端粒酶及pH双重响应的DNA纳米结构用于肿瘤定点药物释放的研究

Tumor specific drug release is of great importance in improving the accuracy in cancer therapy. Controlled drug release serves as a critical strategy to realize specific drug release in tumor. However, current carriers for controlled release suffer from various drawbacks including deficiencies in structural controllability, bio-safety and specificity of stimuli. This project aims to design a highly specific drug delivery system using “double keys” to unlock encapsulated drugs in response to high telomerase activity and acidic microenvironment in tumor. Featured by Bucky ball shape, the DNA based nano drug delivery system also takes advantages of the programmability, controllability and biocompatibility. Surface ligand modification can facilitate active tumor targeting and accumulation. Then, triggered by acidic tumor microenvironment and telomerase inside tumor cells, the double chains connecting each basic unit of DNA nano-structure will respectively undergo unwinding and substitution reactions, leading to the collapse of the Bucky ball structure and fast release of loaded drugs. Therefore, tumor specific drug release can be more comprehensively achieved with enhanced therapeutic accuracy and efficacy. The exploratory design of this study combines the dual-factor triggering by pH and telomerase, which is promising to enlighten new strategies for controlled release of anti-tumor drugs.

肿瘤定点药物释放对提高抗肿瘤治疗的准确性及有效性至关重要。药物控释是实现药物定点释放的一个重要策略，但目前常见的药物控释载体在结构可控性、生物安全性以及控释因子的特异性等方面有所不足。本项目拟结合肿瘤特异性表达的端粒酶活性以及肿瘤酸性微环境作为双重控释因子，设计一种肿瘤高特异性的“双钥匙”控释策略。并融合DNA纳米结构的可编程性、结构可控性及生物安全性，构建端粒酶及pH双重响应的巴基球形DNA纳米结构药物控释系统。通过修饰肿瘤靶向配体，该控释系统可以主动靶向并富集在肿瘤部位。在肿瘤特异性的酸性微环境及肿瘤细胞内端粒酶的联合刺激下，DNA纳米结构中基元连接的双链同时发生置换及解链反应，使得DNA纳米结构崩解，并快速释放装载的药物，从而实现肿瘤内定点的药物释放，提高抗肿瘤治疗的准确性及有效性。项目探索性地将端粒酶及pH双重控释策略与DNA纳米结构相结合，有望为抗肿瘤药物的控释研究提供新的思路。

肿瘤定点的药物释放是提高抗肿瘤治疗准确性和有效性的关键环节。该项目应用DNA结构的精确可控性和良好的生物相容性，并嵌入酸性pH响应序列和端粒酶识别序列为释药开关，构建了一种在肿瘤微环境中控释免疫佐剂R848和化疗药物铂的DNA纳米载体系统，从而极化肿瘤相关巨噬细胞和诱导肿瘤免疫原性细胞死亡。该载药系统在特异性的双响应下，释放R848和化疗药物铂，进一步发挥协同作用，将促肿瘤的M2型肿瘤相关巨噬细胞极化为抗肿瘤的M1型肿瘤相关巨噬细胞，并诱导免疫原性细胞死亡，重塑免疫抑制微环境，并且在乳腺癌肺转移肿瘤模型中发挥了较好的治疗效果。同时在体内外深入地证明了其作用机制。最重要的是，这一策略减轻了单独使用游离药物带来的毒副作用，体现了DNA纳米结构作为免疫治疗载体的优势，为抗肿瘤治疗提供了一个具有潜力的平台。