title: Stabilization of proteins encapsulated in injectable poly (lactide- co-glycolide)
abstract: Controlled release from biodegradable polymers is a novel approach to replace daily painful injections of protein drugs. A major obstacle to development of these polymers is the need to retain the structure and biological activity of encapsulated proteins during months of incubation under physiological conditions. We encapsulated bovine serum albumin (BSA) in injectable poly(DL-lactide- co-glycolide) (PLGA) 50/50 cylindrical implants and determined the mechanism of BSA instability. Simulations of the polymer microclimate revealed that moisture and acidic pH (<3) triggered unfolding of encapsulated BSA, resulting in peptide bond hydrolysis and noncovalent aggregation. To neutralize the acids liberated by the biodegradable lactic/glycolic acid-based polyester, we coincorporated into the polymer an antacid, Mg(OH)2, which increased microclimate pH and prevented BSA structural losses and aggregation for over one month. We successfully applied this stabilization approach in both cylinder- and microsphere-injectable configurations and for delivery of angiogenic basic fibroblast growth factor and bone-regenerating bone morphogenetic protein-2.
authors.affiliation: [1] Colleges of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.forename: S R
authors.initials: SR
authors.lastname: Mallery
authors.forename: S P
authors.initials: SP
authors.lastname: Schwendeman
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000863:Antacids / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000378:metabolism; D003198:Computer Simulation; D003692:Delayed-Action Preparations; D004220:Disulfides / Q000378:metabolism; D004355:Drug Stability; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis / Q000187:drug effects; D007526:Isoelectric Point; D051379:Mice; D008863:Microspheres; D008970:Molecular Weight; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011098:Polyglactin 910 / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D011489:Protein Denaturation / Q000187:drug effects; D011506:Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D012709:Serum Albumin / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D016212:Transforming Growth Factor beta; D014867:Water / Q000378:metabolism
chemical_list: D000863:Antacids; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D003692:Delayed-Action Preparations; D004220:Disulfides; D010446:Peptide Fragments; D011506:Proteins; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; D014867:Water; D016222:Fibroblast Growth Factor 2; D011098:Polyglactin 910