Bismuth Mike, Katz Sharon, Mano Tamar, Aronovich Ramona, Hershkovitz Dov, Exner Agata A, Ilovitsh Tali
Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, Israel.
The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.
Nanoscale. 2022 Sep 29;14(37):13614-13627. doi: 10.1039/d2nr01367c.
Scaling down the size of microbubble contrast agents to the nanometer level holds the promise for noninvasive cancer therapy. However, the small size of nanobubbles limits the obtained bioeffects as a result of ultrasound cavitation, when operating near the nanobubble resonance frequency. Here we show that coupled with low energy insonation at a frequency of 80 kHz, well below the resonance frequency of these agents, nanobubbles serve as noninvasive therapeutic warheads that trigger potent mechanical effects in tumors following a systemic injection. We demonstrate these capabilities in tissue mimicking phantoms, where a comparison of the acoustic response of micro- and nano-bubbles after insonation at a frequency of 250 or 80 kHz revealed that higher pressures were needed to implode the nanobubbles compared to microbubbles. Complete nanobubble destruction was achieved at a mechanical index of 2.6 for the 250 kHz insonation 1.2 for the 80 kHz frequency. Thus, the 80 kHz insonation complies with safety regulations that recommend operation below a mechanical index of 1.9. in breast cancer tumor cells, the cell viability was reduced to 17.3 ± 1.7% of live cells. , in a breast cancer tumor mouse model, nanobubble tumor distribution and accumulation were evaluated by high frequency ultrasound imaging. Finally, nanobubble-mediated low frequency insonation of breast cancer tumors resulted in effective mechanical tumor ablation and tumor tissue fractionation. This approach provides a unique theranostic platform for safe, noninvasive and low energy tumor mechanotherapy.
将微泡造影剂的尺寸缩小到纳米级别为无创癌症治疗带来了希望。然而，纳米气泡的小尺寸限制了在接近纳米气泡共振频率操作时因超声空化而获得的生物效应。在此，我们表明，与远低于这些造影剂共振频率的80kHz低能量超声照射相结合时，纳米气泡可作为无创治疗弹头，在全身注射后在肿瘤中引发强大的机械效应。我们在组织模拟体模中展示了这些能力，在其中对250kHz或80kHz频率超声照射后的微泡和纳米气泡的声学响应进行比较，结果显示与微泡相比，使纳米气泡内爆需要更高的压力。对于250kHz超声照射，在机械指数为2.6时实现了纳米气泡的完全破坏；对于80kHz频率，该指数为1.2。因此，80kHz超声照射符合建议在机械指数1.9以下操作的安全规定。在乳腺癌肿瘤细胞中，细胞活力降低至活细胞的17.3±1.7%。此外，在乳腺癌肿瘤小鼠模型中，通过高频超声成像评估了纳米气泡在肿瘤中的分布和聚集情况。最后，纳米气泡介导的乳腺癌肿瘤低频超声照射导致有效的机械性肿瘤消融和肿瘤组织破碎。这种方法为安全、无创和低能量的肿瘤机械治疗提供了一个独特的诊疗平台。
