新型光诊疗剂的制备及其在肿瘤多模式成像和治疗中的应用研究

The separation of tumor diagnosis and treatment is a major issue in the clinical tumor. Use of advanced nanomaterials and smart stimuli-responsive nanostructures for the diagnosis and treatment of disease can provide the direct evidence to early diagnosis, occurrence and development progresses of disease, and also enables online imaging of drug for the detection of disease,image-guided drug delivery and treatments, guidance of surgical resection, and monitoring of treatment response. Based on our previous studies, we design and prepare a novel multifunctional nanoprobe based on Chlorin e6 (Ce6) conjugated silica coated gold nanorods (GNRs) for multi-modal imaging and synergy treatment. According to metallic surface-enhanced fluorescence theroy, to control the distance between Ce6 and GNRs is promising for enhanced fluorescence imaging of melanoma.Meanwhile, the high atomic number and electron density of gold and photo-thermal effect of GNRs will be employed for X-ray/CT and photoacoustic dual-modal imaging, respectively. The obtained deeper and wider biological information of tumor tissues can improve the imaging diagnostic accuracy and sensitivity of tumor. Finally, the photosensitive effect of Ce6 and photothermal effect of GNRs can be used for simultaneously photodynamic/photothermal therapy of melanoma, as well as further.investigation on the possible mechanism of the treatments. Organic fusion of multi-modal imaging and synergy treatment based on novel nanoplatm enables early diagnosis, accurate positioning, combination therapy, real-time monitoring curative effect of melanoma.

肿瘤的诊断与治疗分离是肿瘤临床主要问题之一。将具有先进功能纳米材料及具有智能响应特性的纳米结构用于肿瘤的诊断和治疗研究，不仅能为肿瘤的早期诊断以及发生发展过程提供更直观的证据，而且还有望实现影像介导的药物递送和治疗、影像指导的手术切除和实时监控的治疗应答等。本项目拟在我们前期工作的基础上，设计和制备二氢卟吩e6共轭的二氧化硅包覆的金纳米棒多功能复合纳米探针，并用于黑色素瘤的多模式成像和协同治疗。利用金属表面增强荧光原理，通过控制二氢卟吩e6与金纳米棒之间的距离，实现黑色素瘤的增强荧光成像。同时利用金纳米棒自身的高密度和光热效应实现黑色素瘤的X-ray/CT和光声成像，提高肿瘤成像诊断的准确性和灵敏性。在实现多模式成像的同时，利用二氢卟吩e6的光敏效应和金纳米棒的光热转换效应，同步实现黑素瘤的光动力/光热联合治疗，并深入探讨该协同治疗的增强效果及其可能机制。

肿瘤的诊断与治疗分离是肿瘤临床诊疗主要问题之一。构建具有先进功能纳米材料及智能响应特性的纳米结构有望实现肿瘤的诊疗一体化。在这个项目（No. 81401465）资助下，我们设计和制备：（1）一种多功能纳米探针，具体为二氢卟吩e6共轭的二氧化硅包覆的金纳米棒纳米探针，用于黑色素瘤的多模式成像指导的光动力（PDT）/光热（PTT）联合治疗；（2）一种光响应生物可降解纳米摇铃，具体为全氟正戊烷负载的介孔二氧化硅薄膜包覆的GNR，用于增强超声和光声双模态成像指导的黑色素瘤PTT；（3）一种双响应纳米诊疗剂，具体为吲哚菁绿（ICG）和5-氟尿嘧啶共同装载到二氧化硅包裹的金纳米棒，用于黑色素瘤的多模态成像指导的PTT、PDT和化疗三模式协同治疗；（4）一种核-卫星结构纳米诊疗剂，具体为64Cu标记的、阿霉素（DOX）装载的聚多巴胺-金属富勒烯复合纳米粒子，可实现核磁共振成像（MRI）、光声（PA）和正电子发射计算机断层显像（PET）三模态成像指导的癌症联合治疗；（5）一种内源磷酸酶诱导的共组装策略，在肿瘤组织特异性形成ICG装载的纳米纤维用于癌症的诊疗一体化；（6）一种葡萄糖刺激响应的纳米药物用于肿瘤“类饥饿/NO气体”协同治疗；（7）一种64Cu标记的磁性黑色素纳米颗粒用于PET/MR/PA多模态成像指导的光热治疗；（8）一种可注射的长余辉水凝胶植入体作为内置光源用于高效的可重复的光动力治疗。基于我们前期的研究工作基础，我们总结最近新兴的深层光动力疗法，详细介绍了近红外光、高能X射线以及自发荧光作为激发源的PDT。最近，我们综述了纳米技术用于肿瘤多模式协同治疗。总结，多功能纳米平台将多模态成像和多模式治疗整合在一个平台上，有望实现个体化治疗纳米药物用于药物递送、诊断和治疗。在此基金资助下，我们以第一/同等贡献或通讯作者身份发表SCI论文31篇，包括Chem. Rev. (1), Chem. Soc. Rev. (2), Adv. Mater. (5), Angew.Chem. (2), ACS Nano (5), Biomaterials (3), Small (2), Nanoscale (5), Theranostics (1), Adv. Drug Deliver. Rev. (1), Nat. Protocols (1)等。同时，申请中国发明专利5项。