基于PXR-P-gp/MRP2信号轴探讨PEG化脂质体产生ABC现象机理

体内重复注射PEG化脂质体(PEG-Lip)会产生“加速血液清除”现象（ABC现象），导致二次注射的PEG-Lip在体内清除加快，其发生机理尚未阐明。课题组前期研究发现核受体孕烷X受体（PXR）通过调控下游靶基因CYP3A1的转录参与诱导ABC现象。由于外排转运蛋白P-gp和MRP2也受到PXR的转录调控，PXR的激活也可能导致靶基因P-gp和MRP2表达和活性的改变。据此假说PXR-P-gp/MRP2信号轴参与诱导ABC现象的发生。本项目拟采用痕量标记方法考察PEG-Lip在体内的药动学行为，探究PXR-P-gp/MRP2信号轴在ABC现象发生过程中的作用及机理，并在体外验证PXR-P-gp/MRP2信号轴对ABC现象的调控机理。从PXR-P-gp/MRP2信号轴角度阐明ABC现象发生的机制，为ABC现象和PEG-Lip体内过程研究提供新视角，也为PEG-Lip转化和临床应用提供依据。

Repeated injection of PEGylated liposomes (PEG-Lip) in vivo will produce the phenomenon of "accelerating blood clearance" (ABC phenomenon), resulting in the accelerated elimination of PEG-Lip from the second injection in vivo. However, its mechanism has not been fully elucidated. Previous studies have found that the nuclear receptor pregnane X receptor (PXR) participates in the occurrence of ABC phenomenon by regulating the transcription of its downstream target gene CYP3A1. The activation of PXR will lead to changes in the expression and activity of P-gp and MRP2 in its target gene transporter. According to this hypothesis, the PXR-P-gp/MRP2 signal axis participates and induces the occurrence of ABC phenomenon. This project intends to use trace labeling method to investigate the pharmacokinetic behavior of PEG-Lip in vivo, and to explore the role and mechanism of PXR-P-gp/MRP2 signal axis in the generation of ABC phenomenon. We also verified that the PXR-P-gp/MRP2 signal axis regulates the ABC phenomenon in vitro. Elucidating the mechanism of ABC phenomenon from the perspective of PXR-P-gp/MRP2 signal axis provides a new perspective for the research of ABC phenomenon and PEG-Lip in vivo. It also provides a basis for PEG-Lip conversion and clinical application.