以较好代谢稳定性和抗肝癌活性的四氟代多烯紫杉醇为母药，针对其在体内对正常组织和肿瘤细胞缺乏选择性而造成较严重杂泛性的缺点，拟采用前药策略对其进行结构优化。创新性地以在恶性肿瘤细胞中高表达，而在人体某些正常或炎症组织中低表达的金属基质蛋白酶（MMP-2和MMP-9）易识别和水解的多肽作为载体靶向基团，选择具有自我降解功能的桥链分子与母药连接，合成具有肿瘤靶向运输和肿瘤定点释放特性的前药。通过其体内外抗肝癌活性、对正常细胞和肿瘤细胞的选择性、血浆中稳定性、母药释放速率及靶向能力等成药性研究，揭示肽结构中基因或氨基酸序列与成药性的构效关系，实现从基因水平调控母药释放和降低系统毒性,从根本上解决临床安全性问题。同时，结合当代氟-核磁共振成像技术，实现实时无害、真实方便地追踪药物在体内，尤其在肝脏部位的分布和代谢，为研发高效、低毒、靶向性强的4FDT-多肽新型抗肝癌紫杉醇前药奠定基础。

Based on the leading compound 4FDT, which had previously demonstrated increased metabolic stability and anti-hepatoma activity compared with Docetaxel, prodrug strategy was adopted to minimize its systemic toxicity because of the lack of selectivity between tumor cells and normal tissues. The anti-hepatoma 4FDT prodrug, with targeted delivery and specifically cleavage on tumor site, was innovatively designed, in which novel substrate peptide of MMP-2/MMP-9, which was over-expressed on tumor site while less expressed on normal tissues, were conjugated with 4FDT via a self-eliminated bridge chain group. The bioactivity and druggability of the prodrug was evaluated by in vitro and in vivo anti-hepatoma activity, the selectivity between tumor cells and normal tissue cells, the stability in blood plasma, the releasing rate of 4FDT from prodrug, and targeting ability. The relationship of amino acid sequence and the bioactivity of prodrug was also studied, aimed to control parent drug release from gene level and reduce the systemic toxicity, and solve clinical safety. Using fluorine - magnetic resonance imaging technology to achieve real-time to track the drug in the body, especially the distribution and metabolism in the liver parts, this proposal will lay the foundation for the R&D of high efficiency, low toxicity, strong targeting 4FDT-polypeptide new anti-hepatoma prodrug.

本项目对照原定预期成果和技术考核指标，重点围绕前期发展具有自主知识产权的抗肝癌及结肠癌活性高、代谢稳定性好的四氟多烯紫杉醇（4FDT）和临床药物多烯紫杉醇（DTX），聚焦它们在体内存在严重的系统毒性这一科学问题，创新性选择特异性MMP-2/7/9酶靶向多肽水解的“前药”设计策略，通过优选具有降解功能且有效调控母药释放的桥链分子PABC，共合成了36个全新靶向MMP-2/7/9酶解多肽前药化合物，通过对它们活性筛选及成药性研究，优选发现了2个针对蛋白酶MMP-9特异性识别和水解的多肽抗肝癌作用的前药侯选化合物24c14（4FDT-PABC-C14）和23c14（DTX-PABC-C14）和1个针对蛋白酶MMP-7特异性识别和水解的多肽抗结肠癌作用的前药侯选化合物23b10（DTX-PABC-B10），它们都相对于母药4FDT和DTX在组织中的系统毒性明显降低，有效提高了安全性。