Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo.
Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo.
复制标题
DOI：
10.1371/journal.pone.0179131
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Haemmerich D
中科院分区：
文献类型：
--
作者：
Rossmann C;McCrackin MA;Armeson KE;Haemmerich D
温度敏感脂质体 (TSL) 是纳米颗粒，可在高温（通常高于约 40°C）下快速释放所含药物。 TSL 已与各种加热方式相结合，但对于所需的热疗持续时间或相对于 TSL 给药的理想加热时间尚未达成共识。本研究的目的是确定将 TSL 与射频消融 (RF) 加热相结合时，加热持续时间和时间变化时药物摄取的变化。我们使用计算机模型来模拟 RF 组织加热和 TSL 药物输送，以计算空间药物浓度图。我们模拟单个 RF 电极加热 5、12 和 30 分钟，以及放置在三角形阵列中的 3 个电极的三个连续 12 分钟消融。为了支持模拟结果，我们在正常肝脏中进行了猪体内研究，其中充满阿霉素（TSL-Dox）的 TSL 以 30 mg 的剂量注入 30 分钟以上。输注后，在不同的肝脏位置进行射频加热 5 分钟 (n = 2) 或 12 分钟 (n = 2)。消融后，对动物实施安乐死，并提取肝脏并冷冻。垂直于电极轴切割肝脏样本，并使用荧光成像来可视化组织阿霉素分布。体内研究和计算机模型均表明，在可见凝固组织的约 1 厘米范围内出现了环形药物沉积。药物摄取与加热持续时间直接相关。在计算机模拟中，当加热时间从 5 分钟延长至 12 分钟或 30 分钟时，药物浓度分别增加了 2.2 倍和 4.3 倍。在体内，12 分钟加热时间与 5 分钟加热时间相比，药物浓度提高了 2.4 倍（7.1 μg/g 至 3.0 μg/g）。计算机模型表明加热应定时以使封装药物的全身血浆浓度曲线下面积最大化。计算机模型和体内研究都表明，组织药物摄取与 TSL 递送的加热持续时间直接相关。计算模型能够预测空间药物输送曲线，并且可以作为理解和优化药物输送系统的有价值的工具。
Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating. We used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine in vivo studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution. Both in vivo studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. In vivo, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 μg/g to 3.0 μg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug. Both computer models and in vivo study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems.