Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan.
Med Phys. 2022 Apr;49(4):2761-2773. doi: 10.1002/mp.15544. Epub 2022 Mar 3.
Gold nanodroplets (AuNDs) have been proposed as agents for photothermal therapy and photoacoustic imaging. Previously, we demonstrated that the sonoporation can be more effectively achieved with synchronized optical and acoustic droplet vaporization. By applying a laser pulse at the rarefactional phase of the ultrasound (US) pulse, the vaporization threshold can be reached at a considerably lower laser average power. However, a large loading quantity of the AuNDs may increase the risk of air embolism. The destruction of phase-shifted AuNDs at the inertial cavitation stage leads to a reduced drug delivery performance. And it also causes instability of echogenicity during therapeutic monitoring.
In this study, we propose to further improve the sonoporation effectiveness with repeated vaporization. In other words, the AuNDs repeatedly undergo vaporization and recondensation so that sonoporation effects are accumulated over time at lower energy requirements. Previously, repeated vaporization has been demonstrated as an imaging contrast agent. In this study, we aim to adopt this repeated vaporization scheme for sonoporation.
Perfluoropentane NDs with a shell made of human serum albumin were used as the US contrast agents. Laser pulses at 808 nm and US pulses of 1 MHz were delivered for triggering vaporization and inertial cavitation of NDs. We detected the vaporization and cavitation effects under different activation firings, US peak negative pressures (PNPs), and laser fluences using 5- and 10-MHz focused US receivers. Numbers of calcein-AM and propidium iodide signals uptake by BNL hepatocarcinoma cancer cells were used to evaluate the sonoporation and cell death rate of the cells.
We demonstrate that sonoporation can be realized based on repeatable vaporization instead of the commonly adopted inertial cavitation effects. In addition, it is found that the laser fluence and the acoustic pressure can be reduced. As an example, we demonstrate that the acoustic and optical energy for achieving a similar level of sonoporation rate can be as low as 0.44 MPa for the US PNP and 4.01 mJ/cm for the laser fluence, which are lower than those with our previous approach (0.53 MPa and 4.95 mJ/cm , respectively).
We demonstrated the feasibility of vaporization-based sonoporation at a lower optical and acoustic energy. It is an advantageous method that can enhance drug delivery efficiency, therapeutic safety and potentially deliver an upgraded gene therapy strategy for improved theragnosis.
金纳米液滴（AuNDs）已被提议用作光热疗法和光声成象的试剂。以前，我们证明了通过同步光学和声学液滴蒸发可以更有效地实现声孔作用。通过在超声波（US）脉冲的稀疏相施加激光脉冲，可以在相当低的激光平均功率下达到蒸发阈值。然而，AuNDs 的大量负载可能会增加空气栓塞的风险。惯性空化阶段中相移 AuNDs 的破坏导致药物输送性能降低。并且在治疗监测过程中也会导致回声强度不稳定。
在这项研究中，我们提出通过重复蒸发进一步提高声孔作用效果。换句话说，AuNDs 反复经历蒸发和再冷凝，从而在较低的能量需求下随时间积累声孔作用效果。以前，已经证明重复蒸发是一种成像造影剂。在这项研究中，我们旨在采用这种重复蒸发方案进行声孔作用。
使用壳为人血清白蛋白的全氟戊烷 ND 作为 US 造影剂。808nm 的激光脉冲和 1MHz 的 US 脉冲用于触发 ND 的蒸发和惯性空化。我们使用 5MHz 和 10MHz 聚焦 US 接收器在不同的激活射击、US 峰负压（PNP）和激光通量下检测蒸发和空化效应。通过 BNL 肝癌癌细胞摄取 calcein-AM 和碘化丙啶信号的数量来评估细胞的声孔作用和细胞死亡率。
我们证明可以基于可重复的蒸发而不是通常采用的惯性空化效应来实现声孔作用。此外，发现可以降低激光通量和声压。例如，我们证明，实现类似声孔率的声能和光能可以低至 US PNP 为 0.44MPa 和激光通量为 4.01mJ/cm，低于我们以前的方法（分别为 0.53MPa 和 4.95mJ/cm）。
我们证明了在较低的光学和声学能量下基于蒸发的声孔作用的可行性。这是一种有利的方法，可以提高药物输送效率、治疗安全性，并有可能提供升级的基因治疗策略，以提高治疗效果。
