桥接细胞与整体的纳米药代动力学研究

Nano-particle (NP) drug delivery system (DDS) has been widely expected to create new pathways for tumor therapy. However, approved NP-DDS based new drugs are rare despite extensive research efforts that have been invested. Nano-scale effects and tumor environmental dependent release mechanisms of NP-DDS based drugs engender dramatically different pharmacokinetics and bio-distribution behavior from that of free drugs in plasma. Consequently, conventional pharmacokinetic theories and methodologies are not effective in disclosing distribution and metabolism of drugs released from NP-DDS. Therefore, lack of proper pharmacokinetic model has been becoming the major bottleneck in development of NP-DDS based drugs. In this study, 10 NP-DDSs are selected for three representative anti-tumor drugs paclitaxel, doxorubicin and cisplatin, and in situ microscopy imaging and in situ quantitation in single cells will be performed in Shanghai Synchrotron Radiation Facility to establish a physiological pharmacokinetic model for these specific NP-DDSs at system, tissue and cellular levels. The model is expected to integrate the in vivo and in vitro drugs release profiles of NP DDS, to bridge the drug profiles at the cellular level with those at the system level, and to give reliable predictions for the NP DDS pharmacokinetic behavior. Implementation of the proposed study is expected to establish a new theory of nano-pharmacokinetics, to facilitate single-cell pharmacokinetics for NP-DDS, and to both enrich and expand basic theories of pharmacokinetics.

抗肿瘤药物纳米给药系统（NP）给肿瘤治疗带来了新的突破口和希望，但大规模NP研究并未带来众多的NP新药。NP的纳米尺度效应及其在体内不同环境下的差异化释放极大地改变了药物的体内动力学和生物分布，基于游离药物血药浓度的传统药代动力学方法和理论没有考虑NP在体内和肿瘤内的释药复杂性，无法揭示NP在体内的复杂分布平衡及代谢机制，NP的药代动力学“盲区”已成为制约NP研发成功率的关键。本课题选择具有代表性的紫杉醇、阿霉素、顺铂等重要抗肿瘤药物的10种不同类型纳米制剂，运用上海同步辐射光源等先进强大的单细胞和原位显微成像、定量分析技术，建立循环系统、组织、肿瘤细胞水平上符合NP药代动力学特征的生理药动学模型，整合NP体内外相关性，建立桥接细胞与整体的纳米药代动力学理论和方法，解决纳米制剂体内药动学的可预测性问题。本项目有望促进NP单细胞药动学的发展，并将丰富和拓展传统药代动力学的基础理论与研究领域。

抗肿瘤药物纳米给药系统（NP）给肿瘤治疗带来了新的希望，但大规模NP研究并未带来众多的NP新药。NP的纳米尺度效应及其在体内不同环境下的差异化释放极大地改变了药物的体内动力学和生物分布，基于游离药物浓度的传统药代动力学方法和理论没有考虑NP在体内和肿瘤内的释药复杂性，无法揭示NP在体内的复杂分布平衡及代谢机制，NP的药代动力学“盲区”已成为制约NP研发成功率的关键。目前，国际药监机构对纳米药物尚无统一认识和指导原则，特别是纳米粒子、高分子辅料以及负载药物三者之间体内时空命运的复杂关系亟待揭示。本课题选择具有代表性的紫杉醇、阿霉素、顺铂等重要抗肿瘤药物的10种不同类型纳米制剂，针对纳米制剂研究的药代“盲区”，采用高分辨质谱、上海同步辐射光源等先进强大的单细胞和原位显微成像以及定量分析新技术，围绕同步释放药物、纳米粒负载药物、关键辅料三个核心目标，发展了测定NP在血液、组织、剂型中药物水平的新方法。应用这些方法进行了细胞及系统水平的纳米制剂药代动力学理论和方法研究，初步构建了细胞-整体水平的整合模型。本课题桥接细胞与整体，发展了药代动力学新理论，为纳米制剂的设计、评价和临床安全用药提供一些可借鉴的药代动力学基础。