缺乏特异性是限制细胞穿膜肽(cell-penetrating peptides, CPPs)发展及临床应用的最主要因素。一直以来，研究人员尝试通过多种手段对CPPs赋予靶向性，但至今仍未有突破性进展。近年来，一种pH敏感的组氨酸-谷氨酸（HE）多肽重复序列被报道可用于调控CPPs的穿膜活性，这种基于不同pH条件下净电荷能够可逆调节的重组多肽HE-CPP被证明可以实现生物大分子的肿瘤靶向性传递。本课题将以HE-CPP的构建理论为基础，同时选用一种常见的两亲性载药系统(mPEG-PLA)为模型，旨在通过载体设计构建一系列具有不同递药机制和释药机制的pH敏感型药物传输系统，达到控制药物释放、提高药物摄取、实现肿瘤靶向性、减少毒副反应等效果，并进一步指导功能多肽设计在一般药物载体中的应用。

Lack of specificity is the major obstacle of cell-penetrating peptides (CPPs) for clinical applications. Many approaches have been investigated to confer CPPs with the property of specific accumulation, but no break-through technology has yet to be achieved. Recent years, we designed a pH sensitive histidine-glutamate acid (HE) repeats which could be used for regulate the activity of cell-penetrating peptides. It has also been verified that recombinant peptide, HE-CPP, with adjustable net charge under different pHs could specifically target the mildly acidic environment at tumor tissue, thereby achieving targeted delivery of biomacromolecules. In this project, a series of pH-sensitive mPEG-PLA-based novel drug delivery systems will be designed and engineered on the basis of the theory of HE-CPP. The novel carriers are expected to have different mechanisms of drug delivery and drug release so as to achieve controlled drug release, increased drug internalization, tumor-targeted drug delivery, reduced toxicity and side-effects. The achivement of this project will be meaningful for the application of functionalized peptides in the modification of normal drug carriers.