Escinosome 热敏凝胶优化 CAI-CORM 在类风湿关节炎大鼠模型中的疗效。

Escinosome thermosensitive gel optimizes efficacy of CAI-CORM in a rat model of rheumatoid arthritis.

机构信息

Department of Chemistry "Ugo Schiff" (DICUS), University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.

Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale G. Pieraccini 6, Firenze 50139, Italy.

出版信息

J Control Release. 2023 Jun;358:171-189. doi: 10.1016/j.jconrel.2023.04.045. Epub 2023 May 4.

DOI:10.1016/j.jconrel.2023.04.045

PMID:37121516

Abstract

Rheumatoid arthritis is among the most common disabling diseases associated with chronic inflammation. The efficacy of the current therapeutic strategies is limited; therefore, new pharmacological agents and formulation approaches are urgently needed. In this work, we developed a thermosensitive gel incorporating escinosomes, innovative nanovesicles made of escin, stabilized with 10% of tween 20 and loaded with a Carbonic Anhydrase Inhibitor (CAI) bearing a Carbon Monoxide Releasing Moiety (CORM) (i.e., CAI-CORM 1), previously synthesized by some of the authors as a new potent pain-relieving agent. The light scattering analysis of the developed formulation showed optimal physical parameters, while the chromatographic analysis allowed the quantification of the encapsulation efficiency (90.1 ± 5.91 and 91.6 ± 8.46 for CAI-CORM 1 and escin, respectively). The thermosensitive gel, formulated using 23% w/v of poloxamer 407, had a sol-gel transition time of 40 s and good syringeability. Its stability in simulated synovial fluid (SSF) was morphologically evaluated by electron microscopy. Nanovesicles were physically stable in contact with the medium for two weeks, maintaining their original dimensions and spherical shape. The viscosity increased by about 30- to 100-fold with the temperature change from 25 °C to 37 °C. The gel erosion in SSF occurred within 9 h (88.2 ± 0.743%), and the drug's passive diffusion from escinosomes lasted 72 h, allowing a potential sustained therapeutic effect. The efficacy of a single intra-articular injection of the gel containing escinosomes loaded with CAI-CORM 1 (3 mg/mL; 30 μL, CAI-CORM 1 formulation) and the gel containing unloaded escinosomes (30 μL, blank formulation) was evaluated in a rat model of Complete Freund's Adjuvant (CFA)-induced rheumatoid arthritis. CAI-CORM 1 formulation was assessed to counteract mechanical hyperalgesia, spontaneous pain, and motor impairments on days 7 and 14 after treatment. The histological evaluation of the joints stressed the improvement of several morphological parameters in CFA + CAI-CORM 1 formulation-treated rats. In conclusion, the hybrid molecule CAI-CORM 1 formulated in escinosome-based thermosensitive gel could represent a new valid approach for managing rheumatoid arthritis.

摘要

类风湿关节炎是最常见的与慢性炎症相关的致残性疾病之一。目前治疗策略的疗效有限；因此，迫切需要新的药理学制剂和制剂方法。在这项工作中，我们开发了一种包含艾沙多辛的温敏凝胶，艾沙多辛是一种由艾沙组成的创新纳米囊泡，用 10%的吐温 20 稳定，并负载一种带有一氧化碳释放部分（CORM）的碳酸酐酶抑制剂（CAI，即 CAI-CORM1），CAI-CORM1 是由一些作者之前合成的一种新的有效的止痛剂。所开发制剂的光散射分析显示出最佳的物理参数，而色谱分析允许定量包封效率（CAI-CORM1 和艾沙的分别为 90.1±5.91%和 91.6±8.46%）。使用 23%w/v 泊洛沙姆 407 配制的温敏凝胶具有 40 s 的溶胶-凝胶转变时间和良好的可注射性。通过电子显微镜对其在模拟滑液（SSF）中的稳定性进行了形态学评估。纳米囊泡在与介质接触两周内物理稳定，保持其原始尺寸和球形。当温度从 25°C 升高到 37°C 时，其粘度增加约 30-100 倍。在 SSF 中，凝胶侵蚀在 9 小时内发生（88.2±0.743%），CAI-CORM1 从艾沙多辛中被动扩散持续 72 小时，从而实现潜在的持续治疗效果。在完全弗氏佐剂（CFA）诱导的类风湿关节炎大鼠模型中，评估了含有负载 CAI-CORM1（3mg/mL；30μL，CAI-CORM1 制剂）的艾沙多辛载体制剂的温敏凝胶和含有未负载艾沙多辛的凝胶（30μL，空白制剂）单次关节内注射的疗效。CAI-CORM1 制剂用于对抗治疗后第 7 天和第 14 天的机械性痛觉过敏、自发性疼痛和运动障碍。对关节的组织学评估强调了 CFA+CAI-CORM1 制剂治疗大鼠的多种形态学参数的改善。总之，CAI-CORM1 与基于艾沙多辛的温敏凝胶联合使用，可能成为治疗类风湿关节炎的一种新的有效方法。