用于多模态显像与治疗的相变金纳米笼双靶向超声分子探针的研制

Ultrasound molecular imaging and therapeutic techniques provide a new efficient method for the atherosclerotic(AS)′ clear imaging and accurate treatment. Ultrasound microbubbles, however, have the disadvantages of large particle size, insufficient stability, short cycle time in vivo and low load drug/gene quantity. Meanwhile, the problem of targeted aggregation and visualization of ultrasound contrast agents in lesion sites needs to be solved. Gold nano cage (GNC) combined with new liquid-vapor phase change fluorocarbon nanoparticles, as well as acoustic and photo phase change technology is expected to solve the above problems. The object of this project is to construct a new photoacoustic imaging and ultrasound imaging molecular probe integrated with diagnostic and treatment. The double-target and multi modal nano-contrast agent with photosensitive drug releasing system was designed and synthesized based on liquid fluorocarbon, enhanced by photoacoustic imaging, bridged with VEGFR-2 and sialyl lewisx to explore the structural effects and regulation of molecular probe between its components、morphology，surface properties and target, imaging, load, phase change, release, etc., This project provides AS patients with efficient early diagnosis, real-time monitoring and early intervention, predictions for the vulnerability, rupture and other risk events of the plaque and a reliable theoretical basis and practical experience to the clinical development of efficient, directional and non-invasive treatment.

超声分子显像与治疗技术为动脉粥样硬化（AS）精准检测及高效治疗提供了一种高效的新手段。但超声微泡存在着粒径较大、稳定性不够、体内循环时间短、荷载药物/基因量低等缺点，同时，超声造影剂在病灶部位的靶向聚集及可视化问题需要解决。金纳米笼(GNC)结合新型液-气相变型氟碳纳米粒联合声、光致相变技术可望解决上述问题，本项目拟以构建诊疗一体化的靶向光声成像及超声成像的超声分子探针为目标，以液态氟碳为基础，GNC为光声成像增强剂，桥联VEGFR-2 及 sialyl lewisx，设计并合成了具有光敏型药物释放体系的双靶向多模态纳米超声造影剂，探索超声分子探针的组分、形貌和表面性质与靶向、成像、载药、相变、释药等功能之间的构效关系和调控规律，为AS患者提供高效的早期诊断，时实监控及早期干预，对斑块的易损程度和破裂等风险事件作出预测，为临床开展高效、定向和无创的治疗提供可靠的理论依据和实践经验。

超声造影作为超声检查的补充检查，可对疾病诊断提供重要辅助，但超声微泡存在着粒径较大、稳定性不够、体内循环时间短、荷载药物/基因量低等缺点，同时，超声造影剂在病灶部位的靶向聚集及可视化问题需要解决。为了解决上述问题，本研究制备了HA靶向的载米托蒽醌相变型PLGA纳米粒（HA/MWCNTs-COOH-PEI-PLGA@MTO/PFP）；金属有机框架（MOFs）与羧基化碳纳米管（MWCNT-COOH）为载体表面修饰MCF-7同源细胞膜负载金丝桃素（Hypericin）靶向超声造影剂（Hy/PFP/MWCNT-COOH/ZIF-8@CM）；构建金纳米棒（GNRs）修饰的包封全氟戊烷（PFP）的载阿霉素（PTX）的脂质体纳米级相变超声造影剂（PFP/PTX@liposome/GNRs）等几种纳米复合材料，获得下列结果：1.以粒径为衡量标准，经工艺优化后的PLGA@MWCNT-COOH/PFP NPs的最优实验条件为：乳化功率40%，乳化时间5min，PFP与MWCNTs水溶液的比例为1:1，MWCNTs水溶液中MWCNTs与H2O比例为1:100，IPA20mlq；2.成功制备了HA靶向的载MTO相变型HA/MWCNTs-COOH-PEI-PLGA@MTO/PFP纳米粒，该纳米粒具有良好的光热能力、相变能力及超声成像能力，在近红外光辐照下，可产生光热治疗的同时使纳米粒涨大，相变增强造影效果，涨破后进而释放出所包载药物，协同高效杀伤肿瘤细胞；3.本研究构建的Hy/PFP/MWCNT-COOH/ZIF-8@CM的新型纳米超声超声造影剂，不仅具有良好的超声成像效果，同时在其表面修饰MCF-7同源细胞膜，能够主动靶向肿瘤细胞，负载Hypericin作为光动力治疗药物，与MWCNT-COOH的光热治疗作用联合，对肿瘤细胞的杀伤能力更强；4.本研究制备的PFP/PTX@liposome/GNRs多功能超声造影剂，药物包封率较高，具有较好的生物相容性，光热转换能力及超声成像效果，5.本实验制备的Mn-TCPP@透明质酸（HA）-姜黄素（Cur）纳米粒子，消耗GSH实现MR成像，光动力及化学治疗。以上材料为扩展肿瘤的诊断、治疗方法，同时为AS患者提供高效的早期诊断，时实监控及早期干预，对斑块的易损程度和破裂等风险事件作出预测，为临床开展高效、定向和无创的治疗提供可靠的理论依据和实践经验。