Center for Ultrasound Molecular Imaging and Therapeutics, Heart and Vascular Medicine Institute, University of Pittsburgh. 200 Lothrop St, Pittsburgh, PA, USA.
Microvascular Therapeutics (MVT), Inc. 1635 E. 18 th Street, Tucson, AZ, USA.
Nanotheranostics. 2024 Jan 1;8(1):33-47. doi: 10.7150/ntno.85092. eCollection 2024.
Microvascular obstruction (MVO) following percutaneous coronary intervention (PCI) is a common problem associated with adverse clinical outcomes. We are developing a novel treatment, termed sonoreperfusion (SRP), to restore microvascular patency. This entails using ultrasound-targeted microbubble cavitation (UTMC) of intravenously administered gas-filled lipid microbubbles (MBs) to dissolve obstructive microthrombi in the microvasculature. In our prior work, we used standard-sized lipid MBs. In the present study, to improve upon the efficiency and efficacy of SRP, we sought to determine the therapeutic efficacy of fibrin-targeted phase shift microbubbles (FTPSMBs) in achieving successful reperfusion of MVO. We hypothesized that owing to their much smaller size and affinity for thrombus, FTPSMBs would provide more effective dissolution of microthrombi when compared to that of the corresponding standard-sized lipid MBs. MVO in the rat hindlimb was created by direct injection of microthrombi into the left femoral artery. Definity MBs (Lantheus Medical Imaging) were infused through the jugular vein for contrast-enhanced ultrasound imaging (CEUS). A transducer was positioned vertically above the hindlimb for therapeutic US delivery during the concomitant administration of various therapeutic formulations, including (1) un-targeted MBs; (2) un-targeted phase shift microbubbles (PSMBs); (3) fibrin-targeted MB (FTMBs); and (4) fibrin-targeted PSMBs (FTPSMBs). CEUS cine loops with burst replenishment were obtained at baseline (BL), 10 min post-MVO, and after each of two successive 10-minute SRP treatment sessions (TX1, TX2) and analyzed (MATLAB). binding affinity assay showed increased fibrin binding peptide (FBP) affinity for the fibrin clots compared with the untargeted peptide (DK12). Similarly, in our model of MVO, we observed a higher binding affinity of fluorescently labeled FTPSMBs with the porcine microthrombi compared to FTMBs, PSMBs, and MBs. Finally, in our hindlimb model, we found that UTMC with FTPSMBs yielded the greatest recovery of blood volume (dB) and flow rate (dB/sec) following MVO, compared to all other treatment groups. SRP with FTPSMBs achieves more rapid and complete reperfusion of MVO compared to FTMBs, PSMBs, and MBs. Studies to explore the underlying physical and molecular mechanisms are underway.
微血管阻塞（MVO）是经皮冠状动脉介入治疗（PCI）后的常见问题，与不良临床结局相关。我们正在开发一种新的治疗方法，称为声复苏（SRP），以恢复微血管通畅。这需要使用静脉内给予的含气脂质微泡（MB）的超声靶向微泡空化（UTMC）来溶解微血管中的阻塞性微血栓。在我们之前的工作中，我们使用了标准大小的脂质 MB。在本研究中，为了提高 SRP 的效率和效果，我们试图确定纤维蛋白靶向相移微泡（FTPSMB）在实现 MVO 成功再灌注方面的治疗效果。我们假设，由于其更小的尺寸和对血栓的亲和力，FTPSMB 在溶解微血栓方面将比相应的标准大小脂质 MB 更有效。通过直接向左侧股动脉注射微血栓在大鼠后肢中创建 MVO。通过颈静脉输注 Definity MB（Lantheus Medical Imaging）进行对比增强超声成像（CEUS）。在同时给予各种治疗制剂期间，将换能器垂直放置在后肢上方以进行治疗性 US 传递，包括（1）未靶向 MB；（2）未靶向相移微泡（PSMB）；（3）纤维蛋白靶向 MB（FTMB）；和（4）纤维蛋白靶向 PSMB（FTPSMB）。在基线（BL）、MVO 后 10 分钟以及两次连续 10 分钟 SRP 治疗后（TX1、TX2）获得 CEUS 电影循环，并进行分析（MATLAB）。结合亲和力测定表明，与未靶向肽（DK12）相比，纤维蛋白结合肽（FBP）对纤维蛋白凝块具有更高的结合亲和力。同样，在我们的 MVO 模型中，我们观察到荧光标记的 FTPSMB 与猪微血栓的结合亲和力高于 FTMB、PSMB 和 MB。最后，在我们的后肢模型中，我们发现与所有其他治疗组相比，用 FTPSMB 进行 UTMC 可使 MVO 后血液体积（dB）和血流速度（dB/sec）的恢复最大。与 FTMB、PSMB 和 MB 相比，FTPSMB 的 SRP 可更快、更完全地再灌注 MVO。正在进行研究以探索潜在的物理和分子机制。
