体外刺激响应型多肽自组装药物载体的设计及控制释放行为

Chemotherapy, one of the main ways to kill cancer cells, is suffered from low drug efficiency, serious side-effects as well as difficulties in tracing drugs in vivo. In this project, we aim to design exogenous stimuli-responsive nanocarriers which based on the assembly of peptides for controlled drug release. The multifuctional nanocarrier systems not only transport the drug to the targeted cancer tissues, but also release the drug responsively under the stimuli and in-situ monitor the drug delivery in vivo. The main work in this project is as follows: (1) Design and synthesis of multifunctional peptides which contain light/thermal-responsive groups, unnatural amino acids and tumor-targeted ligands; (2) Preparation of inorganic nanoparticles, including Au nanoclusters, upconversion fluorescent nanoparticles and magnetic nanoparticles, which can response to the exogenous stimuli (e.g. light or magnetic field); (3) Assembly of nanocarriers for anticancer drugs, which compose of inorganic nanoparticles and peptides, and optimization of the processes; (4) Establishing the animal tumor model, investigation of the release behavior of drugs under the stimuli of light or magnetic fields, and in vivo imaging the stimuli-responsive nanocarrier system to get insight into the biodistribution and drug delivery process. The exogenous stimuli-responsive nanocarriers combine the advantages of both peptides and inorganic nanoparticles, which are less dependence to endogenous stimuli in the highly heterogeneous tumors, potentially controlling the dosage spatially and temporally. As a result, the project should provide useful information for clinic application of stimuli-responsive nanocarrier system.

针对目前抗肿瘤药物存在的药效低、毒副作用大、不易实时监控的缺点，本项目拟设计多功能的多肽纳米药物，用于抗肿瘤药物的靶向运输、控制释放与体内示踪。具体地：(1)设计多功能多肽序列，在多肽链中嵌入非天然氨基酸，同时在侧链引入光/温度敏感的功能基团，并连接与肿瘤细胞高亲和的靶向多肽；(2)制备具有光（磁）信号响应的无机纳米粒子（包括金纳簇、上转换荧光纳米粒子和磁性纳米粒子）；(3)多功能多肽与抗肿瘤药物以及无机纳米粒子组装形成纳米载药体系，优化组装工艺；(4)建立荷瘤动物模型，通过体外光(磁)信号控制药物释放，并结合生物体内成像技术研究药物的运输及释放机理。这种多功能药物载体集成了多肽分子和无机纳米粒子的优点，能克服体内复杂环境的干扰，有望实现时间与空间上对药物剂量的精确控制。本项目将为体外刺激响应型多肽纳米载药体系的临床应用提供理论依据。

常规化疗药物普遍存在剂量大、药效低、毒副作用高的缺点。针对上述问题，本项目设计了多种功能小分子，无机-有机杂化分子等通过自组装的方式对药物进行包覆，制成多功能纳米药物，使其具有靶向性、控制释放、光动力治疗和热动力治疗的特性。本项目的主要内容及取得的主要研究结果有：.(1) 合成了系列功能分子，研究了其自组装行为和刺激响应特性，并将其作为抗肿瘤药物载体，赋予抗肿瘤药物靶向性、荧光特性等；.(2) 制备了无机-有机杂化材料，作为高负载药物载体，并实现了光疗、热疗及化疗等多模式治疗。如以二维黑鳞片作为抗肿瘤药物载体，其负载量高达970%，实现了光疗、热疗和化疗联合治疗；.(3)在功能小分子中嵌入荧光响应基团，利用肿瘤细胞的微环境酸作为刺激因子，有效地控制药物的释放，并且能够在线实时观察药物的释放行为，为诊疗一体化提供了一种新的解决途径；.(4) 通过自组装构筑了各种有序的纳米结构材料，以其为软模板，得到了系列纳米结构的功能分子，并将其用于催化剂以及纳米器件等方面。.本项目所取得的成果为多功能药物载体的设计提供了新的策略，为高效、低毒副作用的抗癌药物的研发奠定了坚实的基础。

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