Tristan Mangeolle1, Ilya Yakavets2, Nicolas Lequeux3, Thomas Pons4, Lina Bezdetnaya5, Frédéric Marchal6. 1. Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, Campus Sciences, Boulevard des Aiguillette, 54506 Vandoeuvre-lès-Nancy, France; Research Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, 54519 Vandoeuvre-lès-Nancy, France. Electronic address: tristanmangeolle1990@hotmail.fr. 2. Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, Campus Sciences, Boulevard des Aiguillette, 54506 Vandoeuvre-lès-Nancy, France; Research Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, 54519 Vandoeuvre-lès-Nancy, France; Laboratory of Biophysics and Biotechnology, Belarusian State University, 4 Nezavisimosti Avenue, 220030 Minsk, Belarus. Electronic address: i.yakavets@nancy.unicancer.fr. 3. LPEM, ESPCI Paris, PSL Research University, CNRS UMR 8213, Sorbonne Université, 10, rue Vauquelin, 75005 Paris, France. Electronic address: nicolas.lequeux@espci.fr. 4. LPEM, ESPCI Paris, PSL Research University, CNRS UMR 8213, Sorbonne Université, 10, rue Vauquelin, 75005 Paris, France. Electronic address: thomas.pons@espci.fr. 5. Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, Campus Sciences, Boulevard des Aiguillette, 54506 Vandoeuvre-lès-Nancy, France; Research Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, 54519 Vandoeuvre-lès-Nancy, France. Electronic address: l.bolotine@nancy.unicancer.fr. 6. Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, Campus Sciences, Boulevard des Aiguillette, 54506 Vandoeuvre-lès-Nancy, France; Surgical Department, Institut de Cancérologie de Lorraine, 6 avenue de Bourgogne, 54519 Vandoeuvre-lès-Nancy, France. Electronic address: f.marchal@nancy.unicancer.fr.
Abstract
BACKGROUND: Quantum dots (QDs) bring new insights in cancer theranostics. Exceptional brightness together with the simple possibility to modify surface with targeting molecules make QDs attractive agents in fluorescence guided surgery and photodynamic therapy. Currently, many targeted QDs have been developed for theranostic purpose. However, their targeting ability was tested mainly in two dimensional monolayer tumor cell models, while our study includes 3D tumor model reflecting the specificity of in vivo tumor environment. METHODS: Core/multilayer shell CdSe/CdS/ZnS QDs were conjugated with folic acid (FA) and characterized spectroscopically. Cytotoxicity of QDs on KB and A549 cells lines were evaluated using the MTT assay. Cellular uptake of QDs was assessed by epifluorescent microscopy. To study the distribution of QDs in tumor tissue, KB spheroids were prepared by means of the liquid overlay technique and then frozen cut of spheroids treated with QDs were imaged by epifluorescence microscopy. RESULTS: We confirmed the specificity of QD-FA for the folic acid receptor positive KB cells. In 3D tumor spheroid model we demonstrated uptake enhancement of QD-FA compared with non-targeted QD. It was demonstrated that penetration profiles were similar for both QDs with penetration depth never exceeding 100 μm. CONCLUSIONS: We have demonstrated the effectiveness of FA conjugated QDs to target tumor spheroids thus confirming the crucial role of FRα receptor as a target. Further improvement of QD-FA targeting ability could be performed using dual targeting different targeting agents, such as FA and cyclic RGD.
BACKGROUND: Quantum dots (QDs) bring new insights in cancer theranostics. Exceptional brightness together with the simple possibility to modify surface with targeting molecules make QDs attractive agents in fluorescence guided surgery and photodynamic therapy. Currently, many targeted QDs have been developed for theranostic purpose. However, their targeting ability was tested mainly in two dimensional monolayer tumor cell models, while our study includes 3D tumor model reflecting the specificity of in vivo tumor environment. METHODS: Core/multilayer shell CdSe/CdS/ZnS QDs were conjugated with folic acid (FA) and characterized spectroscopically. Cytotoxicity of QDs on KB and A549 cells lines were evaluated using the MTT assay. Cellular uptake of QDs was assessed by epifluorescent microscopy. To study the distribution of QDs in tumor tissue, KB spheroids were prepared by means of the liquid overlay technique and then frozen cut of spheroids treated with QDs were imaged by epifluorescence microscopy. RESULTS: We confirmed the specificity of QD-FA for the folic acid receptor positive KB cells. In 3D tumor spheroid model we demonstrated uptake enhancement of QD-FA compared with non-targeted QD. It was demonstrated that penetration profiles were similar for both QDs with penetration depth never exceeding 100 μm. CONCLUSIONS: We have demonstrated the effectiveness of FA conjugated QDs to target tumor spheroids thus confirming the crucial role of FRα receptor as a target. Further improvement of QD-FA targeting ability could be performed using dual targeting different targeting agents, such as FA and cyclic RGD.