Amphipathic weak acid glucocorticoid Prodrugs remote-loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a beagle dog
Amphipathic weak acid glucocorticoid Prodrugs remote-loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a beagle dog
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DOI：
10.1002/art.23230
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发表时间：
2008-01-01
影响因子：
--
通讯作者：
Naparstek, Yaakov
中科院分区：
文献类型：
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作者：
Avnir, Yuval;Ulmansky, Rina;Naparstek, Yaakov
客观的。糖皮质激素（GC）在类风湿性关节炎中的使用受到与不利的药代动力学和生物分布相关的副作用的限制。自 20 世纪 70 年代以来，人们一直在研究脂质体 GC 制剂，试图克服这一障碍，但尚未进入临床应用。我们进行这项研究是为了确定一种新方法是否可以克服迄今为止阻碍这些制剂临床使用的局限性：药物：脂质比低、包封效率低以及缺乏控释。方法。我们使用类似于 80 nm 空间稳定（聚乙二醇化）纳米脂质体 (NSSL)，利用脂质体内（水室）-高/脂质体外（散装介质）-低跨膜醋酸钙梯度，远程装载两亲性弱酸 GC（例如甲基泼尼松龙半琥珀酸酯）。这种独特的方法实际上将 GC 作为钙-GC 沉淀物“捕获”在脂质体水相中。结果。我们的脂质体配方表现出高封装效率（94％）和高药物：脂质摩尔比（0.41），并证明封装的GC在体循环期间和佐剂诱导关节炎大鼠发炎的爪子中受控释放。此外，在关节炎大鼠和比格犬中，我们都展示了使用脂质体作为 GC 载体的药代动力学优势。最后，我们证明了我们的脂质体制剂在关节炎大鼠中的治疗效果优于游离GC，无论是在疾病早期还是在疾病高峰阶段。结论。两亲性弱酸 GC 远程加载到类似于 80 nm NSSL 中，克服了脂质体 GC 配方过去的局限性。独特的加载方法，也导致控制释放，提高了全身和局部的治疗效果。这样的发展对于改善GC治疗具有巨大的潜力。
Objective. The use of glucocorticoids (GCs) in rheumatoid arthritis is limited by side effects related to unfavorable pharmacokinetics and biodistribution. Liposomal GC formulations have been studied since the 1970s in an attempt to overcome this obstacle, but none has entered clinical use. We undertook this study to determine whether a novel approach could overcome the limitations that have thus far prevented the clinical use of these formulations: low drug:lipid ratio, low encapsulation efficiency, and lack of controlled release.Methods. We used similar to 80-nm sterically stabilized (pegylated) nanoliposomes (NSSLs), which were remote-loaded with an amphipathic weak acid GC (such as methyl prednisolone hemisuccinate) utilizing an intraliposome (aqueous compartment)-high/extraliposome (bulk medium)-low transmembrane calcium acetate gradient. This unique method actually "traps" the GC in the liposomal aqueous phase as a calcium-GC precipitate.Results. Our liposome formulation exhibited high encapsulation efficiency (94%) and a high drug:lipid mole ratio (0.41) and demonstrated controlled release of the encapsulated GC during systemic circulation and in inflamed paws in rats with adjuvant-induced arthritis. In addition, both in arthritic rats and in a Beagle dog, we showed the pharmacokinetic advantage of using liposomes as GC carriers. Finally, we demonstrated the superior therapeutic efficacy of our liposome formulation over that of free GCs in arthritic rats, both in early and in peak disease stages.Conclusion. Amphipathic weak acid GCs remote-loaded into similar to 80-nm NSSLs overcome past limitations of liposomal GC formulations. The unique loading method, which also leads to controlled release, improves the therapeutic effect both systemically and locally. Such a development has great potential for improving GC therapy.