刺激响应型DNA折纸纳米载体在疏水药物靶向递送及肿瘤治疗中的应用

Intelligent nanoparticulate-based drug delivery systems (nano-DDSs) with stimuli-triggered drug release and tumor targeting functions have aroused increasing interest. Spatially addressable self-assembled DNA nanostructures have been rationally designed and flexibly functionalized towards a smart biomaterial. We propose to develop a DNA nanoplatform to integrate multiple functional elements for enhanced tumor targeting/penetration as well as stimuli-responsive drug release for intelligent cancer therapy. We devise a DNA origami nanostructure as a template to assemble various agents (chemotherapeutic drugs, tumor-targeting ligands and stimuli-responsive DNA aptamers). The organized DNA amphiphiles on the origami template allow hydrophobic anticancer drug paclitaxel or prodrug molecules to be loaded in high drug loading capacity. Multiple targeting ligands will be precisely positioned on the DNA origami structure, leading to active targeting delivery of the DNA platform to enhance the accumulation and penetration of nanomedicine into tumor tissue. Once delivered to the tumor cells, internal stimuli (such as changes in ATP, pH, temperature, redox condition or the activity of certain enzymes) result in DNA nanostructural reconfiguration, therapeutic cargoes exposure or release. The designed integration of multiple functional elements using spatially addressable DNA origami will generate an intelligent nanoplatform to achieve high drug loading capacity, precise tumor targeting and on-demand drug release. Comprehensive evaluation will be performed in tumor cells and in tumor-bearing animals to assess the efficacy and biosafety of DNA-based nano-DDSs. The project as a whole will provide vital information for the design and construction of smart drug delivery nanoplatforms.

智能纳米药物载体和DNA纳米材料是当前生物化学和材料科学研究领域的研究热点。本项目拟利用DNA折纸术，构建DNA折纸纳米结构作为模板，精确控制疏水化疗药物分子及肿瘤靶向识别核酸适配体等功能元件在DNA纳米模板上的自组装，构建刺激响应型纳米药物运输-释放系统，高效装载疏水药物或前药分子，并具有肿瘤细胞及亚细胞靶向性能，在肿瘤细胞内分子信号刺激下DNA载体纳米结构发生空间构型改变从而控制药物释放。通过设计整合功能元件的种类、数量、空间距离和三维取向等因素控制DNA载体的靶向性能，通过控制DNA纳米结构模板的空间构型调控药物释放，在细胞水平和活体水平探索其生物医学性能，系统研究形貌可控、肿瘤靶向、条件响应结构变化和药物释放的智能化DNA纳米载体构建的主要原理和方法，为智能纳米药物的理论模型提供必要的实验基础。该项研究将为未来智能纳米药物设计提供新的思路和途径。

智能纳米药物载体是当前生物化学和材料科学研究领域的热点。DNA纳米材料具有结构精确可控、可定位修饰、生物可降解等特点，为智能药物载体的构筑提供了一种新颖的解决方案。本项目实施过程中，我们利用DNA纳米结构作为模板，构建了一系列刺激响应性纳米结构和其他功能化组装结构，实现了如小分子疏水药物紫杉醇、功能核酸片段、金属纳米颗粒、小分子染料、酶、影像试剂等多种功能基团的有效装载，发展了一系列高效、低毒、靶向、多功能的肿瘤治疗平台。我们的研究工作为发展基于DNA纳米结构的新型肿瘤治疗策略提供新思路，为开发新一代抗肿瘤药物运输系统提供新途径和新手段，为最终实现攻克肿瘤这一科学目标奠定实验与理论基础。