基于“药物/粒子”动力学差异分析的载体给药系统体内命运研究

Exploration of the in vivo dispostion and fate of active ingredients and the particles themselves of carrier drug delivery systems (CDDS) is of high scientific significance for the elucidation of underlying pharmacological and toxicological mechanisms. So far, little is known about the spatiotemporal evolution and the fate of “drug/particle”, as a dynamic pair, due to the lack of functional quantification methods for the particles. Therefore, this project aims to establish workable methods for the quantification of the particulate carriers, and thereby set up the particokinetics model; it is expected that the in vivo fate of either drug or particles and real-time in vivo drug release characteristics are to be elucidated following differential analysis of the pharmacokinetic (drug) and particokinetic (particle) data obtained. The hypothesis will be testified using paclitaxel as a model drug and both methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles and methoxy polyethylene glycol-poly(d,l-lactic acid) (mPEG-PDLLA) polymeric micelles as model particles following either intravenous or peroral administration. The total drug levels, including both free and bound drugs, will be monitored by conventional chromatographic methods or radiation counting methods. Quantification of the particles in biological samples will be achieved by monitoring the level of particles per se after labeling the particles with water-quenching near-infrared fluorescent probes. Upon differential analysis of “drug/particle” kinetics, the dynamic evolution of both the particulate carriers and free drugs will be unraveled. The successful implementation of this project tends to provide a new mentality for complete unraveling of the in vivo disposition and fate of “drug/particle” of CDDS. The thoughts, concepts, methods and techniques contrived in this project have potential to be used for more model drugs, particulate carriers and administrative routes.

探索给药系统的药物和载体粒子的体内过程及其命运，对于阐释相关药理及毒理作用机制具有重要意义。当前，由于缺乏有效的载体粒子体内定量分析方法，对“药物/粒子”的时空变化过程与最终命运知之甚少。为此，本项目拟建立粒子定量方法，提出粒子动力学概念，通过与药动学进行差异化比较，探索体内动态释药过程以及药物和粒子各自的体内命运。拟以mPEG-PCL纳米粒和mPEG-PDLLA聚合物胶束为模型粒子，包载紫杉醇，静注和口服给药；色谱法或放射计数法测定药物总量，采用水淬灭近红外荧光探针标记粒子，实现生物组织中粒子的定量分析；通过“药物/粒子”动力学的差异化比较，揭示粒子与游离药物的体内过程。本项目将为全面解析载体给药系统“药物/粒子”的体内命运提供一个新思路，相关概念、方法与技术可推广应用于更多药物、载体粒子与给药途径。

本项目的首要目标是建立“粒子动力学”的基本概念与方法，并与药物动力学进行对比分析，从而提取关于药物载体给药系统体内行为的重要信息。而决定能够进行粒子动力学分析的瓶颈在于粒子的体内准确定量分析。.本项目实施过程中，以ACQ探针标记mPEG-PDLLA聚合物胶束、mPEG-PCL纳米粒，建立了各种生物组织中荧光强度与粒子浓度（质量）之间的线性关系，实现了两种粒子的体内准确定量分析。此外，将125I共价结合于材料的疏水端（mPEG-PDLLA-125I），形成胶束后，标记核素位于内核而被保护；通过测定放射计数，可对材料的含量进行初步定量。.基于已建立的生物样品中药物、粒子、材料的定量分析方法，对载紫杉醇mPEG-PDLLA聚合物胶束、载紫杉醇或阿霉素mPEG-PCL纳米粒经静注、口服给药后的药物动力学、粒子动力学、材料动力学进行了考察。其中粒子动力学的概念与模型系本项目首次提出，实践中发现可采用经典药动学中非房室模型的统计矩法对粒子动力学数据进行描述，并据此计算相关的粒子动力学参数。.通过对血液或血浆中紫杉醇动力学与mPEG-PDLLA胶束粒子动力学曲线、紫杉醇动力学与mPEG-PCL纳米粒动力学曲线、阿霉素动力学与mPEG-PCL纳米粒动力学曲线的对比分析，发现“药物/粒子”动力学曲线并不能够重合，粒子动力学曲线水平以及AUC值要显著高于药物动力学曲线。该结果说明载药纳米粒进入血液后药物发生了泄露，药物载体因具有长循环效应而在血液中存留更长时间，已泄露的药物则会很快从血液中被清除。通过对比“材料/粒子”，即mPEG-PDLLA-125I与mPEG-PDLLA胶束的动力学曲线，发现在观察时间内，材料与粒子动力学曲线具有高度的重合性，说明mPEG-PDLLA聚合物胶束在血液中具有相当高的稳定性，可以保持胶束结构的基本稳定。.基于所建立的生物组织中药物、粒子、材料的定量分析方法，对各器官组织中的“药物/粒子/材料”多重动力学进行了考察，并对“药物/粒子”、“材料/粒子”动力学进行了初步分析，结果表明药物在组织中也具有从载体中快速泄露的特征。.本项目所获得的结果结论对于阐释纳米载体给药系统的体内命运，进一步优化处方，优化药理毒理作用具有重要转化意义。

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