肿瘤微血管内外微泡和相变液滴定位复合超分辨超声成像及其引导的液滴介导药物递送

高分辨图像引导下的肿瘤药物递送对于实现个体化治疗，提高治疗效率具有非常重要的意义。本项目针对缺乏高分辨图像引导和评价深部肿瘤治疗药物递送这个难题，旨在研究：1)基于肿瘤微血管内多微泡定位追踪的快速超分辨超声成像方法，以得到具有微米分辨尺度的肿瘤微血管结构超分辨图像；2)设计制备磁性相变纳米液滴作为肿瘤治疗的药物递送载体和造影剂前休，并利用分段超声控制方法，即磁/声协同调控促进其跨越微血管内皮屏障，再在组织内的声致相变、空化增强释药；3)基于肿瘤组织内相变微泡特性，发展定位显微超分辨超声成像方法，在实现肿瘤微血管超分辨成像的基础上进一步获得血管外液滴分布的超分辨超声图像。最终形成肿瘤血管内、外微泡和纳米液滴定位复合超分辨成像技术，对载药磁/声响应纳米液滴在肿瘤部位的密度分布、跨血管壁递送以及超声激励相变释放药物的治疗过程进行图像引导和监控，达到高效精准递送释放和超分辨成像监控成像的双重目的。

Based on the effective delivery of drug carriers across tumor vascular barriers to tumor tissue, this project proposes and investigates a super-resolution ultrasound imaging with a resolution of tens of micron, to monitor in vivo distribution and releasing process of drug carriers for image guided drug delivery, thereby offering precise and effective treatment for tumors. The project is focused on: 1)a fast super-resolution ultrasound imaging method based on multiple microbubble tracking in tumor microvessel; 2) The magnetic phase-shifted nanodroplets were designed to be used as drug delivery carriers for tumor treatment. After their accumulation within the tumor site through magnet/ultrasound synergistic manipulation, they could vaporize into detectable phase-shifted microbubble for imaging under ultrasound exposure, and will furtherly collapse to release their loaded drug; 3) a super-resolution ultrasound imaging method based on acoustic activated localization of nanodroplets within the tumor tissue outside the tumor microvessel, to obtain the super-resolution image of the nanodroplets that were used as drug carriers and extravasated from the leaky vasculature of tumor, in addition to above-mentioned super-resolution image of tumor microvasculature. These super-resolution images of the inside and outside of the microvessel could be used for image-guided drug delivery and monitoring the nanodroplets density distribution within tumor, nanodroplets delivery across the microvascular barriers and ultrasound triggered drug release from the nanodroplets for tumor therapy, thereby to achieve the double purpose of highly effective, precised drug delivery and release, and monitoring under the super-resolution ultrasound images.