title: The effect of polymer size and charge of molecules on permeation through synovial membrane and accumulation in hyaline articular cartilage.
abstract: The treatment of joint related diseases often involves direct intra-articular injections. For rational development of novel delivery systems with extended residence time in the joint, detailed understanding of transport and retention phenomena within the joint is mandatory. This work presents a systematic study on the in vitro permeation, penetration and accumulation of model polymers with differing charges and molecular weights in bovine joint tissue. Permeation experiments with bovine synovial membrane were performed with PEG polymers (6-200 kDa) and methylene blue in customized diffusion chambers. For polyethylene glycol, 2-fold (PEG 6 kDa), 3-fold (PEG 10 kDa) and 13-fold (PEG 35 kDa) retention by the synovial membrane in reference to the small molecule methylene blue was demonstrated. No PEG 200 kDa was found in the acceptor in detectable amounts after 48 h. This showed the potential for a distinct extension of joint residence times by increasing molecular weights. In addition, experiments with bovine cartilage tissue were conducted. The ability for positively charged, high molecular weight chitosans and HEMA-Co-TMAP (HCT) polymers (up to 233 kDa) to distribute throughout the entire cartilage matrix was demonstrated. In contrast, a distribution into cartilage was not observed for neutral PEG polymers (6-200 kDa). Furthermore, the positive charge density of different compounds (chitosan, HEMA-Co-TMAP, methylene blue, MSC C1 (neutral NCE) and MSC D1 (positively charged NCE) was found to correlate with their accumulation in bovine cartilage tissue. In summary, the results offer pre-clinical in vitro data, indicating that the modification of molecular size and charge of a substance has the potential to decelerate its clearance through the synovial membrane and to promote accumulation inside the cartilage matrix.
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany; Pharmbiotec GmbH, Saarland University, Campus C 2.2, 66123 Saarbrücken, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Sterner
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Harms
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Wöll
authors.affiliation: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weigandt
authors.affiliation: Pharmbiotec GmbH, Saarland University, Campus C 2.2, 66123 Saarbrücken, Germany; Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus A 4.1, 66123 Saarbrücken, Germany; Helmholtz Centre for Infection Research and Helmholtz Institute for Pharmaceutical Research Saarland, Campus E 8.1, 66123 Saarbrücken, Germany. Electronic address: m.windbergs@mx.uni-saarland.de.
authors.forename: M
authors.initials: M
authors.lastname: Windbergs
authors.affiliation: Pharmbiotec GmbH, Saarland University, Campus C 2.2, 66123 Saarbrücken, Germany; Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Campus A 4.1, 66123 Saarbrücken, Germany; Helmholtz Centre for Infection Research and Helmholtz Institute for Pharmaceutical Research Saarland, Campus E 8.1, 66123 Saarbrücken, Germany.
authors.forename: C M
authors.initials: CM
authors.lastname: Lehr
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D002417:Cattle; D006818:Hyalin / Q000378:metabolism*; D051457:Hyaline Cartilage / Q000378:metabolism*; D007270:Injections, Intra-Articular / Q000379:methods; D007719:Knee Joint / Q000378:metabolism; D008970:Molecular Weight; D010539:Permeability; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry*; D013583:Synovial Membrane / Q000378:metabolism*
chemical_list: D011108:Polymers; D011092:Polyethylene Glycols
keywords: Cartilage; Drug delivery; Drug targeting; Intra-articular; Polymer; Synovial joint; Synovial membrane