Abstract
After a groundbreaking study demonstrated that a high dose of ascorbic acid selectively kills cancer cells, the compound has been tested in the clinic against various forms of cancers, with some success. However, in vivo tracing of intravenously injected ascorbic acid has not been achieved. Herein, we successfully imaged ascorbic acid intravenously injected into mice based on the discovery of a novel, highly sensitive, and appropriately selective fluorescent probe consisting of silicon phthalocyanine (SiPc) and two 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) radicals, i.e., R2c. The radicals in this R2c were encapsulated in dimeric bovine serum albumin, and the sensitivity was >100-fold higher than those of other R2c-based probes. Ascorbic acid intravenously injected into mice was efficiently transported to the liver, heart, lung, and cholecyst. The present results provide opportunities to advance the use of ascorbic acid as cancer therapy.
Highlights
Oxidative stress due to free radicals and reactive oxygen species is closely associated with various diseases[1]
Ascorbic acid has been investigated as a new class of cancer therapy, as pharmacologic concentrations (0.3–20 mM) of the compound were found to be selectively cytotoxic against cancer cells but not normal cells[4,5,6,7]
This selective toxicity is thought to be due to H2O2 produced from a high dose of ascorbic acid, as cancer cells express catalase and glutathione peroxidase less abundantly compared to normal cells[4,6,7,8,9]
Summary
Oxidative stress due to free radicals and reactive oxygen species is closely associated with various diseases[1]. In vivo (1) the excitation and fluorescence (or luminescence) wavelengths should be >650 nm to penetrate deeply into living tissues, and (2) nitroxide radicals should be shielded from biological redox active species before injection of ascorbic acid, but should efficiently react with ascorbic acid after injection. Dual-modality organic radical contrast agents, the excitation and fluorescence wavelengths of which (~650 nm) are appropriate for deeper tissues[31] These dual-modality and other nitroxide-based luminescence probes are typically unshielded and delivered to biological systems, and the resulting fluorescent traces represent only the redox status. The excitation and fluorescence wavelengths of this probe are >650 nm: the radicals of this hydrophobic probe can be shielded by encapsulation into liposomes to prevent the reaction with various biological redox active species This probe has been used to and fluorescently image ascorbic acid in cancer cells. We characterized the R2c@(BSA)[2] probe in vitro and in vivo
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