生物可降解固泡型(超声/核磁)显影增强剂及其靶向释药溶栓功能研究

Myocardial infarction may be delayed or cured by correct early diagnosis and proper treatment. By now ultrasonography is the preferred method in clinic which can be remarkably enhanced by bubble-type ultrasonic contrast agent (UCA). Commercial UCAs are usually composed of liquid or lipidosome bubbles with excellent imaging enhancing properties, but they still have some disadvantages, such as short sonography time, lack of multiple imaging modalities, none additional healing function. Solid bubbles manufactured by routine technique can not be commercialized for its broad particle size distribution and the resulting risk of pulmonary and capillary embolism. In this study, we employ a premix membrane emulsification technique to prepare uniform sized biodegradable polylactone microcapsules as a ultrasound contrast agent. Furthermore, we will load magnetic nanoparticles in the shell of the solid bubbles to attach Magnetic Resonance Imaging (MRI) function, and load thrombolytic drug to attach drug release and ultrasonic responsive drug release function. The advantages of this microbubbles include uniform size distribution, long imaging time and ultrasonic responsive drug release. We will control the types and ratio of momomers, and the synthetic strategy to study the relationship between polymer and ultrasonic imaging enhancement. We will study the biocompatibility, drug release and ultrasonic drug release behaviors in vitro and in vivo. The ultimate goal is a combination of ultrasonic imaging, MRI and responsive drug release for early diagnosis and therapy.

对心血管病进行早期诊断和治疗可延缓乃至避免急性心肌梗死。超声造影是目前首选的诊断技术。液泡和脂质体微囊造影剂可显著增强影像对比度，实现早期诊断，但显影时间较短、难以实现多模显影、无法附加治疗功能；常规技术制备的固体微泡粒径分布宽，生物安全性难以保证，尚无商用产品。本研究拟采用生物相容性良好的可降解聚酯，通过快速膜乳化技术，构建固体微泡超声造影剂；微泡壳层物理共混磁性纳米粒子，实现超声/核磁双造影功能；微泡内部负载药物实现药物缓释与超声响应性释放功能。该微泡具有粒径接近单分散、造影增强时间长、可超声控制释药等优点。通过材料成分选择和工艺参数调控，研究微泡的成分结构与造影增强效果之间的关系；通过体外和动物实验，研究微泡的生物相容性、药物缓释与响应性控释、局部血栓溶解等性能。最终实现超声造影、核磁造影、药物控释三种功能多种组合的诊疗一体造影剂制备，为心血管病的诊断与治疗提供新思路和新技术。

对心血管疾病和实体肿瘤患处精准成像并获取血流信息，可以显著提高这类疾病的早期诊断率，实现精准地诊断和治疗。超声造影是目前首选的诊断技术，但当前的超声造影增强剂存在显影时间较短、难以实现多模显影、无法附加治疗功能等不足，本项目针对这些问题，开发了一种新型的固泡超声/核磁多模造影增强剂：①以生物相容性良好的聚内酯类高分子为基材，通过快速膜乳化制备了平均粒径为2-8微米、粒径分布接近单分散（DPI<0.1）的固体微泡；通过共聚的方式在聚内酯分子中引入亲水性的PEG链段，改善了微泡的亲水性。②制备了粒径为4、6、8 nm的磁性四氧化三铁粒子，成功将其负载到聚内酯微泡壳层，验证了其高顺磁性。③通过体外/内实验验证了该材料制备的微泡具备良好的细胞相容性和血液相容性，实现了在体内的长循环；通过体外模拟实验验证了微泡的超声/核磁增强效果并优化了微泡结构。④在微泡中负载了抗肿瘤药，探明了药物释放的规律，并在动物实验中验证了肿瘤药物在超声、磁场作用下在体内的富集和靶向规律，实现了超声/核磁双模造影和药物的可控靶向释放，并通过负载生长因子和生物活性物质促进了骨缺损修复，证明了诊疗一体材料在心血管疾病、肿瘤治疗及组织修复方面的潜力。