肿瘤自靶向纳米载药体系的构建及其给药性能研究

Poor targeting ability of anti-cancer drugs is one of the major factors for difficult treatment of cancer, thus it is of great significance for cancer therapy to develop cancer targeted drug delivery technology. However, the targeting recognition performance of existing cancer targeted drug delivery approaches highly rely on the post-decoration of targeting biomolecules, like antibody, which are not only high cost, poor stability and harsh operating conditions, but also the amount of such biomolecules is limited. Thus it is highly desired to explore tumor self-targeting drug delivery strategy without modification of affinity ligands. Molecular imprinting technology (MIT) is a biomimetic molecular recognition technique to mimic the targeting property of biomolecules, such as antibody, here we present that dual-template (antitumor drug and characteristic molecules on the surface of cancer cells) imprinted nanocage with dual recognition sites as drug nanocarrier, combining the advantages of MIT in the area of drug delivery and the excellent performance in cancer cell targeting, establishing tumor self-targeting drug delivery platform without modification of targeting affinity ligands and probing its tumor-targeted drug delivery performance in vitro and in vivo. The objective of this project design is to break through the limitation of high dependence of existing tumor-targeted drug delivery technology on targeting biomolecules and to provide new technical support for cancer-targeted diagnosis and treatment, expanding the application scope of MIT in fields of biochemistry, medicine, and so on.

抗癌药物的靶向性差是癌症治疗难的主要原因之一，发展靶向给药技术对于癌症治疗意义重大。然而，目前绝大多数癌症靶向给药方法的靶向性需修饰抗体等具有靶向识别能力的生物分子才能实现，不仅成本高昂、稳定性差、使用条件苛刻，且靶向生物分子数量有限，难以满足现实需要。因此，探索无需修饰亲和配基的肿瘤自靶向药物递送技术很有必要。分子印迹技术（MIT）是一项模拟抗体等生物分子靶向识别能力的仿生分子识别技术，本项目拟以抗癌药物和癌细胞表面特征分子为双模板制备具有双识别位点的印迹纳米笼药物载体，结合MIT在药物递送方面的优势与其在癌细胞靶向识别方面的优良表现，构建无需修饰靶向亲和配基的肿瘤自靶向纳米载药体系并从细胞与活体水平探索其肿瘤靶向给药效果。本项目的构思旨在突破现有肿瘤靶向药物递送技术对靶向生物分子高度依赖的瓶颈，为癌症靶向诊疗提供新的技术支持，拓展分子印迹技术在生化、医疗等领域的应用范围。

肿瘤靶向诊疗是肿瘤治疗的发展趋势，围绕肿瘤靶向诊断与治疗这一核心问题，本项目发展出了一系列原创性技术并或得了一定的应用，主要包括：①采用表面分子印迹技术分别制备了唾液酸（一种大多数肿瘤细胞表面高表达的小分子单糖）印迹的上转换荧光纳米粒子和肌红蛋白印迹的纳米磁珠，对所得材料的理化性质进行了表征，对其印迹效果和结合性能进行了详细评价，最终以上述材料为人工抗体，分别实现了肿瘤自靶向微创光热诊疗和人血清中肌红蛋白的选择性分离与检测，为肿瘤靶向诊疗和某些心肌疾病的早期诊断提供了有力的技术支持；②比较研究了反溶剂技术与传统药物造粒技术的工艺条件，确定了科学合理的反溶剂技术方案， 并利用该技术一步制得了粒径均一可调的杨梅酮、黄芩素、芹菜素等模型药的药物微纳制剂，且证实了所得药物微纳制剂比相应的小分子药物有着显著更高的生物利用度、抗氧化性和抗肿瘤活性等性能，为提升肿瘤疗效和微纳药物制剂的高效制备提供了参考；③设计制备了多种不同结构微流控芯片用于全血中循环肿瘤细胞（CTCs）的选择性捕获，探索了芯片内部结构设计和通道参数对 CTCs 捕获效率和正确率的影响，结合计算机模拟计算与临床验证，开发出了多种 CTCs 高效捕获芯片，对肿瘤临床分析和治疗过程的监测与评价具有重要意义。