基于亞細胞半機制的藥代動力學/藥效學模型的建立以表征聚合膠束傳遞的紫杉醇效應

2018年11月，北京大學腫瘤醫院與腫瘤研究所癌變與轉化研究教育部重點實驗室；國家藥物臨床試驗中心；北京大學腫瘤醫院與腫瘤研究所腎癌與黑色素瘤科癌變與轉化研究教育部重點實驗室；北京大學腫瘤醫院中心實驗室；首都醫科大學北京天壇醫院藥劑科；北京大學腫瘤醫院胃腸外科；癌變與轉化研究教育部重點實驗室(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老師研究團隊在《Journal of Pharmaceutical Sciences》上發表論文：

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

“基于亞細胞半機制的藥代動力學/藥效學模型的建立以表征聚合膠束傳遞的紫杉醇效應”

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：

轉運室模型被廣泛而成功地應用于表征腫瘤化療在體內或體外的復雜時間過程。然而，潛在的機制并沒有定量描述。本研究旨在建立基于半機制的細胞藥代動力學/藥效學(PK/PD)模型來表征PLGA-PEG膠束傳遞紫杉醇(PTX)效應，該模型基于藥物亞細胞分布、微管蛋白組裝水平、細胞周期偏移和由此產生的細胞毒性分析。人乳腺癌細胞系MCF-7分別暴露于濃度為20和40 ng/mL的PTX中。采用由膜/細胞器、細胞核和細胞骨架組成的3室模型描述了膠束包埋PTX的體外藥動學。使用假設的效應區來表征分配延遲。用間接響應模型擬合微管蛋白聚合刺激的時間過程。用線性模型描述了微管蛋白聚合與G2/M細胞群的關系，用Emax模型描述了G2/M阻滯對細胞毒性的促進作用。該模型成功地捕獲了這些數據，并定量地描述了抗有絲分裂藥物納米顆粒的細胞機制。該方法和模型可作為傳統體內研究的補充。

該論文中，MCF-7人乳腺癌細胞的體外培養是使用Ausbian特級胎牛血清完成的。欲了解或購買Ausbian特級胎牛血清可以聯系北京締一生物400-166-8600.