Wu Ling, Ji Shaoyang, Hu Tao
†National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
‡University of Chinese Academy of Sciences, Beijing 100190, China.
Mol Pharm. 2015 May 4;12(5):1402-11. doi: 10.1021/mp500680p. Epub 2015 Apr 20.
Human growth hormone (hGH) has been used to treat children with short stature, renal failure, and Turner's syndrome. However, clinical application of hGH suffers from its short plasma half-life and low bioavailability. PEGylation and albumin binding are two of the most effective approaches to prolong the plasma half-life of hGH. However, the steric shielding effects of polyethylene glycol (PEG) and albumin can drastically decrease the bioactivity of hGH, which is opposite to the increased pharmacokinetics (PK). In the present study, a long-acting hGH with markedly improved pharmacological profile was rationally designed and prepared by N-terminal modification of hGH with pseudo-bifunctional PEG-hexadecane by using PEG (3.5 kDa or 10 kDa) as the linker. PEGylation and albumin binding with hexadecane can increase the hydrodynamic volume and decrease the immunogenicity of hGH, which thereby markedly increases the PK of hGH. Since N-terminus is far from the bioactive domain of hGH, N-terminal modification of hGH can minimize the steric shielding effects on the bioactive domain of hGH. Hexadecane-bound albumin can be slowly released from hGH during the in vivo circulation, which can slowly restore the bioactivity of hGH. Thus, the high bioactivity of PEG-hexadecane modified hGH (hGH-PEG-HD) was synergistically achieved by N-terminal modification with pseudo-bifunctional PEG-hexadecane and slow-release of albumin. The high pharmacodynamics (PD) of hGH-PEG-HD was due to the synergistic effect of the high bioactivity and the overall increased PK.
人生长激素（hGH）已被用于治疗身材矮小、肾衰竭和特纳综合征的儿童。然而，hGH的临床应用受到其血浆半衰期短和生物利用度低的困扰。聚乙二醇化和白蛋白结合是延长hGH血浆半衰期最有效的两种方法。然而，聚乙二醇（PEG）和白蛋白的空间屏蔽效应会大幅降低hGH的生物活性，这与药代动力学（PK）的增加相反。在本研究中，通过使用PEG（3.5 kDa或10 kDa）作为连接体，用假双功能PEG-十六烷对hGH进行N端修饰，合理设计并制备了一种药理特性显著改善的长效hGH。PEG化和与十六烷结合的白蛋白可以增加流体动力学体积并降低hGH的免疫原性，从而显著提高hGH的PK。由于N端远离hGH的生物活性结构域，对hGH进行N端修饰可以最大限度地减少对hGH生物活性结构域的空间屏蔽效应。与十六烷结合的白蛋白在体内循环过程中可以从hGH中缓慢释放，从而可以缓慢恢复hGH的生物活性。因此，通过用假双功能PEG-十六烷进行N端修饰和白蛋白的缓慢释放，协同实现了PEG-十六烷修饰的hGH（hGH-PEG-HD）的高生物活性。hGH-PEG-HD的高药效学（PD）归因于高生物活性和整体增加的PK的协同作用。
