携载miR-101的可代谢金纳米复合制剂对非小细胞肺癌的靶向治疗研究

Lung cancer is one of the most prevalent cancer, and seriously threatens human’s health in the word. Improving efficacy of the treatment needs to depend on nanomedicine therapy since the current strategy has not always been sufficiently effective. Nanocomposites have been attracted much attention during tumor targeted synthetic therapy, due to the multifunction of drug delivery, diagnosis, therapy and monitoring treatment. Based on our previous study in which functionalized gold nanoclusters realized simutaneous and multisite tumor bioimaging, and mediated the combination modalities of chemotherapy and photo-thermal therapy to induce the remarkable inhibition of cancer cells, we will fabricate the metabolizable gold nanocomposites loaded miR-101 and modified folate donator to explore the new strategy of targeted synthetic therapy for non-small cell lung carcinoma. The nanocompisites could improve tumor target performance because of the integration of active targeting and passive targeting, and miR-101 could be intelligently released by the replacement of glutathione (GSH). The relative efficacy and mechanism of the nanocompisites mediated gene therapy of miR-101, photothermal therapy of gold nanostructure, and the different combinations of the single modality against lung carcinoma cells will be investigated in this study. We investigate the biocompatibility and biodistribution of the nanocompisites in the animal model of non-small cell lung cancer, and monitor the outcome of the targeted synthetic therapy mediated by the nanocompisites with visual optical/CT resonance in vivo, providing evidence for the clinic.

肺癌是最常见的恶性肿瘤之一，治疗效果仍不理想，提高疗效将主要依赖纳米医学的发展。纳米复合物具有药物传输、诊断、治疗及疗效监测等功能，因此纳米药物在肿瘤靶向治疗中倍受关注。基于我们前期研究结果：功能化金纳米簇（GNCs）精确实现肿瘤多位点同步靶向成像，同时携载抗癌药物联合化疗、光热疗高效抑制癌细胞。本项目将构建可代谢金纳米复合物携载miR-101并偶联靶向配体的多功能制剂，将配体主动靶向及纳米药物被动靶向有机结合来提高肿瘤靶向给药的效能，探究非小细胞肺癌（no-small cell lung carcinoma, NSCLC）靶向治疗新策略，研究对NSCLC的金纳米结构光热疗、miR-101基因治疗以及纳米复合制剂靶向综合治疗的效能和机理机制。本项目拟应用NSCLC动物模型，对金基纳米复合制剂进行生物相容性、体内分布及光学/CT可视化监测靶向治疗效能及机制的研究，为临床应用转化提供依据。

肺癌作为全球范围内最为常见的恶性肿瘤，其发病率和死亡率居所有肿瘤前列，其中的非小细胞肺癌（Non-small cell lung cancer, NSCLC）是一种发病率高、死亡率高、对放化疗不敏感的常见恶性肿瘤。探寻非小细胞肺癌新的治疗方法改善其预后显得极为迫切。近年来兴起的纳米复合药物具有药物传输、诊断、治疗及疗效监测等功能，其在肿瘤靶向治疗研究中倍受关注。大量研究表明，类似于原癌基因和抑癌基因的miRNA在肿瘤细胞中发挥重要作用，可通过负向调节把控基因的表达而广泛参与肿瘤的发生、发展，是肿瘤诊疗和预后的一类重要分子靶标。为此，本研究结合具有良好的光学性能和化学性质的金纳米结构，深入研究miRNA纳米复合药物制剂的肿瘤靶向治疗效能及机制，为肿瘤的免疫治疗提供新的理论依据和思路，为临床应用转化提供依据。我们以NSCLC细胞以及NSCLC动物模型为研究对象，构建了可代谢金纳米结构同时携载miR-101的多功能制剂复合物，将配体主动靶向及纳米药物被动靶向有机结合来以提高肿瘤靶向给药的效能，探究了非小细胞肺癌靶向治疗新策略。实验结果证实，所构建的金纳米结构呈现出优良的生物相容性，其联合生物配体叶酸、聚合物（壳聚糖）、温敏分子十四醇所形成的纳米复合物呈现出对miRNA的携载、递送以及控释性能。GNCs/miR-101/FA纳米复合物对非小细胞肺癌细胞具有明显的促凋亡效能，同时GNCs作为荧光标签能够很好地实现肿瘤细胞/组织的实时成像。与此同时，我们还发现GNCs在接受激光辐射时能够产生光热效应，有效杀伤对热敏感的肿瘤细胞，同时促使温敏材料溶胀以释放miRNA促进肿瘤细胞凋亡。本研究结果提示可代谢金纳米结构同时携载miR-101的多功能制剂复合物有可能作为抗肿瘤的有效药物，成为一种新的细胞治疗方式，应用于抗肿瘤的临床治疗。项目资助发表SCI论文2篇，待发表2篇。项目投入经费17万元，支出9.0899万元，各项支出基本与预算相符。剩余经费7.9101万元，剩余经费计划用于本项目研究后续支出。