Sustained release of human growth hormone from heparin-based hydrogel
Sustained release of human growth hormone from heparin-based hydrogel
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DOI：
10.1021/bm701391
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发表时间：
2008-06-01
影响因子：
6.2
通讯作者：
Kim, Young Ha
中科院分区：
文献类型：
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作者：
Choi, Won Il;Kim, Mihye;Kim, Young Ha
人生长激素（hGH）是一种由191个氨基酸组成的蛋白质，分子量约为22 kDa，在促进骨骼纵向生长方面具有独特的作用，并且在调节蛋白质、脂质和碳水化合物代谢中具有重要功能。 1, 2 因此，hGH 用于治疗因生长激素缺乏、特纳综合征或慢性肾功能衰竭引起的身材矮小儿童。此外，hGH 还应用于成人生长激素替代疗法。 3, 4 目前的hGH给药方式是每天或每周3次皮下注射，持续数年，因此存在半衰期短、肾毒性和需要频繁注射的问题。因此，hGH已成为缓释制剂开发的主要靶点之一。 5以前的hGH缓释制剂的方法是通过聚乙二醇化直接修饰hGH以降低清除率，或者通过开发新的封装制剂来获得hGH的缓释。在后一种情况下，研究重点是将 hGH 封装到物理交联制剂中，例如 PLGA 等固体球或水凝胶。 3, 6, 7 无论哪种情况，hGH 的持续释放都是通过基质的扩散/降解来实现的，而不是通过与基质的任何相互作用来实现。因此，这些系统仍然存在诸如负载蛋白质的高初始爆发或变性/聚集等问题。 5, 8–10 本研究的目的是证明基于肝素的水凝胶适用于基于肝素和 hGH 之间相互作用的 hGH 缓释新水凝胶制剂。肝素是一种天然的、高度硫酸化的阴离子多糖，由 1f4 连接的葡萄糖胺和糖醛酸残基的重复二糖组成。肝素以其抗凝特性而闻名，并且还与多种具有肝素结合域的蛋白质（包括大多数生长因子）相互作用。 11, 12 基于肝素对各种生长因子的高特异性结合，已开发出多种含肝素的系统用于生长因子的持续释放。 11, 13–16 此外，还有报道称肝素可与 hGH 络合沉淀。 2 因此，推测基于肝素的水凝胶可以用作 hGH 的缓释系统，在靶分子和基质之间具有结合亲和力，
Human growth hormone (hGH) is a protein of 191 amino acids with a molecular weight of approximately 22 kDa, it has a unique role in promoting longitudinal bone growth, and an important function in the regulation of protein, lipid, and carbohydrate metabolism. 1, 2 Therefore, hGH is used to treat children with short stature caused by growth hormone deficiency, Turner’s syndrome, or chronic renal failure. Also, hGH is applied in growth hormone replacement therapy for adults. 3, 4 The current hGH administration is by injecting subcutaneously daily or three times a week for a period of several years, thus having problems associated with short half-life, renal toxicity, and the requirement of frequent injections. So, hGH has been one of the main targets for the development of sustained release formulation. 5Previous approaches for the sustained release formulations of hGH are either by directly modifying hGH by PEGylation to decrease the rate of clearance, or by developing new encapsulation formulation to obtain the sustained release of hGH. In the latter case, research has been focused on encapsulation of hGH into physically cross-linked formulation either solid spheres like PLGA or hydrogels. 3, 6, 7 In either cases, the sustained release of hGH is achieved by the diffusion/degradation from the matrix, not by any interaction with the matrix. Therefore, these systems still have problems such as a high initial burst or denaturation/aggregation of the loaded protein. 5, 8–10 The objective of this study is to demonstrate that a heparinbased hydrogel is applicable to a new hydrogel formulation for the sustained release of hGH based on the interaction between heparin and hGH. Heparin is a natural, highly sulfated, and anionic polysaccharide composed of repeating disaccharides of 1f4-linked glucosamine and uronic-acid residues. Heparin is best known for its anticoagulant properties, and also interacts with a variety of proteins that have heparin-binding domains including most of growth factors. 11, 12 Based on the high specific binding of heparin for various growth factors, several heparincontaining systems have been developed for the sustained release of growth factors. 11, 13–16 In addition, it was also reported that heparin can make complexation and precipitation with hGH. 2 Therefore, it was hypothesized that a heparin-based hydrogel can be applied as a sustained release system of hGH, having binding affinity between target molecule and the matrix, in