Department of Natural Medicine, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Department of Natural Medicine, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China; State Key Laboratory of Molecular Engineering and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai, 200433, China.
Eur J Med Chem. 2020 May 1;193:112194. doi: 10.1016/j.ejmech.2020.112194. Epub 2020 Feb 28.
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death around the world. The current treatments of CRC exhibited high occurrence rate of side effects. Docetaxel (DTX), an important drug widely used in cancer chemotherapy, showed serious toxicity in CRC. Reducing toxicity of DTX could be a feasible and promising way to achieve the new indication of DTX for CRC. In this study, a series of MMP-7 activated octapeptide-DTX/4FDT prodrugs (6a-10a and 6b-10b) were designed and synthesized based on the features of MMP-7 which is highly expressed in CRC and could specially recognize octapeptides with specific sequences. Among them, 9a and 9b, both possessing an octapeptide Gly-Pro-Gln-Gly-Ile-Ala-Met-Gln moiety, were the most potent prodrugs. Compounds 9a and 9b were also tested their release rate in HCT116 cell culture fluids and tumor homogenate along with in vivo anti-CRC activity and systemic toxicity. Since 9a showed better anti-CRC activity and lower systemic toxicity than 9b in CRC tumor bearing mice, it was further evaluated for its acute toxicity, pharmacokinetics and tissue distribution in comparison with its parent drug DTX. These results revealed that 9a possessed good systemic stability, rapid release rate in CRC and reduced systemic toxicity, while retaining similar anti-CRC activity to its parent drug DTX. Thus, 9a, an MMP-7 polypeptide prodrug of DTX, has been identified as a promising candidate for the treatment of CRC.
结直肠癌（CRC）是全球第三大常见癌症和第四大癌症死亡原因。目前 CRC 的治疗方法副作用发生率较高。多西紫杉醇（DTX）是一种广泛用于癌症化疗的重要药物，在 CRC 中表现出严重的毒性。降低 DTX 的毒性可能是实现 DTX 治疗 CRC 的新适应证的可行且有前途的方法。在这项研究中，基于 MMP-7 在 CRC 中高度表达且能够特异性识别具有特定序列的八肽的特点，设计并合成了一系列 MMP-7 激活的八肽-DTX/4FDT 前药（6a-10a 和 6b-10b）。其中，具有 Gly-Pro-Gln-Gly-Ile-Ala-Met-Gln 八肽部分的 9a 和 9b 是最有效的前药。还测试了化合物 9a 和 9b 在 HCT116 细胞培养液和肿瘤匀浆中的释放率以及体内抗 CRC 活性和全身毒性。由于 9a 在 CRC 荷瘤小鼠中显示出比 9b 更好的抗 CRC 活性和更低的全身毒性，因此进一步对其进行了评价。与母体药物 DTX 相比，它在急性毒性、药代动力学和组织分布方面的情况。这些结果表明，9a 具有良好的全身稳定性、在 CRC 中的快速释放率和降低的全身毒性，同时保留了与其母体药物 DTX 相似的抗 CRC 活性。因此，作为 DTX 的 MMP-7 多肽前药，9a 已被确定为治疗 CRC 的有前途的候选药物。
