Abstract
A nine cyclic peptide(TCP-1)showed excellent specificity for colon cancer.TCP-1 binds with human tu-mor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon cancer.The mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and bioinformatics.After screening and identifying of the possible binding target proteins of TCP-1,keratin,type Ⅱ cytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor tissue.Pharmacokinetics studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/MS.The tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other tissues.Conjugating TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in vivo.In tumor mice,a lower AUC of TCP-1(reduced by almost 35％)and 2-fold higher clearance were found compared to that of normal mice.The proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS"-IT-TOF.The high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the targets.Potential applications for future clinical use,including MRI and PET/CT were also explored,and this re-search may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.
基金项目
Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-027)
国家自然科学基金(T2192972)
国家自然科学基金(81402997)
Key Project of Beijing Natural Science Foundation(7181007)
National Hightech Research and Development Plan(863 Plan)(2014AA020803)
Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study(Z141102004414062)
Shimadzu(China)Co.,Ltd()
NETL
NSTL
万方数据