determined for rPEG-Interleukin 2 (rPEG-IL-2) conjugates in vivo using an ELISA assay. Thus, a systematic study of rPEGylated proteins, either in vivo or in vitro during processing, has been investigated based on regeneration of native protein. The employment of releasable PEG polymers substantially broadens the applications of PEGylation drug delivery technology by introducing the benefits of controlled release of native protein therapeutics.
authors.affiliation: Enzon Pharmaceuticals Inc, 20 Kingsbridge Road, Piscataway, New Jersey 08854, USA. richard.greenwald@enzon.com
authors.forename: Richard B
authors.initials: RB
authors.lastname: Greenwald
authors.forename: Karen
authors.initials: K
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Charles D
authors.initials: CD
authors.lastname: Conover
authors.forename: Stanford
authors.initials: S
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Filpula
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002021:Buffers; D002645:Chickens; D016503:Drug Delivery Systems; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D049452:Green Fluorescent Proteins; D006207:Half-Life; D006868:Hydrolysis; D007202:Indicators and Reagents; D007376:Interleukin-2 / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008164:Luminescent Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D009113:Muramidase / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000890:Anti-Infective Agents; D002021:Buffers; D007202:Indicators and Reagents; D007376:Interleukin-2; D008164:Luminescent Proteins; D011506:Proteins; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D009113:Muramidase