基于"一头多效"靶头高效跨越肿瘤递药屏障的脂质体给药系统的构建及评价

The development for tumor-targeted drug delivery system is still impeded by low targeting efficiency and poor therapeutic efficacy due to the hindrance from the multiple drug delivery barriers in vivo. In order to realize drug delivery to tumor with high efficiency, a novel liposomal drug delivery system was established based on our preliminary study. The liposome was co-modified with pH-responsive cleavable PEG and a multi-functional peptide that is constituted with a specific ligand and cell penetrating peptides (CPPs), with several spacers between these two domains. It can avoid the scavenger hunt of RES system by the cleavable PEG modified on the outer layer and overcome the "kinetic barrier" to acquire sufficient accumulation in tumor, where the acid environment could promote the cleavage of PEG chains and expose the multi-functional peptide. The multi-functional peptide then can mediate the liposome to penetrate into the deep area of tumor tissues and enter tumor cells efficiently, therefore reaching the "chemotherapy blind area" and crossing the "cytomembrane-intracellular barrier". The liposome delivery system combines the advantages of tumor permeability, specific recognition of tumor cells and efficient cellular uptake capacity together and improves tumor delivery efficiency.

由于体内多重屏障的存在，现有肿瘤靶向递药系统仍存在靶向效率低，治疗效果差等缺陷。为实现高效的肿瘤靶向传递，本项目在前期研究基础上，拟构建一类通过一定的桥连基团将特异性配体与细胞穿膜肽CPPs连接而成具有"一头多效"功能的配体靶头，并进而将其与pH敏感的可断裂PEG共同修饰脂质体给药系统。该系统既能通过可断裂PEG在外层的修饰，避免其在体内被网状内皮系统摄取，突破递药系统传递过程中的"动力学屏障"，充分实现肿瘤蓄积，并在肿瘤组织的微酸性环境下使PEG断裂暴露出"一头多效"配体；进一步在内层"一头多效"配体的的介导下，有效的进入深层肿瘤组织，高效入胞并到达胞浆，从而实现对肿瘤组织"化疗盲区"和肿瘤细胞"质膜屏障"的高效跨越。本项目构建的脂质体，将集高效的肿瘤渗透性、选择特异性及高效入胞能力于一体，提高载药系统肿瘤靶向传递的效率。

肿瘤靶向纳米递药系统在体内面临的多级屏障，导致其传递效率很低，且难以渗透到肿瘤深部的“化疗盲区”。为实现高效的肿瘤靶向传递，本项目成功采用以下三种策略构建不同的“一头多效”主动靶向穿膜肽（CPPs）修饰的载药脂质体。① 首先对CPPs进行改构，使其同时靶向两种受体，提高靶向效率。②为克服穿膜肽本身正电性导致的脱靶效应，将CPPs和pH敏感可断裂PEG共修饰于脂质体，特异性提高其在肿瘤部位的渗透。③构建肿瘤微环境可活化的主动靶向CPPs，克服CPPs正电性导致的“动力学屏障”。具体如下，本课题首先构建了三种基于多聚精氨酸结构修饰的串联主动靶向CPPs，其中整合素αvβ3识别的CPPs(R8-c(RGD))修饰的载药脂质体和整合素αvβ3、神经纤毛蛋白-1双受体识别的CPPs(R8-dGR)修饰的载药脂质体均具有较显著的针对脑胶质瘤的靶向功能和治疗作用；在此基础上具有更优的体内行为的串联肽R6-dGR修饰的载药脂质体也具有较强的抗脑胶质瘤疗效。为屏蔽CPPs在血循环中的正电性，本项目成功构建了R8与pH敏感可断裂PEG共修饰的载紫杉醇脂质体（Cl-Lip），并将其与能够降低肿瘤间质压的氯沙坦联合应用，以增强纳米粒在肿瘤部位的渗透。体内外研究表明Cl-Lip具有较强的pH响应性，良好的靶向性和较高的肿瘤组织渗透性。最后，为进一步克服CPPs正电性导致的脱靶效应并增强其靶向性，本项目还构建了肿瘤微环境可活化的CPPs(TR)及可断裂的叶酸配体FA与穿血脑屏障CPPs(dNP2)共修饰的载药脂质体cFd-Lip。二者在体内外表现出增强的靶向性和疗效。这几类具有肿瘤主动靶向能力的串联改构肽为打破CPPs的应用局限提供了多种有效策略，极大提高了CPPs修饰脂质体的靶向性和疗效，具有良好的应用前景。.在该自然基金的资助下，本项目发表SCI论文20篇，包括Biomaterials(IF=8.4), Journal of Controlled Release(IF=7.8), ACS Applied Mterials and Interfaces(IF=7.5), Molecular Pharmaceutics(IF=4.4), Theranostics (IF=8.7)等等。专利授权1项，专利申报3项。培养了毕业博士生4名和毕业硕士生1名。参加国际国内学术会议10次，做邀请报告7次。

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