肝癌的整体化疗效果不佳。癌干细胞（CSC）能够耐受化疗，而癌细胞（NCSC）也可以反向生成CSC，因此同时清除肝癌NCSC和CSC是提高治疗效果的关键。在前期工作中，申请双方合作进行了肿瘤分子靶向成像以及新型64Cu络合剂Sar等方面的研究。本课题拟在以上工作基础上，建立交联多层脂质体（CML）药物输送体系，将抗NCSC化疗药物和抗CSC药物同时装载到一个载体，统一药物的代谢动力学以提高药物的协同效应；进一步建立肿瘤酸性微环境靶向的药物输送体系，实现药物在肿瘤的“定点释放”，增强药物的治疗效果并减轻其毒副作用；设计构建新型双功能64Cu络合剂Sar，赋予载体可视化特性，通过高敏感性、精确定量的PET成像，实时及非侵入性地监测纳米药物在体内的动力学过程，快速筛选出最有效的CML药物。本项目预期建立肿瘤酸性微环境靶向的CML纳米药物输送体系，同时清除NCSC和CSC，以达到“根治”肝癌的目的。

Chemotherapy has been shown to have limited effect on Liver cancer. Cancer stem cells (CSC) are chemo-resistant, and non-CSC cells (NCSC) can convert into CSC reversely. Therefore, to enhance therapeutic efficacy, it’s crucial to co-eradicate both NCSC and CSC simultaneously. In our previous work, the two groups have established a close collaboration and started the research on tumor targeted molecular imaging and the design/synthesis of novel 64Cu chelating agents based on Sarcophagine (Sar). Based on our strong preliminary data, we aim to construct a cross-linked multilamellar liposome (CML) drug delivery system with high serum stability for co-deleivery of anti-NCSC drug and anti-CSC drug. The single carrier of combined drugs can enhance synergestic effect by coordinating the pharmacokinetics of drug combinations. We will further construct tumor-site-directed drug release triggered by acidic tumor microenvironment. This controlled release system are expected to maintain efficient tumor treatment efficacy with significantly decreased toxicity of drugs. Moreover, we intend to design and build novel dual-functional 64Cu chelating agents based on Sar, which would allow us track the nanocarrier's in vivo kinetics using highly sensitive and accurate quantitative PET imaging in a real-time and non-invasive way. As a result, we could quickly select the most promising CML candidate through molecular imaging. In summary, this project expects to establish an CML-based drug delivery system that will allow triggered release by acidic tumor microenvironment to co-eradicate both NCSC and CSC. The success of our approach will potentially lead to radical cure of liver cancer.