Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity.
ZnO nanoparticles (NPs) are reported to show a high degree of cancer cell selectivity with potential use in cancer imaging and therapy. Questions remain about the mode by which the ZnO NPs cause cell death, whether they exert an intra- or extracellular effect, and the resistance among different cancer cell types to ZnO NP exposure. The present study quantifies the variability between the cellular toxicity, dynamics of cellular uptake, and dissolution of bare and RGD (Arg-Gly-Asp)-targeted ZnO NPs by MDA-MB-231 cells. Compared to bare ZnO NPs, RGD-targeting of the ZnO NPs to integrin αvβ3 receptors expressed on MDA-MB-231 cells appears to increase the toxicity of the ZnO NPs to breast cancer cells at lower doses. Confocal microscopy of live MDA-MB-231 cells confirms uptake of both classes of ZnO NPs with a commensurate rise in intracellular Zn(2+) concentration prior to cell death. The response of the cells within the population to intracellular Zn(2+) is highly heterogeneous. In addition, the results emphasize the utility of dynamic and quantitative imaging in understanding cell uptake and processing of targeted therapeutic ZnO NPs at the cellular level by heterogeneous cancer cell populations, which can be crucial for the development of optimized treatment strategies.
Department of Materials, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.
Basmah A
BA
Othman
Cell and Molecular Biology Research Laboratory, Faculty of Medical Sciences, Post Graduate Medical Institute, Anglia Ruskin University, Bishop Hall Lane, Chelmsford, CM1 1SQ, UK.
Christina
C
Greenwood
Cell Migration and Signaling Laboratory, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Engineering (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Ayman F
AF
Abuelela
Department of Bioengineering, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.
Anil A
AA
Bharath
Department of Materials, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.
Shu
S
Chen
Department of Materials, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.
Ioannis
I
Theodorou
Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, IN, 47405, USA.
Trevor
T
Douglas
Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, IN, 47405, USA.
Maskai
M
Uchida
Department of Materials, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.
Mary
M
Ryan
Cell Migration and Signaling Laboratory, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Engineering (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Jasmeen S
JS
Merzaban
Department of Materials, Imperial College London, Royal School of Mines, Exhibition Road, London, SW7 2AZ, UK.|Imperial College London and London Centre for Nanotechnology, London, SW7 2AZ, UK.
Alexandra E
AE
Porter
D017209:Apoptosis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018740:Genetic Heterogeneity / Q000187:drug effects*; D006801:Humans; D008027:Light; D061986:MCF-7 Cells; D053768:Metal Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D008854:Microscopy, Electron / Q000379:methods; D009842:Oligopeptides / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015034:Zinc Oxide / Q000008:administration & dosage* / Q000737:chemistry
D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D015034:Zinc Oxide
cellular targeting; cytotoxicity; integrin αvβ3 receptors; triple negative breast cancer cells; zinc oxide nanoparticles