title: Novel self-assembled tacrolimus nanoparticles cross-linking thermosensitive hydrogels for local rheumatoid arthritis therapy.
abstract: The aim was to explore the potential application of novel self-assembled nanoparticles cross-linking thermosensitive hydrogels composed of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) and tacrolimus (FK-506) for local therapy of rheumatoid arthritis (RA). The sol-gel transition temperature (Tsol-gel), gelation time, rheological behaviors, in vitro release, in vivo gelation and retention, and therapeutic efficacy against adjuvant-induced arthritis (AIA) rats were compared between the Soluplus hydrogels and widely studied poloxamer 407 (P407) delivery systems. In sol, the spherical and uniform FK506 loaded Soluplus nanoparticles (Soluplus-SNPs) were self-assembled with encapsulation efficiency of 99.5±1.5% and particle size of 73.9±2.9nm. The decreased Tsol-gelof Soluplus-SNPs hydrogels was associated with the addition of salts, elevation of pH and ionic strength. The optimal Tsol-gelof Soluplus-SNPs with concentrations of 10%-30% in phosphate buffer (50mM, pH 7.4) was from 37.4±0.1°C to 32.8±0.3°C and the gelation time was not greater than 2min. Soluplus-SNPs gelling systems showed lower viscosity and wider range concentrations in sol state at 25°C and stronger gel strength at 37°C than P407, which resulting in longer sustained release of FK506 but without burst-release in vitro, and longer retention time in the local injection site in vivo. The therapeutic efficacy to treat AIA rats was significantly enhanced from d10 to d17 after a single dose of FK506 loaded in 10% and 20% Soluplus-SNPs hydrogels. In conclusion, Soluplus-SNPs hydrogel is a potential sustainable delivery system for FK506 to treat RA locally.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Wu
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Kaiyuan
authors.initials: K
authors.lastname: Wang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Hanning
authors.initials: H
authors.lastname: Wang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Wencong
authors.initials: W
authors.lastname: Huang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
authors.affiliation: Overseas Pharmaceuticals, Ltd, China Medical City, Taizhou, 225300, PR China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Wen
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China. Electronic address: xiongsb@zjut.edu.cn.
authors.forename: Subin
authors.initials: S
authors.lastname: Xiong
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers; D004339:Drug Compounding; D065546:Drug Liberation; D004487:Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006614:Hindlimb; D020100:Hydrogels / Q000737:chemistry; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D044367:Phase Transition; D020442:Poloxamer / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004337:Drug Carriers; D020100:Hydrogels; D007166:Immunosuppressive Agents; D011145:Polyvinyls; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D020442:Poloxamer; D011092:Polyethylene Glycols; D016559:Tacrolimus
keywords: Kolliphor P407; Rheumatoid arthritis; Self-assembled nanoparticles; Soluplus; Tacrolimus; Thermosensitive hydrogels