多尺度调控的响应性转变功能高分子药物传递系统的研究

In recent years, amphiphilic polymer-based nanotechnology at the interface of biology, pharmacy and medicine has focused on the development of multifunctional nano-scale vehicles that can interact with cellular components, and thus have potential for cancer therapy. However, multiple extra- and intracellular obstacles, including low stability in blood, poor cellular uptake, inefficient endosomal escape and disassembly in cytoplasm, have to be overcome in these drug delivery systems. Inspired by the recent progress in stimuli-responsive degradation, there has been a drive to design advanced polymeric micelles capable of responding to various extra- and intracellular biological stimuli (e.g., pH, redox potential and enzymes) as well as external artificial triggers (e.g., light and ultrasound), which may endow these species with the abilities to undergo structural and property changes in response to the application of an external stimulus. In this study, the applicant plan to prepare a kind of stimuli-modulated multifunctional amphiphilic block copolymeric carriers. Inside of these amphiphilic polymers, hydrophobic hyperbranched polycarbonates with disulfide or diselenide bonds in the mainchain are synthesized as the hydrophobic core of polymeric micelles, which is used to control drug release in cytoplasm. At the same time, some functional groups (e.g., target ligand and cell-penetrating group) and stimuli-responsive groups (e.g., pH-labile group and light-sensitive group) will be introduced into hydrophilic segments. In response to external stimuli, the structure and morphology of hydrophilic shell of polymeric assemblies may be modulated by tuning the molecular architecture of amphiphiles, leading to 'off/on' switch of functional groups. We will study the influence of the structure and properties of these amphiphilic polymers on drug loading, delivery and controlled release, and discuss the inner relationship and optimization methods for the construction of multi-scale regulated multifunctional amphiphilic block copolymeric carriers.

多功能高分子载体的构建应基于多尺度的分析和设计。在"横向"层次上赋予载体多种功能基团，同时在"纵向"层次上能通过不同刺激响应基团对体内微环境的变化或外加刺激的产生的不同响应，从时间和空间上精确调整载体的结构，实现这些功能分子"钝化"/"活化"依次响应性转变，从而依次完成循环系统内稳定输送、肿瘤细胞的定向导入、核内体的快速逃逸及细胞内的可控药物释放等任务。本项目将合成一系列新型两亲性超支化聚碳酸酯嵌段共聚物材料，用其制备具有多刺激响应位点的复合功能药物载体。其中，含有双硫或双硒键的超支化聚碳酸酯作为胶束载体的内核；在亲水壳层部分，则引入生物素、糖基衍生物等功能基团及光、pH等刺激响应基团。研究这些高分子及聚集体的结构、性能对药物的负载保护效果、传送效果、控制释放及表达效果的影响和作用机理，探讨其内在关联及优化方式，为构建可多尺度调控的多功能高分子药物载体材料提供理论依据。

靶向纳米载体在改善化疗药物的溶解性、提高对肿瘤组织和细胞的选择性、降低化疗药物的系统毒性和克服多药耐药等方面具有显著的优势。但是在血液循环过程中，表面暴露靶向配体的纳米载体也可能被正常组分或细胞识别，从而造成体内的快速清除或毒副作用。基于肿瘤内部环境特征（如：pH、还原环境、酶和温度）或者外部刺激（如：光照、磁场等）制备的智能靶向纳米载体，可以通过刺激响应的结构转变实现对纳米载体的靶向功能和药物释放的调控，有助于提高纳米载体的体内稳定性和靶向给药效率。此外，智能靶向纳米载体通过内涵体转运的方式进入细胞内，能够逃避耐药细胞膜上P-糖蛋白（P-gp）的转运，促进化疗药物在细胞内的富集，从而达到克服肿瘤细胞的多药耐药的目的。基于此目的，我们设计制备了一系列刺激响应性智能靶向纳米载体，用于化疗药物的靶向传递和肿瘤细胞多药耐药的逆转。在胶束载体的疏水内核，我们引入了还原敏感的双硫键或酸性敏感的缩醛等基团，用以调控药物的可控释放；在胶束载体的亲水壳层，我们同时引入靶向配体、糖基衍生物等功能基团及刺激响应基团，通过对体内微环境的变化及外加刺激的响应，在时间和空间上调控载体的形态和结构，实现靶向功能基团“钝化”/“活化”响应性转变，提高载药粒子对肿瘤细胞定位及穿越组织细胞屏障的能力。体外毒性、CLSM以及流式等实验结果均表明我们所制备的载药纳米粒子不仅能够抑制正常肿瘤细胞的生长，而且能够逆转肿瘤耐药细胞的多药耐药性。

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