抗癌前药选择性差、易耐药是其化疗失败的主要原因。如何同时提高前药的靶向性和向抗癌活性物质转化的速率来增强疗效，是迄今亟待解决的难题。PEG化脂质体（PEG-L）是抗癌研究的重点药物递送系统，其重复注射产生的“加速血液清除”（ABC）现象促使PEG-L向肝脏蓄积。申请人前期研究发现ABC现象发生的同时CYP3A酶也被激活，导致其底物代谢加速。基于此，本项目将首次利用PEG-L包载经CYP3A代谢的抗癌前药为模型，旨在结合ABC现象的肝蓄积性和CYP3A激活的独特优势，探讨其治疗原发性肝癌（HCC）的机制；拟采用原位肝灌流技术研究预先注射PEG-L对HCC大鼠肝摄取PEG-L的影响，通过液-质联用分析ABC现象对HCC大鼠体内PEG-L分布和代谢的影响，阐明酶活性、前药活性代谢物浓度及药效三者之间的内在关联，诠释PEG-L重复注射治疗HCC的优势及机制，为临床高效、低毒治疗HCC提供科学依据。

Hepatocellular carcinoma (HCC) has been the fast-rising cause of cancer-related deaths. The development of low toxic prodrugs that could be activated by certain enzymes is also not a rational approach for the treatment of HCC, owing to poor selectivity and the emergence of multidrug resistance in chemotherapy. However, so far there have been few studies on anticancer prodrug models that simultaneously show strong targeting and high rate of transformation to anticancer active substances. To bridge this knowledge gap, we and other researchers have previously reported repeated injection of PEGylated liposomes (PEG-L) at certain intervals to the same animal lead to the disappearance of their long-circulating properties and following an extremely increased accumulation in the liver, referred to as “accelerated blood clearance (ABC)” phenomenon. Evidence from our recent studies suggest the increased activities and expression of cytochrome P450s (P450s), especially CYP3A partly contribute to the induction of the ABC phenomenon. Based on the CYP3A activation and liver-targeted characteristic of ABC phenomenon, this study was undertaken to employ two prodrugs metabolized by CYP3A, acted as anticancer model prodrugs for preparing PEGylated anticancer-drug liposomes. We aim to explore whether repeated injection of PEG-L would be more beneficial to the therapy of HCC and its related mechanism. In situ liver perfusion method will be performed to assess the effect of pretreatment with PEG-L on the uptake of the second injection by liver cells in HCC rats. For the purpose of investigating the impact of ABC phenomenon on the bio-distribution and metabolism of PEG-L in HCC rats, liquid chromatography-tandem mass spectrometry will be used for quantitative analysis. The internal relationship among CYP3A activity, active metabolites of anticancer prodrugs and efficacy will be illuminated. Simultaneously, the drug effectiveness and toxicity between repeated injection of PEG-L and conventional administration will be compared in order to further reveal the pharmacokinetic mechanism of repeated injection of PEG-L for the treatment of HCC. The results of this study may provide a certain scientific basis for high efficient and low toxicity treatment for HCC.