A novel polyethylene depot device for the study of PLGA and P(FASA) microspheres in vitro and in vivo.
Polymer microspheres (0.5-5.0 microm) are difficult to characterize in vivo because they degrade, migrate, and are endocytosed. A novel polyethylene mesh pouch containing microspheres allowed for retrieval of degraded polymeric products from rats without affecting the rate of degradation. Pouches containing poly(lactic-co-glycolic acid) (PLGA) or poly(fumaric-co-sebacic acid) (P(FASA)) microspheres were implanted intramuscularly, subcutaneously, and intraperitoneally and analyzed after 3, 7, 14, and 28 days. In vivo, subcutaneous or intraperitoneal implants experienced an immediate mass loss and a delayed decrease in molecular weight (Mw). Intramuscular implants behaved similarly to in vitro samples, decreasing in Mw immediately and lagging in mass loss. These results suggest that mass loss, which is usually dependent on Mw loss in vitro, may be directly due to enzymatic, rather than hydrolytic, degradation subcutaneously and intraperitoneally, while intramuscular implants appear to be mostly dependent on hydrolytic cleavage. This observation is further supported by histology. Additional experiments on pouches loaded with PLGA microspheres encapsulating osteoprotegerin, a protein drug used to prevent bone resorption, revealed that use of the device prevented the artifactual polymer compression inherent to microsphere centrifugation during release studies and allowed for the extraction of active protein from microspheres implanted for 3 days in vivo.
Sandor
Maryellen
M
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
Harris
Joshua
J
Mathiowitz
Edith
E
D020341:Absorbable Implants; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology*; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D003652:Decanoic Acids / Q000737:chemistry* / Q000494:pharmacology*; D003998:Dicarboxylic Acids; D005650:Fumarates / Q000737:chemistry* / Q000494:pharmacology*; D006023:Glycoproteins / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D008970:Molecular Weight; D009132:Muscles / Q000187:drug effects; D009929:Organ Size; D053244:Osteoprotegerin; D011095:Polyethylenes / Q000737:chemistry / Q000494:pharmacology*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D013997:Time Factors
D001672:Biocompatible Materials; D003652:Decanoic Acids; D003998:Dicarboxylic Acids; D005650:Fumarates; D006023:Glycoproteins; D053244:Osteoprotegerin; D011095:Polyethylenes; D011108:Polymers; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506032:Tnfrsf11b protein, rat; C473130:poly(fumaric-co-sebacic acid); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C032005:fumaric acid; C011107:sebacic acid