对于骨关节炎治疗的lorecivivint的阴阳性脂质体介导的关节内输送
Paula Gonzalez-Fernandez1, Luca Morici1, Luca Simula1
1School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland.
概括
阴离子脂质体增强了lorecivivint (LOR) 的溶解性和传递力,用于骨关节炎治疗. 这种新的脂质体配方 (Lipo-LOR) 改善了软骨再生,减少了炎症,显示出对关节内治疗的前景.
科学领域:
- 生物材料科学 生物材料科学
- 药物输送系统 药物输送系统
- 骨关节炎治疗药物 治疗药物
背景情况:
- 骨关节炎 (OA) 是一种普遍的退行性关节疾病,其特点是软骨损失,炎症和疼痛.
- 洛雷西维文特 (LOR) 是一种向Wnt通路的药物,它显示出对软骨再生和降低OA中的促炎细胞因子的潜力.
- 对LOR的临床挑战包括溶解性差和从关节的快速清除,阻碍有效的关节内输送.
研究的目的:
- 开发和评估酸性脂质体,以改善骨关节炎中lorecivivint (LOR) 的关节内输送.
- 为了提高LOR溶解度,控制其释放动力学,并改善局部OA治疗的软骨保留.
主要方法:
- 基于DSPC-Chol-DOTAP的化脂质体的配方,使用微流体来封装LOR.
- 脂质体LOR的体外表征:封装效率,可溶性增强,释放形状,颗粒大小和表面电荷.
- 在人体冠状细胞 (hCHs) 和介酶干细胞 (MSCs) 中评估脂质体LOR细胞毒性和生物活性.
- 在ACLT-hMnX大鼠模型中的体内评估,以评估对骨菌形成和软骨损失的治疗作用.
主要成果:
- 脂质体LOR (Lipo-LOR) 实现了36%的封装效率,在PBS中增加了120倍以上的LOR溶解度,在模拟的突液中增加了100倍.
- 在生理条件下观察到长时间的LOR释放 (17%超过14天),在模拟的突液中释放更快.
- 与自由LOR相比,具有+35mV表面电荷和145nm大小的脂质体增加了1.4至3.6倍的软骨吸收.
- 在hCHs和MSCs中,Lipo-LOR在10μM时没有表现出细胞毒性,维持了药物生物活性,并将TGF-β和IL-6水平减半.
- 试点体内研究表明,在接受治疗的老鼠模型中,骨菌形成减轻,软骨基质损失减少.
结论:
- 阴阳性脂质体有效地提高了lorecivivint溶解性,释放动力学和软骨保留,用于关节内OA治疗.
- 利波-LOR显示出有前途的抗炎和抗纤维性作用,在OA大鼠模型中初步的体内证据表明治疗效益.
- 这种脂质体药物递送系统代表了一种可行的策略,可以克服LOR的局限性,并推进其在骨关节炎的临床应用.
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