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. 2017 Apr 3;7(6):1477-1488.
doi: 10.7150/thno.19099. eCollection 2017.

Theranostic Performance of Acoustic Nanodroplet Vaporization-Generated Bubbles in Tumor Intertissue

Yi-Ju Ho  1 , Chih-Kuang Yeh  1
Affiliations

Theranostic Performance of Acoustic Nanodroplet Vaporization-Generated Bubbles in Tumor Intertissue

Yi-Ju Ho et al. Theranostics. .

Abstract

Solid tumors with poorly perfused regions reveal some of the treatment limitations that restrict drug delivery and therapeutic efficacy. Acoustic droplet vaporization (ADV) has been applied to directly disrupt vessels and release nanodroplets, ADV-generated bubbles (ADV-Bs), and drugs into tumor tissue. In this study, we investigated the in vivo behavior of ADV-Bs stimulated by US, and evaluated the possibility of moving intertissue ADV-Bs into the poorly perfused regions of solid tumors. Intravital imaging revealed intertissue ADV-B formation, movement, and cavitation triggered by US, where the distance of intertissue ADV-B movement was 33-99 µm per pulse. When ADV-Bs were applied to tumor cells, the cell membrane was damaged, increasing cellular permeability or inducing cell death. The poorly perfused regions within solid tumors show enhancement due to ADV-B accumulation after application of US-triggered ADV-B. The intratumoral nanodroplet or ADV-B distribution around the poorly perfused regions with tumor necrosis or hypoxia were demonstrated by histological assessment. ADV-B formation, movement and cavitation could induce cell membrane damage by mechanical force providing a mechanism to overcome treatment limitations in poorly perfused regions of tumors.

Keywords: acoustic droplet vaporization; bubble cavitation.; intertissue bubbles; nanodroplets; poorly perfused regions.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The concept of ADV-B movement into the poorly perfused regions in the intertissue by US stimulation.
Figure 2
Figure 2
(A) The acousto-optical system is used to observe the in vitro and in vivo behaviors of ADV-Bs in a cellular tube, window chamber model, and cell dish. (B) Image enhancement after ADV-B formation in an agarose phantom and solid tumor model induced by US sonication is monitored and guided by the US imaging system. After US sonication, both window chamber and solid tumor models show hemorrhage and petechiae in the post-US photos.
Figure 3
Figure 3
(A) The size distribution and cryotransmission electron microscope image of DiI-NDs. (B) High speed images of ADV-B formation by 5000-cycle single pulse with various acoustic pressures. (C) The US imaging, size distribution, and quantification of enhancement for ADV-Bs († p<0.01).
Figure 4
Figure 4
Intravital images for (A) intravascular and intertissue ADV-B formation, (B) intertissue ADV-Bs movement, (C) distance per pulse of intertissue ADV-B movement (* p<0.05, † p<0.01), and (D) intravascular and intertissue ADV-B cavitation. The arrows indicate new ADV-Bs formation.
Figure 5
Figure 5
Cellular bioeffects induced by ADV and ADV-B movement. (A) Cells were blown away and PI diffusion after ADV. Cells were damaged by ADV-B (B) pulling and (C) shoving. The arrows indicate damaged cells with PI diffusion.
Figure 6
Figure 6
(A) The US enhancement images of solid tumors in the DiI-NDs+US+movement group. The post-movement image shows enhancement of ADV-B accumulation in the poorly perfused region (dotted circles). (B) The ratios of gray level within tumors in various experimental groups († p<0.01). (C) The ratios of gray level within the poorly perfused regions and (D) corresponding US images for four tumor-bearing mice during ADV-B formation and movement. The dotted circles indicate the poorly perfused regions defined by MB perfusion imaging.
Figure 7
Figure 7
(A) Histological images of whole tumors with H&E staining and DiI indicate tissue necrosis and the distribution of DiI-NDs and ADV-Bs, respectively. The squares with number are the locations of high magnification images below. (B) The intratumoral distribution of necrosis and hemorrhage, DiI-NDs and ADV-Bs, vessels, and hypoxic cells are shown in the H&E, DiI (red), CD31 (green), and HIF-1α (blue) images, respectively.
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