Thermal modulation of intracellular drug distribution using thermoresponsive polymeric micelles |
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| Affiliation: | 1. Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666, Japan;2. Department of Applied Chemistry, Waseda University, 3-4-1, Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan;3. Kanagawa Academy of Science and Technology, Yokoyama “Nano-medical polymers” project, KSP East 404, Sakado 3-2-1, Takatsu-ku, Kawasaki-shi, Kanagawa 213-0012, Japan;1. Graduate School of Materials Science, Japan Advanced Institute of Science and Technology, 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan;2. The University of Tokyo, Department of Materials Engineering, Bld. #4, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan;3. Saitama Institute of Technology, Department of Applied Chemistry, 1690 Fusaiji, Fukaya, Saitama, 369-0293 Japan;1. Department of Engineering “Enzo Ferrari”, Via Vignolese 905, 41125, Modena, Italy;2. Department of Industrial Engineering, Parco Area delle Scienze 181/A, 43124, Parma, Italy;3. University of Torino, Department of Chemistry, Via Pietro Giuria 7, 10125, Torino, Italy;4. I.N.Ri.M., Electromagnetism, Strada delle Cacce 91, 10138, Torino, Italy;5. Politecnico di Torino, DISAT, Corso Duca degli Abruzzi 24, 10129, Torino, Italy;1. Département de chimie, Centre de recherche sur les matériaux auto–assemblés (CRMAA/CSACS), Université de Montréal, C.P. 6128 Succ. Centre–ville, Montréal, QC H3C 3J7, Canada;2. Centre d''Étude et de Recherche sur les Macromolécules (CERM), Université de Liège, Sart–Tilman, Liège, Belgium;1. Laboratory for Soft Matter and Biophysics, Department of Physics and Astronomy, KU Leuven, Celestijnenlaan 200D, P.O. Box 2416, 3001 Leuven, Belgium;2. Condensed Matter Physics Department, Jo?ef Stefan Institute, 1000 Ljubljana, Slovenia;3. Faculty of Mechanical Engineering, Czech Technical University in Prague, 16000 Prague 6, Czech Republic;4. Experimental Soft Matter and Thermal Physics Laboratory, Department of Physics, Université Libre de Bruxelles, Boulevard du Triomphe, CP223, 1050 Brussels, Belgium |
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| Abstract: | Intracellular distribution of free doxorubicin (DOX) or DOX-loaded in polymeric micelles with thermoresponsive outer shells of poly(N-isopropylacrylamide) or its copolymers in cultured human breast cancer cells (MCF-7) were investigated by fluorescence and confocal laser scanning microscopy. Free DOX accumulated rapidly and selectively in cell nuclei, independent of temperature changes. In contrast to free drugs, the intracellular distribution of DOX-loaded in the thermoresponsive polymeric micelles was significantly affected by temperature changes across lower critical solution temperature (LCST) of the micelles. Above the micelle LCST, DOX delivered by the micelles was localized uniformly inside of MCF-7 cells. By contrast, the amount of DOX delivered to MCF-7 cells drastically decreased below the micelle LCST due to minimal interaction of the micelles with cell membrane surfaces. These results clearly showed that the mechanism of the intracellular drug localization was different between free drugs and DOX-loaded in the micelles. The thermoresponsive micelles aggressively interacted with the cells and carried DOX into the cells via triggered phase transition of the outer shells. In addition, much lower accumulation of free DOX was observed in the resistant cells compared to its parent sensitive MCF-7 due to the resistant mechanism. Of interest, DOX accumulation in the resistant cells was almost in the same level as with MCF-7 (sensitive) cells for the micelle system above the LCST. |
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