Wu Huimin, Wang Kaiyuan, Wang Hanning, Chen Fang, Huang Wencong, Chen Yuqi, Chen Jiali, Tao Jin, Wen Xiaoguang, Xiong Subin
College of Pharmaceutical Sciences, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou, 310032, PR China.
Overseas Pharmaceuticals, Ltd, China Medical City, Taizhou, 225300, PR China.
Colloids Surf B Biointerfaces. 2017 Jan 1;149:97-104. doi: 10.1016/j.colsurfb.2016.10.013. Epub 2016 Oct 6.
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 (T), 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 T of Soluplus-SNPs hydrogels was associated with the addition of salts, elevation of pH and ionic strength. The optimal T of 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.
目的是探索由聚乙烯己内酰胺 - 聚醋酸乙烯酯 - 聚乙二醇（Soluplus）和他克莫司（FK - 506）组成的新型自组装纳米颗粒交联热敏水凝胶在类风湿性关节炎（RA）局部治疗中的潜在应用。比较了Soluplus水凝胶与广泛研究的泊洛沙姆407（P407）给药系统的溶胶 - 凝胶转变温度（T）、凝胶化时间、流变行为、体外释放、体内凝胶化和滞留情况，以及对佐剂诱导性关节炎（AIA）大鼠的治疗效果。在溶胶状态下，负载FK506的球形且均匀的Soluplus纳米颗粒（Soluplus - SNPs）自组装形成，包封率为99.5±1.5%，粒径为73.9±2.9nm。Soluplus - SNPs水凝胶的T降低与盐的添加、pH值和离子强度的升高有关。在磷酸盐缓冲液（50mM，pH 7.4）中，浓度为10% - 30%的Soluplus - SNPs的最佳T为37.4±0.1°C至32.8±0.3°C，凝胶化时间不超过两分钟。与P407相比，Soluplus - SNPs凝胶系统在25°C的溶胶状态下表现出更低的粘度和更宽的浓度范围，在37°C时具有更强的凝胶强度，这导致FK506在体外具有更长的持续释放时间但无突释现象，在体内局部注射部位具有更长的滞留时间。在单剂量负载于10%和20%的Soluplus - SNPs水凝胶中的FK506给药后，从第10天到第17天对AIA大鼠的治疗效果显著增强。总之，Soluplus - SNPs水凝胶是一种用于FK506局部治疗RA的潜在可持续给药系统。
