Zhou Xi-Rui, Cao Yimeng, Zhang Qiang, Tian Xi-Bo, Dong He, Chen Long, Luo Shi-Zhong
Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Department of Chemistry & Biomolecular Science, Clarkson University, Potsdam, NY 13699, USA, USA.
Int J Pharm. 2017 Aug 7;528(1-2):723-731. doi: 10.1016/j.ijpharm.2017.06.051. Epub 2017 Jun 16.
Peptides are considered as a new generation of drugs due to their high structural and functional diversity. However, the development of peptide drugs is always limited by their poor stability and short circulation time. Carriers are applied for peptide drug delivery, but there may be problems like poor loading efficiency and undesired xenobiotic toxicity. Peptide self-assembly is an effective approach to improve the stability and control the release of peptide drugs. In this study, two self-assembling anticancer peptides are designed by appending a pair of glutamic acid and asparagine to either the N-terminus or the C-terminus of a lytic peptide. This simple, yet rational sequence modification was made to change the amphiphilic pattern and secondary structural content of the parent peptide, thereby modulating its self-assembly process. It was found that the N-terminus modified peptide favors the formation of nanofibrils and the peptide with C-terminal modification formed micelles. Although both nanostructures showed prolonged action profiles and improved serum stability compared to the parent peptide, the morphology of the nanostructures is highly critical to manipulate the release profile of the free peptide from the assembly and regulate their bioactivity. We believe the self-assembly approach demonstrated in this study can be applied to a variety of therapeutic peptide drugs to improve their stability and therapeutic activity for the development of carrier-free drug delivery system.
由于其高度的结构和功能多样性，肽被认为是新一代药物。然而，肽药物的开发一直受到其稳定性差和循环时间短的限制。载体被应用于肽药物递送，但可能存在载药效率低和不良的异源毒性等问题。肽自组装是提高肽药物稳定性和控制其释放的有效方法。在本研究中，通过在裂解肽的N端或C端附加一对谷氨酸和天冬酰胺，设计了两种自组装抗癌肽。进行这种简单但合理的序列修饰是为了改变亲本肽的两亲性模式和二级结构含量，从而调节其自组装过程。发现N端修饰的肽有利于纳米纤维的形成，而C端修饰的肽形成胶束。尽管与亲本肽相比，这两种纳米结构都显示出延长的作用曲线和改善的血清稳定性，但纳米结构的形态对于控制游离肽从组装体中的释放曲线和调节其生物活性至关重要。我们相信，本研究中展示的自组装方法可应用于多种治疗性肽药物，以提高其稳定性和治疗活性，用于开发无载体药物递送系统。
