寻找疗效好、选择性高、毒副作用小的抗癌新药已成为当前医药学领域重点研究方向之一。天然来源的熊果酸以其显著的抗癌作用和良好的护肝功效受到重视，但仍存在水溶性差、肿瘤靶向性弱等不足。本项目提出将叶酸靶向运输与熊果酸衍生物抗癌活性相结合，揭示叶酸靶向的熊果酸衍生物抗癌作用及机制，最终建立并验证熊果酸衍生物-叶酸的设计理论。具体研究内容包括：利用小分子叶酸为药物靶向运输载体，以申请人前期工作中获得的抗癌效果显著的熊果酸衍生物（已申请专利）作为研究对象，构建熊果酸衍生物-叶酸偶联物；分析比较目标药物水溶性和稳定性等理化性质特点；重点研究并阐明其在体内外的靶向抗癌活性及毒性作用；从组织、分子和细胞水平探讨并揭示目标药物在肿瘤靶向治疗方面的作用机制，对其作为新型抗癌药物做出评价。本项目可为相关领域靶向抗癌药物研究及抗癌活性评价提供重要理论参考及实验依据，为肿瘤靶向性治疗提供新的研究思路和方法。

Presently, the search for novel anticancer drugs that are both effective in the treatment of cancers as well as low toxic to normal tissues has become a highly researched field in medicine. Ursolic acid is a naturally occurring bioactive product that possesses significant anticancer effects and prevents liver injury. However,further investigation is needed to improve the weak water-solubility and low tumor-targeting efficiency. Our preliminary study showed that several ursolic acid derivatives(e.g. UDA) had showed significant anticancer activity on different cancer cell lines in vitro and in vivo. In this project, we will design and synthesize a series of folate receptor-targeted, water-soluble, and pharmacomodulated chemotherapy agent that selectively destroys the targeted cancer cells while sparing normal tissue. The new conjugates are composed of two components, i.e., Ursolic acid derivatives (therapeutic agent) and Folate acid (homing molecule targeting FR-expressing cancer cells, and as a stable modulator improving the delivery efficiency as well). Comparative studies between the new folate-drug conjugates and ursolic acid derivatives will be preformed using their water-solubility and stability index. In addition, targeted antitumor activity and toxicity to normal tissues of the candidate drugs will be studied in vitro and in vivo. Finally, the mechanism of the new conjugates will be explored. This study can potentially be generalized to improve the tumor-targeting efficiency of other chemotherapy agents.