title: Mobility of model proteins in hydrogels composed of oppositely charged dextran microspheres studied by protein release and fluorescence recovery after photobleaching.
abstract: In this paper, the release of proteins from a novel self-gelling hydrogel based on biodegradable dextran microspheres is investigated. The protein-loaded macroscopic gels are obtained by hydration of mixtures of oppositely charged hydroxyethyl methacrylate-derivatized dextran microspheres with a protein solution. In media of low ionic strength (100 mM Hepes pH 7.0) it was found that the release of the entrapped model proteins (lysozyme, BSA and IgG) was slower than in saline (150 mM NaCl, 100 mM Hepes pH 7.0). The reason behind this observation is that substantial adsorption of the proteins onto the microspheres' surface and/or absorption in the microspheres takes place. Confocal images showed that independent of their crosslink density the microspheres are impermeable for BSA and IgG. BSA, bearing a negative charge at neutral pH, was adsorbed onto the surface of positively charged microspheres. Lysozyme, which is positively charged at neutral pH, was able to penetrate into the negatively charged microspheres. In saline, the gels showed continuous release of the different proteins for 25 to 60 days. Importantly, lysozyme was quantitatively and with full preservation of its enzymatic activity released in about 25 days. This emphasizes the protein friendly technology to prepare the protein-loaded gels. Mathematical modeling revealed that protein release followed Fick's second law, indicating that the systems are primarily diffusion controlled. These results show that these hydrogels are very suitable as injectable matrix for diffusion-controlled delivery of pharmaceutically active proteins.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), University Utrecht, The Netherlands.
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Van Tomme
authors.forename: Bruno G
authors.initials: BG
authors.lastname: De Geest
authors.forename: Kevin
authors.initials: K
authors.lastname: Braeckmans
authors.forename: Stefaan C
authors.initials: SC
authors.lastname: De Smedt
authors.forename: Florence
authors.initials: F
authors.lastname: Siepmann
authors.forename: Juergen
authors.initials: J
authors.lastname: Siepmann
authors.forename: Cornelus F
authors.initials: CF
authors.lastname: van Nostrum
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
mesh_terms: D000327:Adsorption; D003911:Dextrans / Q000737:chemistry*; D004058:Diffusion; D004337:Drug Carriers / Q000737:chemistry*; D036681:Fluorescence Recovery After Photobleaching; D006531:HEPES / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry*; D007074:Immunoglobulin G / Q000737:chemistry; D008689:Methacrylates / Q000737:chemistry; D018613:Microscopy, Confocal; D008863:Microspheres; D009038:Motion; D009113:Muramidase / Q000737:chemistry; D009994:Osmolar Concentration; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: D003911:Dextrans; D004337:Drug Carriers; D020100:Hydrogels; D007074:Immunoglobulin G; D008689:Methacrylates; D011506:Proteins; D014867:Water; D012710:Serum Albumin, Bovine; C005044:hydroxyethyl methacrylate; D009113:Muramidase; C049840:2-(dimethylamino)ethyl methacrylate; D006531:HEPES