Glucose conjugated aza-BODIPY for enhanced photodynamic cancer therapy

Abstract

Compared with normal cells, cancer cells usually exhibit an increase in glucose uptake as part of the Warburg effect. To take advantage of this hallmark of cancer, glucose transporters could be a good candidate for cancer targeting. Herein, we report novel glycoconjugate aza-BODIPY dyes (AZB-GlcandAZB-Glc-I) that contain two glucose moieties conjugated to near-infrared dyesviathe azide-alkyne cycloaddition reaction. As anticipated, a higher level ofAZB-Glcuptake was observed in breast cancer cells that overexpressed glucose transporters (GLUTs), especially GLUT-1, including the triple-negative breast cancer cell line (MDA-MB-231) and human breast adenocarcinoma cell line (MCF-7), compared to that of normal cells (human fetal lung fibroblasts, HFL1). The cellular uptake ofAZB-Glcwas in a dose- and time-dependent manner and also depended on GLUT, as evidenced by the decreased uptake ofAZB-Glcin the presence ofd-glucose or a glucose metabolism suppressor, combretastatin. In addition, light triggered cell death was also investigated through photodynamic therapy (PDT), since near-infrared (NIR) light is known to penetrate deeper tissue than light of shorter wavelengths.AZB-Glc-I, the analog ofAZB-Glccontaining iodine for enhanced singlet oxygen production upon NIR irradiation, was used for all treatment assays.AZB-Glc-Ishowed significant NIR light-induced cytotoxicity in cancer cells (IC50= 1.4-1.6 μM under 1 min irradiation), which was about 20-times lower than that in normal cells (IC50= 32 μM) under the same conditions, with negligible dark toxicity (IC50> 100 μM) in all cell lines. Moreover, the singlet oxygen was detected inside the cancer cells after exposure to light in the presence ofAZB-Glc-I. Therefore, our glucose conjugated systems proved to efficiently target cancer cells for enhanced photodynamic cancer therapy.