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Title: Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging

Abstract

Fluorescent mitochondria-accumulating delocalized lipophilic cations (DLCs) for cancer therapy have drawn significant attention in the field of cancer theranostics. One of the most promising fluorescent DLCs, F16, can selectively trigger the apoptosis and necrosis of cancer cells, making it an attractive targeted theranostic drug candidate. However, it suffers from low clinical translation potential, largely due to its inefficient anti-cancer activity (IC50 in the μM range) and poorly understood structure–activity relationship (SAR). In this report, eleven indole-ring substituted F16 derivatives (F16s) were synthesized. Among these derivatives, 5BMF was identified as a highly effective theranostic agent, with in vitro studies showing a low IC50 of ~50 nM (to H2228 cells) and high cancer to normal cell selectivity index of 225. In vivo studies revealed that tumors treated with 5BMF were significantly suppressed (almost no growth over the treatment period) compared to the PBS treated control group, and also no obvious toxicity to mice was found. In addition, the tumor imaging capability of 5BMF was demonstrated by in vivo fluorescence imaging. Finally, we report for the first time a proposed SAR for F16 DLCs. Our work lays down a solid foundation for translating 5BMF into a novel and highly promising DLC for cancermore » theranostics.« less

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [4];  [4]; ORCiD logo [3]
  1. Department of Radiology, The First Hospital of Jilin University, Changchun, China, Center for Molecular Imaging Research
  2. Department of Radiology, The First Hospital of Jilin University, Changchun, China, Molecular Imaging Program at Stanford (MIPS)
  3. Molecular Imaging Program at Stanford (MIPS), Bio-X Program, Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University
  4. Department of Radiology, The First Hospital of Jilin University, Changchun, China
Publication Date:
Research Org.:
Stanford Univ., CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1542520
Alternate Identifier(s):
OSTI ID: 1611044
Grant/Contract Number:  
SC0008397
Resource Type:
Published Article
Journal Name:
Chemical Science
Additional Journal Information:
Journal Name: Chemical Science Journal Volume: 10 Journal Issue: 34; Journal ID: ISSN 2041-6520
Publisher:
Royal Society of Chemistry
Country of Publication:
United Kingdom
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES; Chemistry

Citation Formats

Chen, Hao, Wang, Jing, Feng, Xin, Zhu, Mark, Hoffmann, Simon, Hsu, Alex, Qian, Kun, Huang, Daijuan, Zhao, Feng, Liu, Wei, Zhang, Huimao, and Cheng, Zhen. Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging. United Kingdom: N. p., 2019. Web. doi:10.1039/C9SC01410A.
Chen, Hao, Wang, Jing, Feng, Xin, Zhu, Mark, Hoffmann, Simon, Hsu, Alex, Qian, Kun, Huang, Daijuan, Zhao, Feng, Liu, Wei, Zhang, Huimao, & Cheng, Zhen. Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging. United Kingdom. doi:10.1039/C9SC01410A.
Chen, Hao, Wang, Jing, Feng, Xin, Zhu, Mark, Hoffmann, Simon, Hsu, Alex, Qian, Kun, Huang, Daijuan, Zhao, Feng, Liu, Wei, Zhang, Huimao, and Cheng, Zhen. Wed . "Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging". United Kingdom. doi:10.1039/C9SC01410A.
@article{osti_1542520,
title = {Mitochondria-targeting fluorescent molecules for high efficiency cancer growth inhibition and imaging},
author = {Chen, Hao and Wang, Jing and Feng, Xin and Zhu, Mark and Hoffmann, Simon and Hsu, Alex and Qian, Kun and Huang, Daijuan and Zhao, Feng and Liu, Wei and Zhang, Huimao and Cheng, Zhen},
abstractNote = {Fluorescent mitochondria-accumulating delocalized lipophilic cations (DLCs) for cancer therapy have drawn significant attention in the field of cancer theranostics. One of the most promising fluorescent DLCs, F16, can selectively trigger the apoptosis and necrosis of cancer cells, making it an attractive targeted theranostic drug candidate. However, it suffers from low clinical translation potential, largely due to its inefficient anti-cancer activity (IC50 in the μM range) and poorly understood structure–activity relationship (SAR). In this report, eleven indole-ring substituted F16 derivatives (F16s) were synthesized. Among these derivatives, 5BMF was identified as a highly effective theranostic agent, with in vitro studies showing a low IC50 of ~50 nM (to H2228 cells) and high cancer to normal cell selectivity index of 225. In vivo studies revealed that tumors treated with 5BMF were significantly suppressed (almost no growth over the treatment period) compared to the PBS treated control group, and also no obvious toxicity to mice was found. In addition, the tumor imaging capability of 5BMF was demonstrated by in vivo fluorescence imaging. Finally, we report for the first time a proposed SAR for F16 DLCs. Our work lays down a solid foundation for translating 5BMF into a novel and highly promising DLC for cancer theranostics.},
doi = {10.1039/C9SC01410A},
journal = {Chemical Science},
number = 34,
volume = 10,
place = {United Kingdom},
year = {2019},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1039/C9SC01410A

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Cited by: 4 works
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