用于可控纳米粒子递送的功能化磁性微泡的设计与其在治疗血管阻塞的应用

Obstruction of critical blood vessels due to thrombosis is a leading cause of death worldwide. Currently, the low availability, diverse contraindications and severe complications of thrombolytic drugs limit their therapeutic effects. Therefore, a method for controlled targeted thrombolytic drug delivery holds great promise to improve the therapeutic efficacy for obstructed blood vessels. In this proposal, magnetic microbubbles functionalized with therapeutic nanocarriers will be designed as a targeted, ultrasound responsive drug delivery system with improved tissue penetration depth of drugs. When the functionalized magnetic microbubbles are administered by intravenous injection/infusion, they can be rapidly targeted to the obstructed locations under magnetic field. Upon a trigger of acoustic field, the therapeutic nanoparticles will be released through stable microbubble oscillations with improved tissue penetration depth of released nanoparticles due to generated shear stress on clots surface. The low ultrasound energy used to trigger stable microbubble oscillations will further reduce the risks of injuries to surrounding healthy tissues by microbubble cavitation. This proposal will first design and fabricate magnetic microbubble based thrombolytic drug delivery system, and then elucidate the key role of different parameters (i.e. magnetic and acoustic field) in their thrombolytic efficacy. This work will provide theoretical and practical basis for the development of effective therapy for obstructed blood vessels by exploring magnetic and ultrasound responsive drug carriers, and will hold great potential in translating into clinical settings.

由血栓而导致的重要血管阻塞是世界首要致死原因。目前溶栓药物低的血液半衰期以及多样的禁忌症和并发症是治疗血管阻塞类疾病所面临的重大挑战。因此溶栓药物的有效可控靶向递送是提高血管阻塞类疾病疗效的有效手段。本项目拟采用磁性微泡作为载体，同时携载包裹溶栓药物的聚合物纳米颗粒，构建磁性靶向、超声响应释放和药物组织穿透深度增强的溶栓药物递送系统。药物注射进入血管后，利用磁场操控靶向到阻塞/血栓处，施加超声诱导磁性微泡的稳定振动，既可释放药物纳米颗粒并通过微流体作用在血栓表面的剪切力提高药物在血栓中的穿透深度，又可以有效降低微泡气穴化产生的高能量对周围健康血管的损伤。本项目通过靶向、可控释放、组织穿透深度增强的一体化载药磁性微泡的构建，明确各因素对溶栓效果的影响，有望探索新型的微纳米药物载体，为开发高效的阻塞血管治疗提供有益的理论和实践依据，具有较大的理论研究意义和临床转化前景。

本研究针对当前临床和研究中用于治疗血管阻塞类疾病药物递送系统的不足，开发同时具有磁靶向性和超声响应性的微泡系统，即精准血管递送策略。首先基于纳米颗粒表面修饰和纳米颗粒之间弱的相互作用，形成了多种纳米颗粒在气液界面的自组装，形成尺寸可调的纳米颗粒包裹空气微泡，尺寸与临床医用微泡相当，具有稳定性高、磁场响应性好及生物相容性好的优点。其次设计合成了携载PTX@PLGA的磁性微泡，经磁场可靶向磁化的金属血管支架。经超声诱导微泡稳定振动后，释放的药物纳米颗粒可穿透进入血管壁组织，其血管富集浓度是未施加超声组的2倍，并具有良好的生物安全性。最后，针对血管支架处晚期易形成血栓再次堵塞血管的难题，设计合成了携载溶栓药物tPA@SiO2的磁性微泡。超声治疗组可协助纳米药物穿透进入到小鼠腿静脉栓块内部，加速血栓溶解，残留栓块比tPA治疗组降低63%。该精准递送策略可显著提高堵塞血管处药物递送效率，并降低高能量超声对血管内皮的损伤。