title: A mechanistic study on the chemical and enzymatic degradation of PEG-Oligo(epsilon-caprolactone) micelles.
abstract: The chemical and enzymatic degradation of monodisperse oligo(epsilon-caprolactone) (OCL) and its amphiphilic block oligomer with methoxy poly(ethylene glycol) (mPEG) were investigated in order to obtain insight into the degradation of mPEG-b-OCL micelles. Hydrolytic degradation was studied as function of pH and dielectric constant of the medium, and enzymatic degradation was investigated at different enzyme and substrate concentrations. The degradation was monitored by HPLC and MS, and the micelle destabilization with DLS. It was found that the hydrolytic degradation followed pseudo first order kinetics, and that the rate depended on the pH and dielectric constant. Degradation essentially occurred via a random scission process, and induced micelle destabilization after approximately 1.5 degradation half-lives. At physiological pH and temperature, OCLs are very stable, reflected by an estimated degradation half-life of mPEG-b-OCL micelles of several years. However, the presence of lipase resulted in an accelerated degradation with half-lives of a few days to hours. The enzymatic degradation of mPEG-b-OCL followed Michaelis-Menten kinetics. The results indicate that mPEG-b-OCL micelles are very stable in vitro, but their susceptibility to enzymes such as lipase makes these systems suitable for the hydrolysis controlled release of drugs in vivo.
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Myrra G
authors: MG
authors: Carstens
authors: Cornelus F
authors: CF
authors: van Nostrum
authors: Ruud
authors: R
authors: Verrijk
authors: Leo G J
authors: LG
authors: de Leede
authors: Daan J A
authors: DJ
authors: Crommelin
authors: Wim E
authors: WE
authors: Hennink
mesh_terms: D000465:Algorithms; D002851:Chromatography, High Pressure Liquid; D004337:Drug Carriers; D004563:Electrochemistry; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008049:Lipase / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D014677:Pharmaceutical Vehicles; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004337:Drug Carriers; D008823:Micelles; D014677:Pharmaceutical Vehicles; D011091:Polyesters; C405621:poly(epsilon-caprolactone-co-ethylene oxide); D011092:Polyethylene Glycols; D008049:Lipase