Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer

Yang-Yang Wang; Liang Li; Xiu-Jun Liu; Qing-Fang Miao; Yi Li; Meng-Ran Zhang; Yong-Su Zhen

doi:10.1016/j.jpha.2021.07.001

Volume 12 Issue 2

May 2022

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Article Navigation > Journal of Pharmaceutical Analysis > 2022 > 12(2): 232-242

Yang-Yang Wang, Liang Li, Xiu-Jun Liu, Qing-Fang Miao, Yi Li, Meng-Ran Zhang, Yong-Su Zhen. Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer[J]. Journal of Pharmaceutical Analysis, 2022, 12(2): 232-242. doi: 10.1016/j.jpha.2021.07.001

Citation:

Yang-Yang Wang, Liang Li, Xiu-Jun Liu, Qing-Fang Miao, Yi Li, Meng-Ran Zhang, Yong-Su Zhen. Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer[J]. Journal of Pharmaceutical Analysis, 2022, 12(2): 232-242. doi: 10.1016/j.jpha.2021.07.001

Citation:

Yang-Yang Wang, Liang Li, Xiu-Jun Liu, Qing-Fang Miao, Yi Li, Meng-Ran Zhang, Yong-Su Zhen. Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer[J]. Journal of Pharmaceutical Analysis, 2022, 12(2): 232-242. doi: 10.1016/j.jpha.2021.07.001

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Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer

doi: 10.1016/j.jpha.2021.07.001

a. Department of Pediatric Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China;
b. NHC Key Laboratory of Biotechnology of Antibiotics, Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

Funds:

This work was supported by grants from CAMS Innovation Fund for Medical Sciences (Grant No.: 2021-I2M-1-026), Scientific Research Project of Tianjin Education Commission (Grant No.: 2020KJ140), and Tianjin Health Research Project (Grant No.: KJ20017). The authors are grateful for all the participants in this study.

Received Date: Oct. 12, 2020
Accepted Date: Jul. 02, 2021
Rev Recd Date: Jun. 17, 2021
Publish Date: Jul. 03, 2021

Abstract

Abstract

Folate receptor (FR) overexpression occurs in a variety of cancers, including pancreatic cancer. In addition, enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer. Furthermore, the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic cancer. In this study, a novel FR-directed, macropinocytosis-enhanced, and highly cytotoxic bioconjugate folate (F)-human serum albumin (HSA)-apoprotein of lidamycin (LDP)-active enediyne (AE) derived from lidamycin was designed and prepared. F-HSA-LDP-AE consisted of four moieties: F, HSA, LDP, and AE. F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer cells. Its uptake in wild-type cells was more extensive than in K-Ras mutant-type cells. By in vivo optical imaging, F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice, showing clear and lasting tumor localization for 360 h. In the MTT assay, F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell lines. It also induced apoptosis and caused G2/M cell cycle arrest. F-HSA-LDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic mice. At well-tolerated doses of 0.5 and 1 mg/kg, (i.v., twice), the inhibition rates were 91.2% and 94.8%, respectively (P<0.01). The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.
- Pancreatic cancer,
- Folate receptor,
- Multi-functional,
- Macropinocytosis-enhanced,
- Bioconjugate,
- K-Ras,
- PEGylation

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References(46)

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