基于“适配体捕获-磁分选”评价体系的中药抗肿瘤活性成分纳米脂质体的药动学研究

Anti-tumor active ingredients of Traditional Chinese medicine (TCM) have received enough attention for their obvious curative effect. However, their clinical applications have been limited due to the poor solubility and short half-life. By nano-lioposomes (NL) modification, the increased water solubility and the desirable pharmacokinetic behavior of the ingredients could be obtained. Because NL pharmacokinetic behavior is different from traditional medicine, classic pharmacokinetic evaluation method does not determine the exact amount of NL and the free drug in vivo at the same time. Instead of determining the release, when we study the NL pharmacokinetic, the determination of total amount could lead to the virtually increases of the apparent exposure levels and biological distribution. This could provide unreliable pharmacokinetic data and seriously restrict the NL research and clinical transformation. In view of the above problems, the project would take the paclitaxel( Paclitaxel injection have been listed ) and another antitumor active ingredient -GNA(Gambogenic acid) which is also from traditional Chinese medicine (TCM), as model drug, use the NL and magnetic beads modified with adapter to build a new analysis method - "adapters catch - magnetic separation" which can accurately determine NL and free drugs. This project will carry out the pharmacokinetic research from the system level and cell level. Through in-depth research, the project would intend to make up for the deficiency of the evaluation with classic pharmacokinetic, attempt to put forward a new NL pharmacokinetic research model, provide new thinkings and methods for efficacy and safety evaluation of NL and promote the transformation of NL containing anti-tumor active ingredients of TCM to clinical.

中药抗肿瘤活性成分因其疗效确切而倍受关注，但其水溶性差、半衰期短限制其临床应用；通过纳米脂质体(NL)的包载可显著改善其水溶性及体内药动学行为。然NL药动学行为不同于传统药物，经典药动学评价方法无法同时精确测定体内NL与已释放游离药物，且以总药量代替释放药物量研究NL药动学无形中增加了表观暴露量与表观生物分布，不能为NL的安全性和有效性评价提供可靠的药动学数据，严重制约了NL的研究及临床转化。基于上述，本课题拟以已上市的紫杉醇及课题组深入研究的新藤黄酸为模型药物，采用核酸适配体修饰NL和磁珠，构建“适配体捕获-磁分选”NL评价新方法，精确测定NL药物和游离药物，并从系统水平和细胞水平进行NL药动学研究；以克服经典药动学研究方法在NL药动学评价中的不足，并尝试提出NL药动学研究新模型，为合理评估NL的有效性和安全性提供新思路与方法，进而提高中药抗肿瘤活性成分NL的临床转化。

中药抗肿瘤活性成分因其疗效确切而倍受关注，但其水溶性差、半衰期短限制其临床应用；通过纳米脂质体（NL）的包载可显著改善其水溶性及体内药动学行为。然NL药动学行为不同于传统药物，经典药动学评价方法无法同时精确测定体内NL与已释放游离药物，且以总药量代替释放药物量研究NL药动学无形中增加了表观暴露量与表观生物分布，不能为NL的安全性和有效性评价提供可靠的药动学数据，严重制约了NL的研究及临床转化。本项目以新藤黄酸、多西紫杉醇、紫杉醇为模型药物分别构建了PEG化脂质体和仿生纳米脂质体（外泌体）给药体系，并探究其体内药动学过程，发现新藤黄酸PEG化脂质体能够延长新藤黄酸在体内的半衰期。紫杉醇M1外泌体给药体系通过caspase-3介导的NF-κB信号通路改善肿瘤微环境，增强紫杉醇对乳腺癌模型的抗肿瘤效果。然后，本课题成功制备了功能化磁珠，并构建了“配体捕获-磁分选”提取、分离NL的新方法，用于精确测定生物样品中NL药物和游离药物。所制备的功能化磁珠可以在磁场存在下从血浆中有效分离超过75％的NL，分离过程仅需20分钟，并且该方法准确、精密、具有选择性和相对不受内源性物质的干扰。NL渗漏动力学研究发现脂质体在50%血浆中泄露较多，并且减少NL中胆固醇的含量会增加NL的渗漏，而PEG对NL渗漏的没有明显影响。体内药动学研究结果发现，血浆中总药物和血浆中游离药物的药代动力学参数之间存在很大差异，游离药物是血浆中的主要成分。因此，通过确定血浆中药物的总量来评估NL的体内药代动力学是不准确的。对于NL，应分别分析脂质体药物和游离药物的药代动力学，以准确了解和预测体内纳米递送系统的功效和/或毒性。研究结果克服了经典药动学研究方法在NL药动学评价中的不足。在探究多西紫杉醇PEG化脂质体体内过程中，发现ABC现象与细胞色素P450酶和核受体PXR有关，从代谢酶与核受体的角度阐明了ABC现象的机理。

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