Nanodroplet-mediated histotripsy for image-guided targeted ultrasound cell ablation.
Nanodroplet-mediated histotripsy for image-guided targeted ultrasound cell ablation.
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作者：
Vlaisavljevich E;Durmaz YY;Maxwell A;Elsayed M;Xu Z
这篇论文是一项初步的工作，旨在开发一种图像引导的、靶向的超声消融技术，将组织摩擦与可以选择性地输送到肿瘤细胞的纳米液滴相结合。利用极短的高压脉冲，组织摩擦学产生密集的空化微泡云，使组织分裂。我们假设包裹全氟戊烷(PFP)核心的合成纳米液滴在暴露于超声波脉冲时将转变为气体微泡，微泡将迅速膨胀和崩溃，导致细胞破坏，类似于组织摩擦过程，但声压明显较低。显著降低的空化阈值将允许组织摩擦有选择地输送到肿瘤组织，并极大地提高治疗效率，同时保留邻近的健康组织。为了验证我们的假设，我们在37℃下通过在PFP核周围自组装两亲性三嵌段共聚物，然后将聚合物外壳交联形成稳定的纳米液滴，制备了平均直径为204±4.7 nm的纳米液滴。这些纳米液滴被嵌入到含有一张红细胞(RBC)的琼脂糖组织模体中，这些RBC暴露在由500 kHz聚焦换能器施加的2周期脉冲中。用高速相机监测微泡的产生，测得在含有纳米液滴的琼脂糖模中产生气泡所需的峰值负压阈值>；50μm为10.8 Mpa，明显低于单独使用超声脉冲所观察到的28.8 Mpa。高速图像还显示，由纳米液滴产生的空化微泡在较高压力下表现出类似于单独组织摩擦检查的膨胀和崩溃。纳米液滴介导的组织摩擦检查在琼脂糖组织模体中以10赫兹的脉冲重复频率产生一致的、明确的红细胞分离，与单独组织摩擦产生的损伤相似，但压力显著降低。这些结果支持了我们的假设，并证明了使用纳米液滴介导的组织摩擦技术进行靶向细胞消融的潜力。
This paper is an initial work towards developing an image-guided, targeted ultrasound ablation technique by combining histotripsy with nanodroplets that can be selectively delivered to tumor cells. Using extremely short, high-pressure pulses, histotripsy generates a dense cloud of cavitating microbubbles that fractionates tissue. We hypothesize that synthetic nanodroplets that encapsulate a perfluoropentane (PFP) core will transition upon exposure to ultrasound pulses into gas microbubbles, which will rapidly expand and collapse resulting in disruption of cells similar to the histotripsy process but at a significantly lower acoustic pressure. The significantly reduced cavitation threshold will allow histotripsy to be selectively delivered to the tumor tissue and greatly enhance the treatment efficiency while sparing neighboring healthy tissue. To test our hypothesis, we prepared nanodroplets with an average diameter of 204±4.7 nm at 37°C by self-assembly of an amphiphilic triblock copolymer around a PFP core followed by cross-linkage of the polymer shell forming stable nanodroplets. The nanodroplets were embedded in agarose tissue phantoms containing a sheet of red blood cells (RBCs), which were exposed to 2-cycle pulses applied by a 500 kHz focused transducer. Using a high speed camera to monitor microbubble generation, the peak negative pressure threshold needed to generate bubbles >50 μm in agarose phantoms containing nanodroplets was measured to be 10.8 MPa, which is significantly lower than the 28.8 MPa observed using ultrasound pulses alone. High speed images also showed cavitation microbubbles produced from the nanodroplets displayed expansion and collapse similar to histotripsy alone at higher pressures. Nanodroplet-mediated histotripsy created consistent, well-defined fractionation of the RBCs in agarose tissue phantoms at 10 Hz pulse repetition frequency similar to the lesions generated by histotripsy alone but at a significantly lower pressure. These results support our hypothesis and demonstrate the potential of using nanodroplet-mediated histotripsy for targeted cell ablation.
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