多功能金纳米棒诊疗系统在肿瘤靶向与光热治疗以及肿瘤成像中的研究

Cancer continues to be one of the world's most devastating diseases, with more than 10 million new cases each year. Nanotechnology provides extraordinary opportunities to address these challenges as nanocarriers can offer both passive and active targeting abilities towards cancerous tissues/cells. The current focus of nanomedicine is to develop multifunctional tumor-targeting drug/agent nanocarriers, including those capable of co-delivering anti-cancer drugs and imaging contrast agents which are termed cancer theranostics (i.e., combined therapy and diagnostics), thereby providing a more effective and multimodality approach in cancer management. In this proposal, a multifunctional gold nanorod (GNR)-based nanoplatform for targeted anti-cancer drug delivery and positron emission tomography (PET) imaging of tumors will be developed and characterized. An anti-cancer drug (i.e., doxorubicin (DOX)) will be covalently conjugated onto PEGylated GNR nanocarriers via a hydrazone bond to achieve pH-sensitive controlled drug release. Tumor-targeting ligands (i.e., the cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides, cRGD) and 64Cu-chelators (i.e., 1,4,7-triazacyclononane-N, N', N''-triacetic acid (NOTA)) will be conjugated onto the distal ends of the PEG arms to achieve active tumor-targeting and PET imaging, respectively. Cellular uptake, cytotoxicity, in vivo PET imaging and photothermal therapy will be tested. This multifunctional GNR-based nanoplatform can potentially be optimized for combined cancer therapies (chemotherapy and photothermal therapy) and multimodality imaging (PET, optical, CT, etc.).

本项目旨在设计一种基于金纳米棒的兼具诊断与治疗的多功能肿瘤靶向纳米递释系统，目的是同时实现分子诊断试剂和抗肿瘤药物的肿瘤靶向递释，同步对肿瘤进行诊断与治疗。该多功能纳米体系的结构以金纳米棒做为结构的主体，在其表面共价连接聚乙二醇（PEG）亲水链，在PEG的外端用靶向于整合素受体的cRGD环肽来实现体系的肿瘤靶向性，同时在PEG链上连接双功能螯合剂1,4,7-triazacyclononane-1,4,7-triacetic acid(NOTA)，用正电子核素64Cu (t1/2: 12.7 h)进行标记，用于肿瘤的PET分子显像；此外，通过具有pH敏感性的腙键共价连接肿瘤治疗药物阿霉素（DOX）于金纳米棒上，由于金纳米棒独特的近红外吸收能力,本课题将有望协同肿瘤的化疗和光热治疗于一体。本课题将通过系统性的细胞及分子生物学实验考察对构建的靶向纳米递送系统的的肿瘤靶向性和肿瘤治疗效果。

本项目设计了一种基于金纳米棒的兼具肿瘤的诊断与靶向治疗的多功能纳米递释系统。该多功能纳米体系的合成是以金纳米棒为主体，在金棒的表面共价连接聚乙二醇（PEG）亲水链段，在PEG 的外端用靶向于整合素受体的cRGD 环肽作为肿瘤靶向的配体；同时，我们在PEG 链上连接双功能螯合剂1,4,7-triazacyclononane-1,4,7-triacetic acid(NOTA)，用正电子核素64Cu (t1/2: 12.7 h)进行了标记，进行了肿瘤的PET 分子显像；另外，我们选用了阿霉素（DOX）为模型药物，通过具有pH 敏感性的腙键将其共价连接到纳米体系上面。此外，我们借助金纳米棒独特的光学性质，考察了金纳米棒的热疗性能，并对我们所合成的纳米体系的热疗和化疗相结合的效果进行了考察。本课题也对我们所构建的靶向纳米递送系统的的肿瘤靶向性和肿瘤治疗效果进行了评价。