以癌症治疗为目的的载药DNA纳米笼到癌细胞线粒体的靶向递送

Development of method and vehicle for selective delivery of active drug molecules to the site of mitochondria will introduce new therapies for the treatment of mitochondria-related diseases, e.g cancers. By taking the advantages of the programmability and predictability of DNA hybridization and the versatility of DNA self-assembly approaches, self-assembled DNA nanostructures will be one of the most promising candidates to be biocompatible and selective carriers for targeted drug delivery within a specific cellular environment. Understanding of the self-assembled DNA nanostructures interfacing with a specific cellular environment is of great research interests for further development of novel intracellular DNA-based materials for diagnostics, therapeutics and drug delivery in vivo. By combining DNA nanotechnology with molecular biology, the goal of this three-year project is to design and assemble anticancer drug-loaded 3D DNA nanocages using a modular approach via supramolecular DNA assembly, and to systematically investigate their cellular delivery to the cytoplasma of human cancer cells via vertical silicon nanowire approach as well as selective targeting to specific organelles such as in mitochondria. Targeted drug loaded DNA nanocages are expected to relase the anticaner drugs in response to the environmental change of pH value in mitochondria, thus increasing the efficiency of apoptosis. This will be the first example of drug loaded DNA-based nanocarrier targeting to mitochondria for enhancing the efficiency of apoptosis which is induced by anticancer agents. From both scientific and technological points of view, finding of this proposed research is of great importance to provide a better knowledge of further advancement of novel DNA-based drug carriers in the treatment of diseases by inducing apoptosis via targeting subcellular organelles of specific cell types in vitro and in vivo.

开发能够把药物分子选择性地投送到线粒体的新方法和载体可以为治疗线粒体相关的疾病，如癌症，提供新的治疗方法。由于DNA杂交具有可编译性、可预见性，而且DNA自组装方法具有多样性，因此自主装的DNA纳米结构作为具有生物相容性的靶向药物载体，具有十分诱人的应用前景。了解DNA自组装纳米结构与细胞内环境的相互作用以开发基于这些结构的新型诊断和治疗试剂已经引起了极大的兴趣。结合DNA纳米技术和分子生物学，本项目旨在通过模式化的方法，设计和组装负载抗癌药物的DNA纳米笼，并系统研究通过硅纳米线将其投送到癌细胞内特定的细胞器的方法。在线粒体内富集的DNA纳米笼由于经历了pH的变化而解体释放出抗癌药物分子，这将大大增加其与线粒体的DNA相互作用以诱导细胞凋亡的机率。这将是首个通过DNA纳米载体把抗癌药物运送到线粒体诱导细胞凋亡的例子。通过攻击特定细胞器诱导细胞凋亡以治疗疾病，在科学和技术上，都具有重要意义

开发靶向药物的纳米运载体在生物医学领域有着重要的意义。DNA纳米结构由于其良好的生物相容性和较低的细胞毒性以及相对简单的修饰，使得其作为纳米运载体有着特殊的优势。因此我们的研究旨在开发一种新型的基于DNA纳米笼的靶向药物的运载体。在我们的研究中，自组装的3维DNA纳米笼，在硅纳米线的帮助下，或者在双十八碳链的协助下，均可实现对癌细胞MCF-7线粒体的靶向递送。首先我们运用超分子DNA自组装技术，制备了离散的修饰有靶向基团，荧光基团和携带有分子药物的3维DNA纳米笼。在硅纳米线的协助下，DNA纳米笼可以避开细胞的内吞作用直接进入癌细胞的细胞质，并且不会对细胞造成伤害。进入了细胞质的DNA纳米笼在靶向基团的引导下选择性地进入癌细胞的线粒体，这可在共聚焦的荧光显微镜下观察到。但是此种递送方式高度依赖于物理的递送平台，这将极大限制DNA纳米笼的应用。因此我们对DNA纳米笼做了进一步的改性。通过亚林酰胺DNA化学技术，我们在DNA纳米笼上整合了疏水性的双十八碳链，由此DNA纳米笼可以在不需要任何转染试剂的协助，通过网格蛋白主导的内吞作用就进入细胞，并且在线粒体定位多肽序列的帮助下，靶向到癌细胞的线粒体。共聚焦荧光显微镜下可以看到，我们的DNA纳米笼相对集中到了线粒体，体现了较好的靶向性。而MTT实验证明，我们的DNA纳米笼有着较低的细胞毒性。因此，我们的研究开发了一种新的靶向递送工具，为将来癌症的靶向治疗提供了一个种新的手段。本项目研究中，我们发表核心论文2篇，培养在读博士生3名。

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