相变型HER2靶向磁性脂质纳米粒多模态显像及磁热治疗乳腺癌的研究

With the fasten development of nanotechnology and minimally invasive treatment tumor technology, molecular imaging and magnetic hyperthermia therapy based on the magnetic nanoprobe shows attractive application prospect in the experimental study. However, due to inaccurate positioning and restricted by the depth, the traditional heat magnetic seeds impeded the clinical application and popularization of moxibustion.Moreover, commonly used ultrasound molecular probes have some drawbacks, such as microbubbles can not pass through the vascular endothelial gap due to the large particle size, and have short duration time in body. Nanoparticles made by perfluoropentane(PFP) with ability of phase trasition can solve this difficult problem.This project proposed to develop a kind of phase-shifted targeted magnetic lipid nanoparticles which stabilized by PEGylated phospholipid coatings and HER2 antibody-Herceptin on the surface. The prepared nanoparticles can pass through the vascular endothelial gap and actively target to the breast cancer, which can realize real-time imaging tracing in vivo by MR.This magnetic-sensitive phase-transitional agent--HER2-targeted magnetic lipid nanoparticles, with high magnetic-thermal energy-transfer capability, could quickly respond to external alternating magnetic fields(AMF) to produce thermal energy and trigger the vaporization of the liquid PFP, which can enhance ultrasound molecular imaging. Moreover, Integration of complementary advantages of MRI/US tracing in vivo, SPIO which site-specifically in the targted cells can generate heat to achieve the purpose of intracellular hyperthermia. Integrating the advantages of targeting diagnosis and magnetic hyperthermia therapy, targeted lipid magnetic nanoparticles could produce "a whole greater than the sum of the parts." This project has great research value,its success will provide a new efficacy method in non -invasive, early diagnosis and treatment of breast cancer in the future.

随着纳米材料及肿瘤微创治疗技术的发展，基于磁性纳米探针的分子显像及磁热治疗在实验研究中展示了诱人的应用前景。但是，传统的磁热籽因定位不准确及受深度的限制，在临床应用上受到阻碍。另外，常用的超声分子探针存在微泡粒径太大，不能穿过血管内皮间隙，持续时间短等缺点，具有液气相变功能的液态氟碳纳米探针有望解决这一难题。本课题拟构建一种能够穿过肿瘤血管内皮细胞间隙，并能靶向乳腺癌细胞、性质稳定的HER2靶向相变型磁性纳米粒，经MR成像可实现体内实时示踪。在高频交变磁场下，纳米粒内包裹的SPIO产热使温度升高达到液态氟碳相变阈值时，促发液气相变，纳米粒变为微泡可极大地增强超声信号，同时实现超声显像；更重要的是，靶向细胞内的磁粒子吸收电磁能转化为热能，产生细胞内磁热治疗效应，从而发挥磁热疗联合靶向治疗的双重优势。所研究新型相变型磁性纳米粒集高效诊疗于一体，为乳腺癌的早期诊断、靶向精准热疗提供新的技术方案。

在肿瘤治疗领域，为了克服传统肿瘤细胞失去发生凋亡的能力从而产生治疗逃逸的弊端，基于非凋亡形式的细胞死亡方式--铁死亡的纳米药物逐渐被深入研究。另外，肿瘤纳米医学还存在的问题是：纳米制剂在到达肿瘤部位后，难以从表面向肿瘤核心进一步渗透，限制了纳米药物的效能最大化。为此，本课题采用磷脂成膜材料、磁性材料、相变型液态氟碳及兼具乳腺癌CD71靶向功能和铁死亡激活功能的Art药物，构建出一种基于铁死亡的全新靶向磁性纳米脂滴，并联合温和磁热效应，以同步解决肿瘤细胞凋亡逃逸与纳米渗透深度的问题。通过研究，我们取得了如下成果：1、成功制备出稳定的磁性纳米脂滴，且其作为一种高安全性载体，可以同时携带多功能药物和成像材料；2、所制备的磁性纳米脂质体可以通过主动靶向 (多功能药物寻靶)和被动靶向(增强渗透性和滞留效应)双重作用，最终在肿瘤部位高效积聚；3、在多模态成像引导下，通过施加外部交变磁场产生温和磁流体热效应，伴随的磁致相变生物学效应使得该纳米粒子由肿瘤表面渗透进入核心；4、验证了该纳米粒子在肿瘤核心深部释放药物激活铁死亡治疗途径的机制。来自于温和磁热产生的磁致相变效应能够使得纳米材料通过血管-肿瘤屏障，从而实现由肿瘤表面到核心区域的穿透，进一步放大铁死亡的抗肿瘤效能。我们将这一全新的方法命名为“磁热致铁死亡敏感”。更重要的是，这种治疗进程可以在多模态成像的指导下进行，使得用于肿瘤治疗的磁性纳米材料设计更加合理及安全，具有广阔应用前景，为项目未来的临床转化和进一步推广打下基础。