Biodistribution of Fracture-Targeted GSK3β Inhibitor-Loaded Micelles for Improved Fracture Healing.
Biodistribution of Fracture-Targeted GSK3β Inhibitor-Loaded Micelles for Improved Fracture Healing.
复制标题
靶向骨折的GSK3β抑制剂胶束的生物分布可改善断裂愈合。
DOI：
10.1021/acs.biomac.5b00777
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发表时间：
2015-10-12
影响因子：
6.2
通讯作者：
Kopeček J
中科院分区：
文献类型：
--
作者：
Low SA;Galliford CV;Yang J;Low PS;Kopeček J
骨折是发病率和死亡率的主要原因，特别是在老年人中。与骨质疏松症药物和患者年龄相关的并发症会减缓骨转换，并使此类骨折难以愈合。通过给予骨折靶向的骨合成代谢药物来提高骨折修复的速度可以得到相当大的应用。天冬氨酸寡肽是在生理pH下吸附到羟基磷灰石上的带负电荷的分子，羟基磷灰石是骨骼的矿物部分。在骨周转率最高的地方或羟基磷灰石刚刚暴露的地方，这种普遍的吸附作用最强。重要的是，这两种情况在骨折部位都很突出。GSK3β抑制剂是一种有效的合成代谢药物，当集中在受损组织中时，可以促进组织修复。不幸的是，它们在全身给药时也会造成严重的毒性，而且由于其强烈的疏水性而难以传递。在本文中，我们通过使用可水解键将疏水性的GSK3β抑制剂偶联到亲水性天冬氨酸八肽上，从而产生针对骨折靶向的药物的水溶性形式，从而解决了这两个问题。由此产生的两亲分子被证明可以组装成胶束，在保持其裂缝靶向能力的同时延长其循环时间。为了测量药代动力学，在GSK3β抑制剂中溴的位置引入了125I，以最大限度地减少任何结构差异。生物分布研究表明，在健康的骨骼上，骨折累积增加了4倍以上。
Bone fractures constitute a major cause of morbidity and mortality especially in the elderly. Complications associated with osteoporosis drugs and the age of the patient slow bone turnover and render such fractures difficult to heal. Increasing the speed of fracture repair by administration of a fracture-targeted bone anabolic agent could find considerable application. Aspartic acid oligopeptides are negatively charged molecules at physiological pH that adsorb to hydroxyapatite, the mineral portion of bone. This general adsorption is the strongest where bone turnover is highest or where hydroxyapatite is freshly exposed. Importantly, both of these conditions are prominent at fracture sites. GSK3β inhibitors are potent anabolic agents that can promote tissue repair when concentrated in a damaged tissue. Unfortunately, they can also cause significant toxicity when administered systemically and are furthermore difficult to deliver due to their strong hydrophobicity. In this paper, we solve both problems by conjugating the hydrophobic GSK3β inhibitor to a hydrophilic aspartic acid octapeptide using a hydrolyzable bond, thereby generating a bone fracture-targeted water-soluble form of the drug. The resulting amphiphile is shown to assemble into micelles, extending its circulation time while maintaining its fracture-targeting abilities. For measurement of pharmacokinetics, an 125I was introduced at the location of the bromine in the GSK3β inhibitor to minimize any structural differences. Biodistribution studies demonstrate a greater than 4-fold increase in fracture accumulation over healthy bone.