Abstract

Focused Ultrasound (FUS)-triggered nano-sized drug delivery, as a smart stimuli-responsive system for treating solid tumors, is computationally investigated to enhance localized delivery of drug and treatment efficacy. Integration of thermosensitive liposome (TSL), as a doxorubicin (DOX)-loaded nanocarrier, and FUS, provides a promising drug delivery system. A fully coupled partial differential system of equations, including the Helmholtz equation for FUS propagation, bio-heat transfer, interstitial fluid flow, drug transport in tissue and cellular spaces, and a pharmacodynamic model is first presented for this treatment approach. Equations are then solved by finite element methods to calculate intracellular drug concentration and treatment efficacy. The main objective of this study is to present a multi-physics and multi-scale model to simulate drug release, transport, and delivery to solid tumors, followed by an analysis of how FUS exposure time and drug release rate affect these processes. Our findings not only show the capability of model to replicate this therapeutic approach, but also confirm the benefits of this treatment with an improvement of drug aggregation in tumor and reduction of drug delivery in healthy tissue. For instance, the survival fraction of tumor cells after this treatment dropped to 62.4%, because of a large amount of delivered drugs to cancer cells. Next, a combination of three release rates (ultrafast, fast, and slow) and FUS exposure times (10, 30, and 60 min) was examined. Area under curve (AUC) results show that the combination of 30 min FUS exposure and rapid drug release leads to a practical and effective therapeutic response.

摘要

聚焦超声（FUS）触发的纳米药物输送作为治疗实体瘤的智能刺激响应系统，经过计算研究可增强药物的局部输送和治疗效果。热敏脂质体 (TSL) 作为负载阿霉素 (DOX) 的纳米载体与 FUS 的整合提供了一种有前景的药物递送系统。首次针对这种治疗方法提出了完全耦合的偏微分方程组，包括用于 FUS 传播、生物传热、间质液流动、组织和细胞空间中的药物转运的亥姆霍兹方程，以及药效学模型。然后通过有限元方法求解方程，以计算细胞内药物浓度和治疗效果。本研究的主要目的是提出一个多物理场和多尺度模型来模拟药物释放、运输和递送到实体瘤，然后分析 FUS 暴露时间和药物释放速率如何影响这些过程。我们的研究结果不仅显示了模型复制这种治疗方法的能力，而且还证实了这种治疗的益处，即改善肿瘤中的药物聚集并减少健康组织中的药物递送。例如，由于向癌细胞输送了大量药物，这种治疗后肿瘤细胞的存活率下降至62.4%。接下来，检查了三种释放速率（超快、快速和慢速）和 FUS 暴露时间（10、30 和 60 分钟）的组合。