聚合物纳米胶束对淫羊藿黄酮类化合物代谢特征的影响及其抗肿瘤药效物质基础研究

Epimedium flavonoids have a wide range of pharmacological effects. In recent years, its anti-tumor activity has attracted a lot of people's attention as Icaritin, an anti-advanced hepatocellular carcinoma drug has successfully entered the phase III clinical trials. However, some studies have revealed that the bioavailability of epimedium flavonoids is low, affecting its druggability. Based on the previous work, this project comprises the targeted design of PLA-PNIPAAm/PLA-PEG@Au polymer nanomicelles to alter the in vivo absorption and distribution process of epimedium flavonoids, and the utilization of gold nanoflower’s photothermal effect to achieve targeted release of the compound in tumors in situ. In terms of analysis technology, the chromatography-mass spectrometry and microdialysis techniques were applied in combination with the mass spectral trees similarity filter (MTSF) technology to achieve the monitoring of in vivo process of nano-drug and provide new analytical method for the in vivo metabolism of nano-drugs. The bio-statistics method was adopted to construct the dose-effect relationship of epimedium flavonoids in vivo and discover the exposed components of epimedium related to the efficacy, which can provide a basis for the drug development of epimedium flavonoids from the perspective of drug metabolism.

近些年因为国家一类抗晚期肝细胞癌新药阿可拉定（淫羊藿素）成功进入III期临床阶段，淫羊藿黄酮类化合物的抗肿瘤活性引起了人们的广泛关注。但是已有研究表明该类化合物药代特性差，体内生物利用度低，这影响了这类化合物的成药性。本项目基于前期工作基础，针对性的设计PLA-PNIPAAm/PLA-PEG@Au聚合物纳米胶束来改变淫羊藿黄酮类化合物的体内代谢分布过程，并利用金纳米花的光热效应实现化合物肿瘤原位的靶向释放。在分析技术方面，运用色谱质谱技术和微透析技术，结合质谱树状图相似度过滤（mass spectral trees similarity filter，MTSF）技术，实现纳米药物体内过程的动态监控，为纳米药物的体内代谢过程研究提供新的分析思路。项目采用生物统计学方法，构建淫羊藿黄酮类化合物体内成分的量效关系，找到与药效相关的淫羊藿体内暴露成分，从药物代谢角度为淫羊藿黄酮成分的开发提供依据。

淫羊藿黄酮类化合物的抗肿瘤活性引起了人们的广泛关注。但是已有研究表明该类化合物药代特性差，体内生物利用度低，这影响了这类化合物的成药性。本项目通过大分子引发剂成功合成了PEG-PLLA / PDLA-PNIPAM聚合物载体材料，采用乳化法制备了PEG-PLLA / PDLA-PNIPAM-ICA和F127-ICA载药胶束。PEG-PLLA / PDLA-PNIPAM聚合物胶束的粒径分布、Zeta电位大小、EE%和DL%分别为（128.53 ± 4.89）nm、（−3.50 ± 0.57）mV、（85.76 ± 1.90）%和（7.74 ± 0.17）%，F127聚合物胶束的粒径分布、Zeta电位大小、EE%和DL%分别为（177.76 ± 3.23）nm、（−3.26 ± 0.67）mV、（70.86 ± 2.19）%和（6.45 ± 1.78）%。在48 h内PEG-PLLA / PDLA-PNIPAM较F127聚合物胶束稳定性好。分别在pH 1.2、6.8和7.4释放介质中进行体外释放实验，PEG-PLLA / PDLA-PNIPAM-ICA聚合胶束缓释效果均优于F127-ICA聚合物胶束。PEG-PLLA / PDLA-PNIPAM所产生的细胞毒性均小于F127所产生的。此外，体内实验表明，ICA在PEG-PLLA / PDLA-PNIPAM聚合物胶束中的生物利用度明显高于传统的Pluronic F127胶束中的ICA和单体ICA。最后，构建了肿瘤动物模型，将金纳米花和PEG-PLLA/PDLA-PNIPAM载体进行乳化混合，通过近红外激光定点照射裸鼠肿瘤组织实现了药物的原位释放，药效学结果表明，构建的原位治疗模型，可以提升淫羊藿素（阿可拉定）的治疗效果。