Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Int J Hyperthermia. 2012;28(4):337-48. doi: 10.3109/02656736.2012.677930.
To develop and validate a computational model that simulates (1) tissue heating with high intensity focused ultrasound (HIFU), and (2) resulting hyperthermia-mediated drug delivery from temperature-sensitive liposomes (TSL).
HIFU heating in tissue was simulated using a heat transfer model based on the bioheat equation, including heat-induced cessation of perfusion. A spatio-temporal multi-compartment pharmacokinetic model simulated intravascular release of doxorubicin from TSL, its transport into interstitium, and cell uptake. Two heating schedules were simulated, each lasting 30 min: (1) hyperthermia at 43 °C (HT) and (2) hyperthermia followed by a high temperature (50 °C for 20 s) pulse (HT+). As preliminary model validation, in vivo studies were performed in thigh muscle of a New Zealand White rabbit, where local hyperthermia with a clinical magnetic resonance-guided HIFU system was applied following TSL administration.
HT produced a defined region of high doxorubicin concentration (cellular concentration ∼15-23 µg/g) in the target region. Cellular drug uptake was directly related to HT duration, with increasing doxorubicin uptake up to ∼2 h. HT+ enhanced drug delivery by ∼40% compared to HT alone. Temperature difference between model and experiment within the hyperthermia zone was on average 0.54 °C. Doxorubicin concentration profile agreed qualitatively with in vivo fluorescence profile.
Computational models can predict temperature and delivered drug from combination of HIFU with TSL. Drug delivery using TSL may be enhanced by prolonged hyperthermia up to 2 h or by local cessation of vascular perfusion with a high temperature pulse following hyperthermia.
开发和验证一种计算模型，该模型模拟（1）高强度聚焦超声（HIFU）引起的组织加热，以及（2）热敏脂质体（TSL）介导的热疗后药物释放。
采用基于生物热方程的传热模型模拟组织中的 HIFU 加热，包括热诱导的血流停止。时空多室药代动力学模型模拟 TSL 中阿霉素的血管内释放、向间质的转运以及细胞摄取。模拟了两种加热方案，每种方案持续 30 分钟：（1）43°C 的热疗（HT）和（2）热疗后高温（50°C 持续 20s）脉冲（HT+）。作为初步的模型验证，在新西兰白兔的大腿肌肉中进行了体内研究，其中在 TSL 给药后，采用临床磁共振引导 HIFU 系统局部加热。
HT 在靶区产生了高阿霉素浓度（细胞浓度约为 15-23μg/g）的明确区域。细胞内药物摄取与 HT 持续时间直接相关，随着时间的增加，阿霉素摄取量增加到约 2 小时。与单独 HT 相比，HT+ 可将药物输送增加约 40%。在高温区，模型与实验之间的温度差平均为 0.54°C。药物浓度分布与体内荧光分布具有定性一致性。
计算模型可以预测 HIFU 联合 TSL 产生的温度和输送的药物。通过延长 HT 时间（长达 2 小时）或在 HT 后通过高温脉冲局部停止血管灌注，可以增强 TSL 的药物输送。
