2. Academic Validation
  3. Novel octapeptide-DTX prodrugs targeting MMP-7 as effective agents for the treatment of colorectal cancer with lower systemic toxicity

Novel octapeptide-DTX prodrugs targeting MMP-7 as effective agents for the treatment of colorectal cancer with lower systemic toxicity

  • Eur J Med Chem. 2020 May 1:193:112194. doi: 10.1016/j.ejmech.2020.112194.
Zheng-Yu Liu 1,  Mei-Lin Tang 2,  Jin-Feng Ning 1,  Yun-Peng Hao 1,  Lu Zhou 3,  Xun Sun 4
Affiliations

Affiliations

  • 1 Department of Natural Medicine, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
  • 2 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.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
  • 4 Department of Natural Medicine, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China; The Institutes of Integrative Medicine of Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, China. Electronic address: sunxunf@shmu.edu.cn.
PMID: 32203786 DOI: 10.1016/j.ejmech.2020.112194
Abstract

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.

Keywords

CRC; DTX; MMP-7; Prodrug; Systemic toxicity.

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