靶向Bcl-2功能转换的纳米核受体药物的构建及其在精准癌症治疗中的应用

Cancer is a serious disease that threatens the human health, and the research hotspot of treatment is focused on the molecular-targeted drugs. However, some of the nuclear receptor Nur77-targeted drugs have the disadvantages such as the off-target effect, the serious toxic-side effect, the drug resistance or the poor cell-penetrating ability. Hence, it’s badly needed to improve the treatment strategy by making the combination between nanotechnology and molecular-targeted drugs. Breaking the existing design thinking of nanomaterials-based drugs targeting single or two surface biomarkers, we will, for the first time, fabricate the dual targeting-based nanodrugs in this project by selecting the membrane and nuclear receptors as the double targets, utilizing the mechanism of action of Nur77 binding Bcl-2, and employing the PAMAM dendrimers with multivalent conjugation effect as carriers coupled with the targeting ligand against the surface biomarker of cancer cells and the nuclear receptor (Nur77)-targeted drug that targets Bcl-2 function conversion. The dual targeting-based nanodrugs will be skillfully constructed with the function of targeted recognition, intracellular penetration, specific-site binding and induced apoptosis. The in vitro and in vivo assays will be performed to demonstrate their anticancer capabilities with high efficiency and great precision from the molecular, cellular, and animal levels using electron microscopy, confocal and flow cytometry analysis methods. This study will provide a novel strategy for the design of a new generation of dual targeting-based nanodrugs for precise cancer treatment.

癌症是一种威胁人类健康的重大疾病，其治疗的研究热点主要集中于分子靶点药物，但部分基于核受体Nur77的靶点药物存在脱靶、毒副作用大、易产生耐药性、穿透细胞能力差等缺点，因此迫切需要将纳米技术与靶点药物相结合的改进策略。本项目突破现有单/双靶向膜受体纳米药物的思维，首创以膜受体和核受体为双靶点的设计思路，运用Nur77 结合Bcl-2诱发癌细胞凋亡的作用机制，采用具有多价络合效应的PAMAM dendrimers载体偶联能特异性识别癌细胞表面生物标记物的靶向配体和靶向Bcl-2功能转换的Nur77靶点药物，巧妙地构建集靶向识别、胞内穿透、定点结合和诱导凋亡功能为一体的双靶向纳米核受体药物，并从细胞、分子、动物水平，离体和在体条件下，运用电镜、共聚焦、流式等分析手段，研究其高效精准的靶向抗癌能力。本研究将为设计新型的双靶向纳米抗癌药物提供研发策略。

部分核受体靶点药物在癌症治疗过程中存在脱靶、毒副作用大、生物利用度低、穿透细胞能力差等问题，本项目在国家自然科学基金的支持下，聚焦以膜受体和核受体为双靶点的功能化纳米药物设计策略，旨在构建能靶向识别、胞内穿透、定点结合和诱导凋亡的纳米核受体药物，从而在多种癌症模型中研究其精准的抗癌能力。本项目初步构建了不同表面官能团修饰的大孔硅纳米载体，用于Bcl-2功能转换肽和化疗药物DOX在耐药性癌症中的定点递送；接着又构建了叶酸修饰的大孔硅纳米载体及有机/无机杂化树状物/大孔二氧化硅纳米载体，进行癌症的靶向双药输送和高效低毒抗癌研究；随后我们又构建了核酸适配体修饰的功能化树状大分子载体，成功实现了雷公藤红素的高效负载及在结肠癌中的靶向治疗，提高了药物的在体安全性；最后又构建了生物稳定性增强的闭环靶向核酸适配体修饰的树状大分子来实现对微量循环肿瘤细胞的捕获和活性抑制；并设计了聚合驱动的DNA多米诺骨牌折叠（PDDC）策略，来实现对富含p53靶基因的结肠癌细胞的高灵敏度检测。总之，以上研究结果为促进核受体靶点药物的精准癌症应用提供了可行性的生物纳米技术研发策略。通过本项目研究，我们在cancer letter、chemical engineering journal、journal of controlled release、Chemistry of Materials等国际主流期刊上发表SCI论文10篇，获得发明专利2项；培养硕士研究生2人，圆满完成了研究计划。