title: Self-assembling nanoparticles for intra-articular delivery of anti-inflammatory proteins.
abstract: Intra-articular delivery of therapeutics to modulate osteoarthritis (OA) is challenging. Delivery of interleukin-1 receptor antagonist (IL-1Ra), the natural protein inhibitor of IL-1, to modulate IL-1-based inflammation through gene therapy or bolus protein injections has emerged as a promising therapy for OA. However, these approaches suffer from rapid clearance and reduced potency over time. Nano/microparticles represent a promising strategy for overcoming the shortcomings of intra-articular drug delivery. However, these delivery vehicles are limited for delivery of protein therapeutics due to their hydrophobic character, low drug loading efficiency, and harsh chemical conditions during particle processing. We designed a new block copolymer that assembles into submicron-scale particles and provides for covalently tethering proteins to the particle surface for controlled intra-articular protein delivery. This block copolymer self-assembles into 300 nm-diameter particles with a protein tethering moiety for surface covalent conjugation of IL-1Ra protein. This copolymer particle system efficiently bound IL-1Ra and maintained protein bioactivity in vitro. Furthermore, particle-tethered IL-1Ra bound specifically to target synoviocyte cells via surface IL-1 receptors. Importantly, IL-1Ra nanoparticles inhibited IL-1-mediated signaling to equivalent levels as soluble IL-1Ra. Finally, the ability of nanoparticles to retain IL-1Ra in the rat stifle joint was evaluated by in vivo imaging over 14 days. IL-1Ra-tethered nanoparticles significantly increased the retention time of IL-1Ra in the rat stifle joint over 14 days with enhanced IL-1Ra half-life (3.01 days) compared to that of soluble IL-1Ra (0.96 days) and without inducing degenerative changes in cartilage structure or composition.
authors: George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Georgia, USA.
authors: Rachel E
authors: RE
authors: Whitmire
authors: D Scott
authors: DS
authors: Wilson
authors: Ankur
authors: A
authors: Singh
authors: Marc E
authors: ME
authors: Levenston
authors: Niren
authors: N
authors: Murthy
authors: Andrés J
authors: AJ
authors: García
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D002356:Cartilage / Q000187:drug effects / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage* / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism; D007596:Joints / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D010641:Phenotype; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013264:Stifle / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D011108:Polymers