Abstract
A novel molecular therapeutic agent was designed and synthesized, which contains three functional components, namely, a zinc(II) phthalocyanine substituted with a 2,4-dinitrobenzenesulfonate (DNBS) group as a glutathione (GSH)-activated photosensitizer, a chemo-prodrug based on combretastatin A-4 (CA4) with a singlet oxygen-cleavable aminoacrylate linker, and a biotin moiety as a tumor-targeting ligand. The conjugate showed preferential uptake toward the biotin-receptor-positive HepG2 cells compared with the low biotin-receptor-expressed HCT-116 cells used as the negative control, resulting in the restoration of the fluorescence emission and singlet oxygen generation upon removal of the DNBS group by intracellular GSH. The singlet oxygen produced not only induced a significant photodynamic effect against HepG2 cells but also triggered the cascaded release of the chemocytotoxic CA4, leading to synergistic cytotoxicity as shown by the less-than-unity combination index.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Benzenesulfonates / administration & dosage
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Benzenesulfonates / pharmacokinetics
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Benzenesulfonates / pharmacology
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Bibenzyls / administration & dosage*
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Bibenzyls / pharmacokinetics
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Bibenzyls / pharmacology
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Drug Delivery Systems
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Glutathione / metabolism
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HCT116 Cells
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Hep G2 Cells
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Humans
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Indoles / administration & dosage*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Isoindoles
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Neoplasms / drug therapy
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Organometallic Compounds / administration & dosage*
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Organometallic Compounds / pharmacokinetics
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Organometallic Compounds / pharmacology
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Photochemotherapy
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Photosensitizing Agents / administration & dosage*
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Photosensitizing Agents / pharmacokinetics
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Photosensitizing Agents / pharmacology
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Prodrugs / administration & dosage*
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Prodrugs / pharmacokinetics
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Prodrugs / pharmacology
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Zinc Compounds
Substances
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Antineoplastic Agents
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Benzenesulfonates
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Bibenzyls
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Indoles
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Isoindoles
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Organometallic Compounds
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Photosensitizing Agents
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Prodrugs
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Zinc Compounds
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Zn(II)-phthalocyanine
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2,4-dinitrobenzenesulfonic acid
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combretastatin
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Glutathione