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Abstract
The selective delivery of small molecule compounds such as Gemcitabine to tumor cells is a promising methodology for enhancing therapeutic efficacy and attenuating the side effects of anticancer drugs. Aptamers are useful as target-directed ligands for tumor-selective drug delivery due to their ability to bind specific proteins. However, the drug must be released from the aptamer after the conjugate is taken up by the cell to exert its pharmacological effect. In this study, we designed and synthesized a conjugate in which a linker cleaved by glutathione, which is highly expressed in tumor cells, was inserted between the aptamer (AS1411) and Gemcitabine. Almost all Gemcitabine was released from the conjugate after 30 min in the presence of 6 mM glutathione. AS1411 is known to bind to nucleolin, which is highly expressed on tumor cells. The cytotoxicity of the AS1411 and Gemcitabine conjugate with a disulfide bond on A549 cells was higher than that of the conjugate without a disulfide bond. Furthermore, the cytotoxicity of the disulfide-linked conjugate of AS1411 and Gemcitabine was higher in A549 cells than in MCF10A cells, which were used as the model of normal cells. These results indicate that disulfide conjugation enhanced the tumor cell-selective cytotoxicity of Gemcitabine with AS1411.Graphical
Highlights
Small molecule antitumor drugs have been widely used as a primary approach to cancer treatment since the start of Various targeting ligands have been developed for antitumor targeting
For purposes of comparison with the AS1411-S-S-Gem conjugate, which contains both the AS1411 aptamer and a disulfide bond linker, AS1411-Gem was synthesized by substituting the disulfide bond with a non-cleavable carbon-carbon linker
The disulfide bond serves as a cleavable linker that is responsive to GSH, which is concentrated within tumor cells but remains insufficient in normal cells
Summary
Small molecule antitumor drugs have been widely used as a primary approach to cancer treatment since the start of Various targeting ligands have been developed for antitumor targeting These ligands bind to receptors overexpressed on tumor cells, and thereby actively deliver drugs to the tumor site and enhance therapeutic efficacy. The AAPS Journal (2025) 27:95 dimensional configurations that, like conventional antibodies, can recognize and bind to specific targets, making them effective as targeting ligands in drug delivery systems While they function to antibodies, aptamers offer several key advantages that make them promising therapeutic agents, including high specificity, relatively small size, thermodynamic stability, non-immunogenicity, chemical synthesizability, ease of modification for conjugation, and the ability to target small molecules [8–13]. McNamara II et al developed an aptamersiRNA molecule whose aptamer portion binds to PSMA, a cell-surface receptor overexpressed in prostate cancer cells and the tumor vascular endothelium, resulting in delivery of the functional siRNA to the tumor site to inhibit tumor growth [19]
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