基于亞細(xì)胞半機(jī)制的藥代動(dòng)力學(xué)/藥效學(xué)模型的建立以表征聚合膠束傳遞的紫杉醇效應(yīng)

2018年11月，北京大學(xué)腫瘤醫(yī)院與腫瘤研究所癌變與轉(zhuǎn)化研究教育部重點(diǎn)實(shí)驗(yàn)室；國(guó)家藥物臨床試驗(yàn)中心；北京大學(xué)腫瘤醫(yī)院與腫瘤研究所腎癌與黑色素瘤科癌變與轉(zhuǎn)化研究教育部重點(diǎn)實(shí)驗(yàn)室；北京大學(xué)腫瘤醫(yī)院中心實(shí)驗(yàn)室；首都醫(yī)科大學(xué)北京天壇醫(yī)院藥劑科；北京大學(xué)腫瘤醫(yī)院胃腸外科；癌變與轉(zhuǎn)化研究教育部重點(diǎn)實(shí)驗(yàn)室(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；Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),   Central Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, China；Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China；Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China) Jiafu Ji老師研究團(tuán)隊(duì)在《Journal of Pharmaceutical Sciences》上發(fā)表論文：

“Development of a Subcellular Semimechanism-Based Pharmacokinetic/Pharmacodynamic Model to Characterize Paclitaxel Effects Delivered by Polymeric Micelles”

“基于亞細(xì)胞半機(jī)制的藥代動(dòng)力學(xué)/藥效學(xué)模型的建立以表征聚合膠束傳遞的紫杉醇效應(yīng)”

Abstract：

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_max
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.

摘要：

轉(zhuǎn)運(yùn)室模型被廣泛而成功地應(yīng)用于表征腫瘤化療在體內(nèi)或體外的復(fù)雜時(shí)間過(guò)程。然而，潛在的機(jī)制并沒(méi)有定量描述。本研究旨在建立基于半機(jī)制的細(xì)胞藥代動(dòng)力學(xué)/藥效學(xué)(PK/PD)模型來(lái)表征PLGA-PEG膠束傳遞紫杉醇(PTX)效應(yīng)，該模型基于藥物亞細(xì)胞分布、微管蛋白組裝水平、細(xì)胞周期偏移和由此產(chǎn)生的細(xì)胞毒性分析。人乳腺癌細(xì)胞系MCF-7分別暴露于濃度為20和40 ng/mL的PTX中。采用由膜/細(xì)胞器、細(xì)胞核和細(xì)胞骨架組成的3室模型描述了膠束包埋PTX的體外藥動(dòng)學(xué)。使用假設(shè)的效應(yīng)區(qū)來(lái)表征分配延遲。用間接響應(yīng)模型擬合微管蛋白聚合刺激的時(shí)間過(guò)程。用線性模型描述了微管蛋白聚合與G2/M細(xì)胞群的關(guān)系，用Emax模型描述了G2/M阻滯對(duì)細(xì)胞毒性的促進(jìn)作用。該模型成功地捕獲了這些數(shù)據(jù)，并定量地描述了抗有絲分裂藥物納米顆粒的細(xì)胞機(jī)制。該方法和模型可作為傳統(tǒng)體內(nèi)研究的補(bǔ)充。

該論文中，MCF-7人乳腺癌細(xì)胞的體外培養(yǎng)是使用Ausbian特級(jí)胎牛血清完成的。欲了解或購(gòu)買(mǎi)Ausbian特級(jí)胎牛血清可以聯(lián)系北京締一生物400-166-8600.