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Imaging oxygen in neural cell and tissue models by means of anionic cell-permeable phosphorescent nanoparticles

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Abstract

Cell-permeable phosphorescent probes enable the study of cell and tissue oxygenation, bioenergetics, metabolism, and pathological states such as stroke and hypoxia. A number of such probes have been described in recent years, the majority consisting of cationic small molecule and nanoparticle structures. While these probes continue to advance, adequate staining for the study of certain cell types using live imaging techniques remains elusive; this is particularly true for neural cells. Here we introduce novel probes for the analysis of neural cells and tissues: negatively charged poly(methyl methacrylate-co-methacrylic acid)-based nanoparticles impregnated with a phosphorescent Pt(II)-tetrakis(pentafluorophenyl)porphyrin (PtPFPP) dye (this form is referred to as PA1), and with an additional reference/antennae dye poly(9,9-diheptylfluorene-alt-9,9-di-p-tolyl-9H-fluorene) (this form is referred to as PA2). PA1 and PA2 are internalised by endocytosis, result in efficient staining in primary neurons, astrocytes, and PC12 cells and multi-cellular aggregates, and allow for the monitoring of local O2 levels on a time-resolved fluorescence plate reader and PLIM microscope. PA2 also efficiently stains rat brain slices and permits detailed O2 imaging experiments using both one and two-photon intensity-based modes and PLIM modes. Multiplexed analysis of embryonic rat brain slices reveals age-dependent staining patterns for PA2 and a highly heterogeneous distribution of O2 in tissues, which we relate to the localisation of specific progenitor cell populations. Overall, these anionic probes are useful for sensing O2 levels in various cells and tissues, particularly in neural cells, and facilitate high-resolution imaging of O2 in 3D tissue models.

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Abbreviations

3D:

Three-dimensional

BLBP:

Brain lipid-binding protein

CPZ:

Chlorpromazine

CTX:

Cholera toxin, subunit B

DIV:

Days in vitro

DMF:

N,N-dimethylformamide

DMSO:

Dimethyl sulfoxide

EIPA:

5-(N-ethyl-N-isopropyl)amiloride

GFP:

Green fluorescent protein

HBSS:

Hanks balanced salt solution

HXT:

Hoechst 33342

iO2 :

Intracellular O2

MβCD:

Methyl-β-cyclodextrin

NP:

Nanoparticles

PA:

Polyacrylate NP

PBS:

Phosphate buffered saline

PDL:

Poly-d-lysine

PDT:

Photodynamic therapy

PLIM:

Phosphorescence lifetime imaging microscopy

PMMA-MA:

Poly(methyl methacrylate-co-methacrylic acid

PFO:

Poly(9,9-diheptylfluorene-alt-9,9-di-p-tolyl-9H-fluorene)

PtPFPP:

Pt(II)-tetrakis(pentafluorophenyl)porphine

ROI:

Region of interest

RT:

Room temperature

TBST:

Tris-buffered saline, tween 20

TCSPC:

Time-correlated single photon counting

TR-F:

Time-resolved fluorescence

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Acknowledgments

This work was supported by the Science Foundation Ireland, Grant 12/RC/2276, the European Commission FP7 Program, grant FP7-HEALTH-2012-INNOVATION-304842-2, the Irish Research Council for Science, Engineering and Technology, the Health Research Board, the Programme for Research at Third Level Institutions Cycle 4 and Marie Curie IAPP Oxy-Sense (No. 230641). We thank T. Foley and Dr. Y. Nolan (Department of Anatomy and Neuroscience, UCC) for the help with primary neuronal cultures and Dr. Heiko Dussmann (Royal College of Surgeons in Ireland, Dublin) for help with microscopy imaging.

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Authors and Affiliations

  1. School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland

    Ruslan I. Dmitriev, Alina V. Kondrashina, Alexander V. Zhdanov & Dmitri B. Papkovsky

  2. Institute of Analytical Chemistry and Food Chemistry, Graz University of Technology, Stremayrgasse 9, 8010, Graz, Austria

    Sergey M. Borisov & Ingo Klimant

  3. Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland

    Janelle M. P. Pakan & Kieran W. McDermott

  4. Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland

    Ujval Anilkumar & Jochen H. M. Prehn

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  1. Ruslan I. Dmitriev
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Correspondence to Ruslan I. Dmitriev.

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Dmitriev, R.I., Borisov, S.M., Kondrashina, A.V. et al. Imaging oxygen in neural cell and tissue models by means of anionic cell-permeable phosphorescent nanoparticles. Cell. Mol. Life Sci. 72, 367–381 (2015). https://doi.org/10.1007/s00018-014-1673-5

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