基于载顺铂纳米靶向探针对NPC多模态分子影像诊断及可视化精准治疗一体化的研究

Nasopharyngeal carcinoma is one of the most common malignancies in south China，especially in Guangdong，Hainan and Guangxi provinces．Now high incidence of nasopharyngeal carcinoma of hainan province, and tend to be younger. Radiotherapy and chemotherapy are main methods for NPC treatment．In recent years，great developments have taken place in the outcomes of radiotherapy；however,the 5 year survival rates of cases at III—IV clinical stage and those not sensitive to radiation do not improved because of the secretiveness of nasopharyngeal carcinoma for difficult early detection. Targeted chemotherapy for tumors is the hot research which has a high degree of selectivity to tumor cells，is competent in recognition and binding with the specific molecule of tumor focus．Imaging technology play an important role on the early diagnosis and visualization precise targeting individualized treatment with NPC. Multimodality molecular imaging technology has developed rapidly, molecular probe is its foundation.At present, the main ultrasonic molecular imaging as the core of multimodality molecular imaging technology combined with the advantage of the other technologies.Multifunctional ultrasound contrast agents is the key factor to realize ultrasonic molecular imaging and therapy.Along with the development of nanotechnology, nanoparticle was prepared as ultrasound molecular probe , which can cross the endothelial gap for molecular imaging and treatment with tumor cell out of vascular. In order to enhance the ability of ultrasound imaging, nanoparticles ultrasound contrast agent encapsulated with liquid perfluorocarbon was prepared. In this study, we will prepared a new multimodality and multifunctional folate targeted nanoparticles molecular probe, loaded with cisplatin and Fe3O4 , encapsulated with liquid perfluorocarbon, which can accomplish the multimodal targeted molecular imaging and precision therapy for nasopharyngeal carcinoma. We expected to provide a highly efficient, small side effects，visible and precisely diagnosis and treatment for nasopharyngeal carcinoma patients.

海南省鼻咽癌（NPC）发病率高，中晚期及对放射线不敏感的NPC，治疗效果差。肿瘤分子靶向研究对NPC的早期发现、早期诊断及可视化精准靶向治疗，还需影像学技术支持。多模态分子影像技术中分子探针是基础。目前，其主要以超声分子显像为核心，并结合其它技术的优势。多功能超声造影剂是实现超声分子显像与治疗的关键因素。纳米级超声分子探针可以穿过血管内皮间隙，对血管外肿瘤细胞分子显像与治疗。为了增强超声显像能力，液态氟碳纳米粒超声造影剂应用而生。本研究拟研制一种多模态多功能的纳米级分子探针，具有叶酸（FA）分子靶向性，载顺铂（CDDP）和超顺磁性Fe3O4纳米颗粒，并包裹液态氟碳（PFH），实现对NPC的US、MRI及光声等多模态分子靶向显像，同时超声辐照诱发PFH发生液-气相变，通过空化作用和声孔效应使顺铂在肿瘤组织细胞内高效释放，发挥精准靶向治疗，为NPC患者提供一种高效、可视化的诊断及治疗方法。

鼻咽癌（nasopharyngeal carcinoma，NPC）是一种发生于鼻咽腔或上咽喉部的恶性肿瘤，占我国头颈部恶性肿瘤的首位。目前，放、化疗是NPC主要的临床治疗手段，但是副作用较大，限制了其应用范围和效果。如果能使化疗药物集中于肿瘤部位，实现对肿瘤细胞的靶向杀伤，则有望解决上述临床中的问题。超声分子靶向显像与治疗研究的核心问题是超声分子探针，具有多功能的超声分子探针是实现超声分子显像与治疗的关键因素。随着纳米技术的发展，为研制一种新型的纳米级超声分子探针，以穿过血管内皮间隙，实现对血管外肿瘤细胞的分子显像与治疗提供了基础。因此，本研究拟制备FA-PLGA- PFP-DOX-Fe3O4纳米粒(FPPDF)，实现其对NPC的光声显像，并通过一定剂量的超声辐照诱发空化作用和声孔效应的机制使阿霉素药物在肿瘤组织和细胞内高效释放，从而发挥精准靶向治疗作用，为NPC患者提供一种高效的、副作用小的可视化的诊断与精准个性化治疗一体化模式的方法。. 本项目成功制备FPPDF纳米粒，观察和测量其外观、形态、结构、分散度、粒径、电位、包封率、载药量等基本特征，结果显示，该纳米粒形态粒径，分散度及电位均符合我们的预期。并计算了DOX及Fe3O4的包封率及载药量；体外及体内验证了其超声成像及光声成像效果。从溶液层面、体外及体内观察并验证了其靶向性，检测健康大鼠的心、肝、肾脏功能及治疗后DOX在 NPC小鼠体内各组织、器官的分布情况及浓度小鼠体内各组织、器官的分布情况及浓度，评价了其生物安全性。建立肿瘤动物模型，观察治疗后肿瘤的生长状态、计算抑瘤率及生存时间，成功验证了该纳米粒在动物模型上对鼻咽癌的具有明显的治疗效果。. 该研究证明了超声协同FPPDF纳米粒可以实现NPC的多模态分子影像诊断与精准治疗，为NPC的治疗提供了一种高效及副作用小的理想方法，具有一定的科学意义。