Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China.
Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
Br J Pharmacol. 2017 Sep;174(17):2862-2879. doi: 10.1111/bph.13909. Epub 2017 Jul 30.
Effective drug delivery in the avascular regions of tumours, which is crucial for the promising antitumour activity of doxorubicin-related therapy, is governed by two inseparable processes: intercellular diffusion and intracellular retention. To accurately evaluate doxorubicin-related delivery in the avascular regions, these two processes should be assessed together. Here we describe a new approach to such an assessment.
An individual-cell-based mathematical model based on multicellular tumour spheroids was developed that describes the different intercellular diffusion and intracellular retention kinetics of doxorubicin in each cell layer. The different effects of a P-glycoprotein inhibitor (LY335979) and a hypoxia inhibitor (YC-1) were quantitatively evaluated and compared, in vitro (tumour spheroids) and in vivo (HepG2 tumours in mice). This approach was further tested by evaluating in these models, an experimental doxorubicin derivative, INNO 206, which is in Phase II clinical trials.
Inhomogeneous, hypoxia-induced, P-glycoprotein expression compromised active transport of doxorubicin in the central area, that is, far from the vasculature. LY335979 inhibited efflux due to P-glycoprotein but limited levels of doxorubicin outside the inner cells, whereas YC-1 co-administration specifically increased doxorubicin accumulation in the inner cells without affecting the extracellular levels. INNO 206 exhibited a more effective distribution profile than doxorubicin.
The individual-cell-based mathematical model accurately evaluated and predicted doxorubicin-related delivery and regulation in the avascular regions of tumours. The described framework provides a mechanistic basis for the proper development of doxorubicin-related drug co-administration profiles and nanoparticle development and could avoid unnecessary clinical trials.
在肿瘤无血管区域中进行有效的药物输送，对于多柔比星相关治疗的有希望的抗肿瘤活性至关重要，这受到两个不可分割的过程的控制：细胞间扩散和细胞内保留。为了准确评估无血管区域中与多柔比星相关的输送，应将这两个过程一起评估。在这里，我们描述了一种评估方法。
我们开发了一种基于多细胞肿瘤球体的基于单个细胞的数学模型，该模型描述了多柔比星在每个细胞层中的不同细胞间扩散和细胞内保留动力学。体外（肿瘤球体）和体内（小鼠中的 HepG2 肿瘤）定量评估并比较了 P-糖蛋白抑制剂（LY335979）和缺氧抑制剂（YC-1）的不同作用。通过在这些模型中评估正在进行的 II 期临床试验的实验性多柔比星衍生物 INNO 206，进一步测试了这种方法。
不均匀的缺氧诱导的 P-糖蛋白表达损害了远离血管的中央区域（即远离血管）中多柔比星的主动转运。LY335979 抑制了由于 P-糖蛋白引起的外排，但限制了内层细胞外的多柔比星水平，而 YC-1 联合用药特异性地增加了内层细胞中的多柔比星积累，而不影响细胞外水平。INNO 206 表现出比多柔比星更有效的分布特征。
基于单个细胞的数学模型准确评估并预测了肿瘤无血管区域中与多柔比星相关的输送和调节。所描述的框架为多柔比星相关药物联合给药方案和纳米颗粒开发提供了机制基础，并可以避免不必要的临床试验。
