Degradable Polyphosphoester-Protein Conjugates: "PPEylation" of Proteins.
Pharmacokinetic properties determine the efficacy of protein therapeutics. The covalent attachment of poly(ethylene glycol) (PEG) extends the half-life of such biologicals to maintain a therapeutically effective concentration over a prolonged period of time and improves administration and compliance. A major obstacle of these polymer-protein conjugates is the chemical stability of the PEG preventing its metabolism and leading to side effects. Instead, we propose the PPEylation, that is, the conjugation of degradable poly(phosphoester)s (PPE) to proteins, in order to generate fully biodegradable polymer-protein conjugates. The structure of the PPEylated protein conjugates was verified with mass spectrometry and size exclusion chromatography. They were compared to structural analogues, except classical, PEGylated proteins, and exhibit comparable bioactivity, but avoiding any nondegradable polymer in the conjugate. We proved the degradation of the protective polymer shell surrounding the conjugate in aqueous environments at physiological conditions by online triple detection size exclusion chromatography and gel electrophoresis. We believe that this research will provide an attractive alternative for future drug design with implications for the clinical use of biologicals.
Graduate School Material Science in Mainz , Staudinger Weg 9, 55128 Mainz, Germany.|Max Planck Institute for Polymer Research , Ackermannweg 10, 55128 Mainz, Germany.
Tobias
T
Steinbach
Max Planck Institute for Polymer Research , Ackermannweg 10, 55128 Mainz, Germany.
Frederik R
FR
Wurm
D002850:Chromatography, Gel; D004337:Drug Carriers / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000627:therapeutic use; D011108:Polymers / Q000737:chemistry* / Q000627:therapeutic use; D011506:Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D059748:Proteolysis / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D004337:Drug Carriers; D011108:Polymers; D011506:Proteins; D011092:Polyethylene Glycols