Department of Biomedical Engineering, University of California at Davis, Davis, California 95616, USA.
Med Phys. 2013 Aug;40(8):083301. doi: 10.1118/1.4813299.
Ultrasound-induced mild hyperthermia has advantages for noninvasive, localized and controlled drug delivery. In this study, a tissue-mimicking agarose-based phantom with a thermally sensitive indicator was developed for studying the spatial drug delivery profile using ultrasound-induced mild hyperthermia.
Agarose powder, regular evaporated milk, Dulbecco's phosphate-buffered saline (DPBS), n-propanol, and silicon carbide powder were homogeneously mixed with low temperature sensitive liposomes (LTSLs) loaded with a self-quenched near-infrared (NIR) fluorescent dye. A dual-mode linear array ultrasound transducer was used for insonation at 1.54 MHz with a total acoustic power and acoustic pressure of 2.0 W and 1.5 MPa, respectively. After insonation, the dye release pattern in the phantom was quantified based on optical images, and the three-dimensional release profile was reconstructed and analyzed. A finite-difference time-domain-based algorithm was developed to simulate both the temperature distribution and spatial dye diffusion as a function of time. Finally, the simulated dye diffusion patterns were compared to experimental measurements.
Self-quenching of the fluorescent dye in DPBS was substantial at a concentration of 6.25×10(-2) mM or greater. The transition temperature of LTSLs in the phantom was 35 °C, and the release reached 90% at 37 °C. The simulated temperature for hyperthermia correlated with the thermocouple measurements with a mean error between 0.03±0.01 and 0.06±0.02 °C. The R2 value between the experimental and simulated spatial extent of the dye diffusion, defined by the half-peak level in the elevation, lateral and depth directions, was 0.99 (slope=1.08), 0.95 (slope=0.99), and 0.80 (slope=1.04), respectively, indicating the experimental and simulated dye release profiles were similar.
The combination of LTSLs encapsulating a fluorescent dye and an optically transparent phantom is useful for visualizing and modeling drug release in vitro following ultrasound-induced mild hyperthermia. The coupled temperature simulation and dye-diffusion simulation tools were validated with the experimental system and can be used to optimize the thermal dose and spatial and temporal dye release pattern.
超声诱导的轻度热疗具有非侵入性、局部性和可控性给药的优点。本研究开发了一种基于琼脂糖的组织模拟体，该模拟体含有热敏指示剂，用于研究超声诱导的轻度热疗下的空间药物输送分布。
将琼脂糖粉末、普通炼乳、杜氏磷酸盐缓冲盐水（DPBS）、正丙醇和碳化硅粉末与装载自猝灭近红外（NIR）荧光染料的低温敏感脂质体（LTSL）均匀混合。使用双模线性阵列超声换能器在 1.54MHz 下进行超声，总声功率和声压分别为 2.0W 和 1.5MPa。超声后，根据光学图像定量测定体模中的染料释放模式，并对三维释放分布进行重建和分析。开发了一种基于有限差分时间域算法的方法，以模拟随时间变化的温度分布和空间染料扩散。最后，将模拟的染料扩散模式与实验测量结果进行比较。
在浓度为 6.25×10(-2)mM 或更高时，DPBS 中荧光染料的自猝灭作用显著。体模中 LTSL 的相变温度为 35°C，在 37°C 时释放达到 90%。高温疗法的模拟温度与热电偶测量结果相关，平均误差在 0.03±0.01 至 0.06±0.02°C 之间。实验和模拟的空间扩展的染料扩散的 R2 值（通过垂直、水平和深度方向的半峰高水平定义）分别为 0.99（斜率=1.08）、0.95（斜率=0.99）和 0.80（斜率=1.04），表明实验和模拟的染料释放分布相似。
封装荧光染料的 LTSL 和光学透明体模的组合可用于可视化和模拟超声诱导的轻度热疗后体外药物释放。结合温度模拟和染料扩散模拟工具与实验系统进行了验证，并可用于优化热剂量和时空染料释放模式。
