智能靶向性介孔二氧化硅药物输送载体的制备和应用研究

Engineering drug nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Conventional chemotherapeutic agents are distributed non-specifically in the body where they affect both cancerous and normal cells, thereby limiting the dose achievement within tumors and also resulting in systemic toxicity and the induction of multiple drug resistance. The proposed work aims to develop multifunctional mesoporous silica nanoparticles (MSNPs), whose surfaces were functionalized with folate and Tat peptide. Multifunctional MSNPs can be efficiently trapped by folate-receptor-rich cancer cells through receptor-mediated endocytosis, while Tat peptide can mediate the entrance of MSNPs into the cell nucleus. The drug-delivery efficacy of nanocarriers will be investigated to confirm the cooperative effects of folate and Tat peptide modified on the nanoparticle surface. Thus, multifunctional MSNPs will achieve folate-mediated targeting in vivo and deliver anticancer drug more effectively into cell nucleus to eradicate cancer cells. This work could provide more theoretical and scientific basis for targeted drug delivery of multifunctional MSNP-based drug nanocarriers, and should be helpful to develop new drug delivery systems for diagnosis and treatment of cancers.

药物载体是实现靶向药物输送治疗癌症的关键。传统药物载体经静脉注射后在体内的靶向性差，毒副作用严重，而且长期使用容易产生耐药性。本项目拟将制备表面叶酸和透膜肽两种功能分子修饰的介孔二氧化硅（MSNPs）纳米载体。叶酸分子的作用是促使MSNPs与肿瘤细胞表面叶酸受体特异性识别而被细胞内吞，透膜肽的作用是在肿瘤细胞内介导MSNPs进入细胞核，在静脉注射给药中实现药物载体在肿瘤细胞核内释放药物的目的。通过研究两种功能分子协同发挥作用的条件，揭示功能分子结构与性能之间的内在联系，实现提高抗癌药物输送的治疗效率、降低毒副作用以及克服肿瘤细胞多药耐药性的研究目标。本项目的研究结果将为开发高效低毒的智能靶向性介孔二氧化硅药物载体提供实验和理论依据，并为获得可在癌症的诊疗中有应用价值的靶向药物输送载体提供有益探索。

开发靶向药物输送载体是提高癌症治疗效率和降低药物毒副作用的关键，本项目以制备新型靶向性药物输送载体为主线，研究工作分为两个部分：1）智能靶向抗癌药物输送：制备了基于介孔二氧化硅、两亲性β-环糊精和聚合物胶束的药物输送载体，并通过引入靶向基团研究纳米载体靶向输送抗癌药物的性能，经过体外细胞实验和体内动物实验初步评价其药效和生物安全性，实验结果表明新型载体可提高抗癌药物的靶向输送效率和降低其毒副作用；2）智能靶向光敏剂药物输送：通过对光敏剂氟硼二吡咯衍生物的分子设计和合成，研究了其与功能化β-环糊精或吐温80的共组装，得到了表面具有靶向基团甘露糖的纳米颗粒或胶束等组装体，并研究了它们对乳腺癌的靶向光动力治疗效果，实验结果表明组装体提高了光敏剂药物输送的效率，有效地降低了对正常乳腺细胞的光毒副作用。总之，开发新型智能靶向药物输送载体增加对乳腺癌细胞的特异性和选择性药物输送，提高疗效和降低毒副作用，对提高癌症的治疗效果具有重要意义。在本项目的资助下共发表标注论文9篇（其中SCI论文6篇，项目负责人为第一作者或通讯作者6篇），申请发明专利4项，其中1项已获授权。