Hypoxia-Activated and Indomethacin-Mediated Theranostic Prodrug Releasing Drug On-Demand for Tumor Imaging and Therapy

A smart theranostic prodrug IMC-FDU-TZBC-NO2, releasing active drug on-demand based on hypoxia-activated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiet...

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Published inBioconjugate chemistry Vol. 30; no. 11; pp. 2828 - 2843
Main Authors Peng, Xiaoran, Gao, Jiaxin, Yuan, Yumeng, Liu, Haitong, Lei, Weiyan, Li, Shenghui, Zhang, Jinchao, Wang, Shuxiang
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 20.11.2019
Amer Chemical Soc
Subjects
Biochemical Research Methods
Biochemistry & Molecular Biology
Chemistry
Chemistry, Multidisciplinary
Chemistry, Organic
Chemotherapy
Demand
Drug delivery systems
Dyes
Fluorescent dyes
Fluorescent indicators
Hypoxia
Indomethacin
Life Sciences & Biomedicine
Medical imaging
Nitrogen dioxide
Physical Sciences
Science & Technology
Side effects
Solid tumors
Tumor cells
Tumors
VISUALIZATION
NANOPARTICLES
CYCLOOXYGENASE-2
INFLAMMATION
IN-VIVO
CONJUGATE
PENETRATION
MICELLES
CANCER
TARGETED DELIVERY
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Summary:A smart theranostic prodrug IMC-FDU-TZBC-NO2, releasing active drug on-demand based on hypoxia-activated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiety indomethacin (IMC), and the hypoxic trigger 4-nitrobenzyl group to a fluorescent dye precursor, which was mediated by IMC and activated by NTR under hypoxic conditions. The fluorescent dye IMC-TZBCM was generated and FDU was released at the same time in tumor cells. The rates and amounts of FDU release and IMC-TZBCM generation were regulated by hypoxia status, and increased with increasing degree of hypoxia. Nevertheless, it is “locked” in normal cells. It combined the advantages of tumor targeting, diagnosis, and chemotherapy functions, showed excellent targeting ability to cancer cells, excellent stability in physiological conditions, high cellular uptake efficiency, and on-demand drug release behavior. The in vitro and in vivo assays demonstrated that IMC-FDU-TZBC-NO2 exhibits enhanced anticancer potency and low side effects. The novel targeted theranostic prodrug activated by hypoxia shows a great potential in cancer therapy.
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ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.9b00564