Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model  

作　　者：Jian Guan Mingyang Liu Xin Li Liangrui Zhou Xueyu Dong Wei Dai Yu Xia Tao Yang Shaojuan Guo Xingqi Li Yehua Han Yufeng Luo 

机构地区：[1]The National Population and Health Scientific Data Centre(Clinical Medicine) [2]Department of Pathology [3]Department of Nuclear Medicine,Peking Union Medical College Hosptial,Chinese Academy of Medical Sciences(CAMS)and Peking Union Medical College(PUMC),Beijing [4]Department of Nuclear Medicine,The Cancer Hospital of the University of Chinese Academy of Sciences(Zhejiang Cancer Hospital),Institute of Basic Medicine and Cancer(IBMC),Chinese Academy of Sciences,Hangzhou,Zhejiang Province [5]National Laboratory of Medical Biology,Institute of Basic Medical Sciences [6]The Electron Microscope Laboratories Center,Institute of Basic Medical Sciences [7]Department of Ultrasound,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences(CAMS)and Peking Union Medical College(PUMC),Beijing,China

出　　处：《Journal of Bio-X Research》2022年第4期181-196,共16页生物组学研究杂志（英文）

基　　金：supported partly by the National Human and Health Scientific Data Sharing Platform,Clinical Center of China(No.2004DKA20240-2014);National Program funded by the Ministry of Science and Technology of China(No.2015KJRK1L01).

摘　　要：Objective: To explore the antitumor and potential off-target effects of systemically delivered cholesterol-conjugatedlet-7a mimics(Chol-let-7a) and control mimics(Chol-miRCtrl) on hepatocellular carcinomain vivo.Methods: The antitumor effects of two intravenous dosing regimens ofChol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in theChol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then,let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution ofChol-let-7a andChol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital.Results: Continuous treatment withChol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in theChol-miRCtrl and blank xenograft group (P < 0.01 andP < 0.01, respectively), while intermittent dosing withChol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in theChol-miRCtrl and the blank control group, respectively (P < 0.05 andP < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosingChol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues;mild hypercellularity with dilated capillary lumens in the renal tissue;and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed thatChol-let-7a andChol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concent

关 键 词：drug-induced renal injury hepatic toxicity in vivo off target effects let-7 mimics nonviral delivery vector 

分 类 号：R735.7[医药卫生—肿瘤]