载PTX的、具有液气相变能力的纳米超声分子探针靶向显影和治疗卵巢癌的研究

The technology of ultrasound molecular imaging can not only enhance molecular imaging of tumor, but also bring a new idea for the early diagnosis and targeted therapy of tumor by ultrasound targeted microbubbles destruction (UTMD) controlled drug release. However, 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. The nanoscale perfluorooctanoate bromine (PFOB) emulsions has poor contrast during ultrasound imaging, and can not make full use of UTMD for the release of drugs. These shortcomings greatly limit the further application of the ultrasound molecular probes. With the support of NSFC and other foundings, our preliminary experiments show that low-intensity ultrasound can promote the phase trasition of nanoparticles made by perfluorohexan (PFH), a low boiling point of liquid fluorocarbon, by changing it into gas from liquid phase. on this basis, the project intends to develop a PTX loaded nanoparitcles ultrasound contrast agent with lipid membrane, liquid fluorocarbon core and the capacity of the liquid-gas phase transition. The agent will target to highly expressed folate receptor in cells of ovarian caner, which leading to gathering of nanoparticles on tumor. With the irradiation of low power ultrasound, the nanoparticles of the ultrasound contrast agent will undergo a liquid- gas phase transition and produce microbubbles in situ in tumor and release PTX from bubbles, thus realizing the ultrasound molecular imaging and targeted therapy of ovarian cancer. After elucidating the mechanism of molecular probe liquid-gas phase transition as well as drug release in vitro and in vivo conditions, a new, efficient ultrasound molecular imaging and drug targeting delivery mode for tumor would be established.

超声分子影像学技术不仅可以增强肿瘤分子显像，而且可通过超声空化效应控释药物（UTMD），为肿瘤早期诊断和靶向治疗带来了新思路。但是，常用的超声分子探针存在缺点，如微泡粒径太大，不能穿过血管内皮间隙，持续时间短；纳米级的全氟辛溴（PFOB）乳剂超声显影差，且不能实现UTMD控释。这限制了超声分子探针的进一步应用。在NSFC等支持下，我们的前期实验表明，低功率超声可以促进低沸点的液态氟碳纳米粒（PFH）发生液气相转变。本课题拟以脂质为膜材，以PFH为核心，针对卵巢癌细胞高表达的叶酸受体，研发一种载紫杉醇（PTX）的、具有液气相变能力的纳米超声分子探针，使纳米粒靶向聚集于卵巢癌组织；通过低功率超声辐照，促使其在肿瘤区域相变，产生微泡并释放PTX，从而实现卵巢癌的超声分子显像与靶向治疗。通过阐明液气相变以及药物释放的体内外机制及条件探索，以期建立一种新型、高效的肿瘤超声分子显像与药物靶向传递模式。

摘要：卵巢癌是临床最常见的妇科肿瘤之一，其发病率和死亡率高居不下。对卵巢癌的早期诊断并加以有效治疗是临床一直追寻的目标。超声分子影像学借助于分子探针，从分子水平解决卵巢癌的早期诊断和动态监控带来曙光，既能对肿瘤细胞发生、发展的过程在体显示，又能在分子显像的监控下对肿瘤进行靶向的药物治疗。本课题以卵巢癌细胞高表达的叶酸受体为靶点，制备出一种以相变液态氟碳材料PFH为核心的，脂质材料为壳材的包载化疗药物PTX的，靶向相变液态氟碳纳米超声分子探针，使其选择性浓聚于卵巢癌细胞表面，或被卵巢癌细胞吞噬，并通过低功率聚焦超声的辐照，使载药纳米超声分子探针发生液气相变，实现卵巢癌的超声分子显像，同时在肿瘤局部甚至肿瘤细胞内部释放PTX，杀灭癌细胞，治疗裸鼠移植瘤。在此基础上研究探讨纳米粒相变和释药的相关机制，以期建立一种新型的、高效的的肿瘤超声分子显像诊断与药物靶向治疗模式，并为超声分子影像学提供新的研究平台。