Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), National Drug Clinical Trial Center, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.
J Pharm Sci. 2019 Jan;108(1):725-731. doi: 10.1016/j.xphs.2018.10.062. Epub 2018 Nov 8.
A transit compartment model was widely and successfully applied to characterize the complex time course of cancer chemotherapeutic effects in vivo or in vitro. However, the underlying mechanisms were not quantitatively depicted. This study aimed to develop a semimechanism-based cellular pharmacokinetic/pharmacodynamic (PK/PD) model to characterize paclitaxel (PTX) effect delivered by PLGA-PEG micelles which was based on analysis of drug subcellular distribution, the tubulin assembly level, the cell cycle shift, and the resulting cytotoxicity. Human breast cancer cell line MCF-7 was exposed to PTX at the concentration of 20 and 40 ng/mL. The in vitro pharmacokinetics of micelle-entrapped PTX was described by a 3-compartment model composed of membrane/organelle, nucleus, and cytoskeleton. A hypothetical effect compartment was used to characterize the distribution delay. The time course of tubulin polymerization stimulation was fitted by the indirect response model. The relationship between tubulin polymerization and G2/M cell population was described by a linear model, and the promoting effect of G2/M arrest on the cytotoxicity was characterized by the E model. The proposed model captured the data successfully and described the cellular mechanism of antimitotic drug nanoparticles quantitatively. The methodology and the resulting model could be a supplement for traditional in vivo studies.
转运隔室模型广泛而成功地应用于描述体内或体外癌症化学治疗效果的复杂时程。然而，其潜在机制并未被定量描述。本研究旨在开发一种基于半机理的细胞药代动力学/药效动力学（PK/PD）模型，以描述基于分析药物亚细胞分布、微管蛋白组装水平、细胞周期转移以及由此产生的细胞毒性的 PLGA-PEG 胶束递送的紫杉醇（PTX）的作用。将 MCF-7 人乳腺癌细胞系暴露于浓度为 20 和 40ng/mL 的 PTX 下。胶束包封的 PTX 的体外药代动力学由由膜/细胞器、核和细胞骨架组成的 3 隔室模型描述。使用假设的效应隔室来描述分布延迟。通过间接反应模型拟合微管蛋白聚合刺激的时间过程。微管蛋白聚合与 G2/M 细胞群之间的关系通过线性模型描述，G2/M 阻滞对细胞毒性的促进作用通过 E 模型进行特征描述。所提出的模型成功地捕获了数据，并定量描述了抗有丝分裂药物纳米颗粒的细胞机制。该方法和所得模型可以作为传统体内研究的补充。
