Nanovalve Platform: Targeted, Controlled, Release of Anticancer Drugs

描述(申请人提供)：拟议研究的目标是使用介孔二氧化硅纳米颗粒和双稳分子机器来输送抗癌药物。活性结构是纳米机器，由含有设计好的孔的固体二氧化硅载体和仅在外部命令或所需条件下捕获药物分子并将其从孔中释放的移动部件组成。两种类型的机器，主动从毛孔中排出分子的纳米推进器，以及堵塞和疏通毛孔入口的纳米阀门将被用来控制药物的输送。该组件被覆盖有分子或蛋白质，这些分子或蛋白质将胶囊靶向癌细胞。第一个具体目标是改进和优化主要研究实验室开发的纳米机器(pH激活的阀门、光激活的叶轮、光激活的阀门)，为特定的癌细胞靶向修改表面，并优化它们的性能。第二个目标将通过研究荧光DNA结合剂的释放来展示机器在人类癌细胞中的操作，并展示抗癌药物(紫杉醇、喜树碱和阿霉素)在人类癌细胞系中的输送和按需释放。最后，第三个目标是评估和利用纳米颗粒在裸鼠体内生长的人肿瘤异种移植瘤中的应用。通过只在肿瘤中打开阀门，就有可能只在特定部位或对特定刺激做出反应时释放抗癌药物，从而消除对非癌症细胞的有害影响。纳米阀门和叶轮可以对药物的输送进行复杂的控制。 与公共健康相关：含有由分子机器控制的毛孔的纳米颗粒将被用来释放受控的抗癌药物。这项研究的结果将是一种新的癌症化疗系统，它可以消除对非癌细胞的有害影响。

DESCRIPTION (provided by applicant): The goal of the proposed research is to use mesoporous silica nanoparticles with bistable molecular machines to deliver anticancer drugs. The active structures are nanomachines that consist of a solid silica support that contains designed pores, and moving parts that trap drug molecules and release them from the pores only on external command or under desired conditions. Two types of machines, nanoimpellers that actively eject molecules from the pores, and nanovalves that block and unblock the entrances to the pores will be used to control the delivery of drugs. The assembly is coated with molecules or proteins that target the capsules to cancer cells. The first specific aim is to improve and optimize nanomachines (a pH activated valve, a light-activated impeller, a light activated valve) that were developed in the principal investigators laboratories, modify the surfaces for specific cancer cell targeting, and optimize their performance. The second aim will demonstrate operation of the machines in human cancer cells by studying the release of a fluorescent DNA binding agent and to demonstrate the delivery and on-demand release of anticancer drugs (paclitaxel, camptothecin and doxorubicin) in human carcinoma cell lines. Finally, the third aim will evaluate and utilize the nanoparticles in human tumor xenografts grown in athymic mice. By having the valves open only in a tumor, it will be possible to achieve release of anticancer drugs only at specific sites or in response to specific stimuli, thus eliminating unwanted effects on non-cancerous cells. The nano valves and impellers allow sophisticated control of the delivery of the drugs. PUBLIC HEALTH RELEVANCE: Nanoparticles that contain pores controlled by molecular machines will be used to release anticancer drugs under control. The result of the research will be a novel system for cancer chemotherapy that eliminates unwanted effects on non-cancerous cells.