Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer
- Author:
Yang-Yang WANG
1
,
2
;
Liang LI
;
Xiu-Jun LIU
;
Qing-Fang MIAO
;
Yi LI
;
Meng-Ran ZHANG
;
Yong-Su ZHEN
Author Information
1. Department of Pediatric Oncology,Tianjin Medical University Cancer Institute and Hospital,Tianjin,300060,China
2. 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
- Keywords:
Pancreatic cancer;
Folate receptor;
Multi-functional;
Macropinocytosis-enhanced;
Bioconjugate;
K-Ras;
PEGylation
- From:
Journal of Pharmaceutical Analysis
2022;12(2):232-242
- CountryChina
- Language:Chinese
-
Abstract:
Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic cancer.In addi-tion,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.
