Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom Room ST409, Hong Kong SAR, PR China; School of Basic Medicine, Qingdao University, Qingdao, PR China.
Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hung Hom Room ST409, Hong Kong SAR, PR China.
Acta Biomater. 2021 Dec;136:533-545. doi: 10.1016/j.actbio.2021.09.010. Epub 2021 Sep 13.
Sonodynamic therapy (SDT) is a promising alternative for cancer therapy, understood to exert cytotoxicity through cavitation and subsequent production of large amounts of reactive oxygen species (ROS). Gas-filled protein nanostructures (gas vesicles or GVs) produced by cyanobacteria have a hollow structure similar to microbubbles and have demonstrated comparable enhancement of ultrasound imaging contrast. We thus hypothesized that GVs may act as stable nuclei for inertial cavitation to enhance SDT with improved enhanced permeability and retention (EPR) effects due to their nanometer scale. The function of GVs to mediate cavitation, ROS production, and cell-targeted toxicity under SDT was determined. In solution, we found that GVs successfully increased cavitation and enhanced ROS production in a dose- and time-dependent manner. Then, GV surfaces were modified (FGVs) to specifically target CD44 cells and accumulate preferentially at the tumor site. In vitro sonodynamic therapy (SDT) showed ROS production and tumor cell toxicity substantially elevated in the presence of FGVs, and the addition of FGVs was found to enhance cavitation and subsequently inhibit tumor growth and exert greater damage to tumors under SDT in vivo. Our results thus demonstrate that FGVs can function as stable, nanosized, nuclei for spatially accurate and cell-targeted SDT. STATEMENT OF SIGNIFICANCE: The initiation of inertial cavitation is critical for ROS generation and subsequent cellular toxicity in SDT. Thus, precise control of the occurrence of cavitation is a key factor in increasing SDT's therapeutic efficacy. We explored nanometer-sized gas vesicles (GVs) as a new class of cavitation nuclei for molecule-specific sonodynamic therapy. Our results showed that GV-mediated SDT treatment enabled targeted disruption of specific cells expressing a known surface marker within the area of insonation, providing a spatially specific and targeted SDT treatment.
声动力学疗法（SDT）是一种很有前途的癌症治疗替代方法，据认为它通过空化作用和随后产生大量活性氧（ROS）发挥细胞毒性作用。蓝细菌产生的充气体蛋白纳米结构（气腔或 GV）具有类似于微泡的中空结构，并已证明可在超声成像对比度方面具有相当的增强作用。因此，我们假设 GV 可能作为惯性空化的稳定核，通过其纳米级尺寸增强 SDT，从而改善增强通透性和保留（EPR）效应。研究了 GV 在 SDT 下介导空化、ROS 产生和细胞靶向毒性的作用。在溶液中，我们发现 GV 成功地增加了空化并以剂量和时间依赖的方式增强了 ROS 的产生。然后，对 GV 表面进行了修饰（FGV）以特异性靶向 CD44 细胞并优先在肿瘤部位积累。体外声动力学疗法（SDT）显示，在 FGV 的存在下，ROS 的产生和肿瘤细胞毒性显著增加，并且发现添加 FGV 可以增强空化，从而抑制肿瘤生长并在体内 SDT 下对肿瘤造成更大的损害。我们的结果表明，FGV 可以作为稳定的纳米级核，用于空间精确和细胞靶向的 SDT。 意义声明：惯性空化的引发对于 SDT 中 ROS 的产生和随后的细胞毒性至关重要。因此，精确控制空化的发生是提高 SDT 治疗效果的关键因素。我们探索了纳米级气腔（GV）作为一种新的空化核，用于分子特异性声动力学疗法。我们的结果表明，GV 介导的 SDT 治疗能够靶向破坏在照射区域内表达已知表面标记的特定细胞，提供了一种空间特异性和靶向性的 SDT 治疗。
