人生长激素（hGH）可用于治疗儿童矮小症、Turner氏综合症和大面积创伤等疾病。hGH在体内的血浆半衰期短，需要频繁给药，这严重限制了它的临床应用。聚乙二醇（PEG）修饰和白蛋白偶联能延长hGH的血浆半衰期，却极大地降低了hGH的生物活性，导致提高hGH的药代动力学特性不能有效地弥补其生物活性的损失。本项目拟通过PEG定点修饰和长链脂肪烷结合白蛋白的技术，开发治疗效果好的hGH长效剂型。低分子量的双功能PEG的一端可定点结合hGH的N末端，另一端结合十六烷，并提高十六烷的水溶性；十六烷在体内与白蛋白进行非共价结合，可提高hGH的血浆半衰期；白蛋白与十六烷的缓慢解离可逐渐恢复hGH的生物活性；PEG能保护解离的hGH并减小其生物活性的损失，同时调节白蛋白从结合物中解离的速率。通过设计这种新型的药物传递方式，为开发治疗效果好的蛋白质药物长效剂型奠定科学基础。

Human growth hormone (hGH) has been used in the treatment of children with short stature, Turner's Syndrome and extensive wound. The short plasma half-life of hGH has to be compensated by frequent dosing, which significantly limits its clinical application. Conjugation of polyethylene glycol (PEG) and serum albumin can prolong the plasma half-life of hGH. However, conjugation significantly decreases the bioactivity of hGH and thus inefficiently compensates the loss of the bioactivity by increasing the pharmacokinetics. The present project aims to develop long-acting hGH formulation with high therapeutic efficacy through PEGylation and long aliphatic chain modification. One side of low molecular weight bifunctional PEG specifically modified at the N-terminus of hGH and the other side can attach hexadecane to improve the solubility of hexadecane. Hexadecane can non-covalently bind albumin in vivo to improve the plasma half-life of hGH. The slow dissociation of albumin from the conjugated hGH can gradually recover the bioactivity of hGH. PEG can protect the dissociated hGH, decrease the loss of the bioactivity of hGH and adjust the dissociation rate of albumin from the conjugated hGH. Through designing this novel drug delivery approach, the scientific basis can be established for development of long-acting protein drug formulation with high therapeutic efficacy.