Development of a novel multi-functional integrated bioconjugate effectively targeting K-Ras mutant pancreatic cancer
作者机构：Department of Pediatric OncologyTianjin Medical University Cancer Institute and HospitalTianjin300060China NHC Key Laboratory of Biotechnology of AntibioticsDepartment of OncologyInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100050China
出 版 物：《Journal of Pharmaceutical Analysis》 (药物分析学报（英文版）)
年 卷 期：2022年第12卷第2期
页 面：232-242页
核心收录：
学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：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) Tianjin Health Research Project(Grant No.:KJ20017)
主 题：Pancreatic cancer Folate receptor Multi-functional Macropinocytosis-enhanced Bioconjugate K-Ras PEGylation
摘 要：Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic *** addition,enhanced macropinocytosis exists in K-Ras mutant pancreatic ***,the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic *** 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 *** uptake in wild-type cells was more extensive than in K-Ras mutant-type *** 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 *** the MTT assay,F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell *** also induced apoptosis and caused G2/M cell cycle arrest.F-HSALDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic *** well-tolerated doses of 0.5 and 1 mg/kg,(i.v.,twice),the inhibition rates were 91.2%and 94.8%,respectively(P0.01).The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.
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