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Hybrid imaging labels : providing the link between mass spectrometry-based molecular pathology and theranostics

Tessa Buckle, Steffen van der Wal, Stijn Van Malderen UGent, Larissa Müller, Joeri Kuil, Vincent van Unen, Ruud JB Peters, Margaretha EM van Bemmel, Liam A McDonnell, Aldrik H Velders, et al. (2017) THERANOSTICS . 7(3). p.624-633
abstract
Background: Development of theranostic concepts that include inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS (LA-ICP-MS) imaging can be hindered by the lack of a direct comparison to more standardly used methods for in vitro and in vivo evaluation; e.g. fluorescence or nuclear medicine. In this study a bimodal (or rather, hybrid) tracer that contains both a fluorescent dye and a chelate was used to evaluate the existence of a direct link between mass spectrometry (MS) and in vitro and in vivo molecular imaging findings using fluorescence and radioisotopes. At the same time, the hybrid label was used to determine whether the use of a single isotope label would allow for MS-based diagnostics. Methods: A hybrid label that contained both a DTPA chelate (that was coordinated with either Ho-165 or In-111) and a Cy5 fluorescent dye was coupled to the chemokine receptor 4 (CXCR4) targeting peptide Ac-TZ14011 (hybrid-Cy5-Ac-TZ4011). This receptor targeting tracer was used to 1) validate the efficacy of (Ho-165-based) mass-cytometry in determining the receptor affinity via comparison with fluorescence-based flow cytometry (Cy5), 2) evaluate the microscopic binding pattern of the tracer in tumor cells using both fluorescence confocal imaging (Cy5) and LA-ICP-MS-imaging (Ho-165), 3) compare in vivo biodistribution patterns obtained with ICP-MS (Ho-165) and radiodetection (In-111) after intravenous administration of hybrid-Cy5-Ac-TZ4011 in tumor-bearing mice. Finally, LA-ICP-MS-imaging (Ho-165) was linked to fluorescence-based analysis of excised tissue samples (Cy5). Results: Analysis with both mass-cytometry and flow cytometry revealed a similar receptor affinity, respectively 352 +/- 141 nM and 245 +/- 65 nM (p = 0.08), but with a much lower detection sensitivity for the first modality. In vitro LA-ICP-MS imaging (Ho-165) enabled clear discrimination between CXCR4 positive and negative cells, but fluorescence microscopy was required to determine the intracellular distribution. In vivo biodistribution patterns obtained with ICP-MS (Ho-165) and radiodetection (In-111) of the hybrid peptide were shown to be similar. Assessment of tracer distribution in excised tissues revealed the location of tracer uptake with both LA-ICP-MS-imaging and fluorescence imaging. Conclusion: Lanthanide-isotope chelation expands the scope of fluorescent/ radioactive hybrid tracers to include MS-based analytical tools such as mass-cytometry, ICP-MS and LA-ICP-MS imaging in molecular pathology. In contradiction to common expectations, MS detection using a single chelate imaging agent was shown to be feasible, enabling a direct link between nuclear medicine-based imaging and theranostic methods.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
bimodal, fluorescence, molecular imaging, molecular pathology, mass spectrometry, mass cytometry, LA-ICP-MS imaging, radioisotopes, SPECT, CHEMOKINE RECEPTOR CXCR4, MULTIPLE-MYELOMA, BREAST-CANCER, EXPRESSION, CYTOMETRY, BIOASSAYS, THERAPY, POLYMER, TISSUES, DESIGN
journal title
THERANOSTICS
Theranostics
volume
7
issue
3
pages
624 - 633
Web of Science type
Article
Web of Science id
000396557300010
ISSN
1838-7640
DOI
10.7150/thno.17484
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8505996
handle
http://hdl.handle.net/1854/LU-8505996
date created
2017-01-28 17:07:06
date last changed
2017-09-18 14:57:57
@article{8505996,
  abstract     = {Background: Development of theranostic concepts that include inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS (LA-ICP-MS) imaging can be hindered by the lack of a direct comparison to more standardly used methods for in vitro and in vivo evaluation; e.g. fluorescence or nuclear medicine. In this study a bimodal (or rather, hybrid) tracer that contains both a fluorescent dye and a chelate was used to evaluate the existence of a direct link between mass spectrometry (MS) and in vitro and in vivo molecular imaging findings using fluorescence and radioisotopes. At the same time, the hybrid label was used to determine whether the use of a single isotope label would allow for MS-based diagnostics. 
Methods: A hybrid label that contained both a DTPA chelate (that was coordinated with either Ho-165 or In-111) and a Cy5 fluorescent dye was coupled to the chemokine receptor 4 (CXCR4) targeting peptide Ac-TZ14011 (hybrid-Cy5-Ac-TZ4011). This receptor targeting tracer was used to 1) validate the efficacy of (Ho-165-based) mass-cytometry in determining the receptor affinity via comparison with fluorescence-based flow cytometry (Cy5), 2) evaluate the microscopic binding pattern of the tracer in tumor cells using both fluorescence confocal imaging (Cy5) and LA-ICP-MS-imaging (Ho-165), 3) compare in vivo biodistribution patterns obtained with ICP-MS (Ho-165) and radiodetection (In-111) after intravenous administration of hybrid-Cy5-Ac-TZ4011 in tumor-bearing mice. Finally, LA-ICP-MS-imaging (Ho-165) was linked to fluorescence-based analysis of excised tissue samples (Cy5). 
Results: Analysis with both mass-cytometry and flow cytometry revealed a similar receptor affinity, respectively 352 +/- 141 nM and 245 +/- 65 nM (p = 0.08), but with a much lower detection sensitivity for the first modality. In vitro LA-ICP-MS imaging (Ho-165) enabled clear discrimination between CXCR4 positive and negative cells, but fluorescence microscopy was required to determine the intracellular distribution. In vivo biodistribution patterns obtained with ICP-MS (Ho-165) and radiodetection (In-111) of the hybrid peptide were shown to be similar. Assessment of tracer distribution in excised tissues revealed the location of tracer uptake with both LA-ICP-MS-imaging and fluorescence imaging. 
Conclusion: Lanthanide-isotope chelation expands the scope of fluorescent/ radioactive hybrid tracers to include MS-based analytical tools such as mass-cytometry, ICP-MS and LA-ICP-MS imaging in molecular pathology. In contradiction to common expectations, MS detection using a single chelate imaging agent was shown to be feasible, enabling a direct link between nuclear medicine-based imaging and theranostic methods.},
  author       = {Buckle, Tessa and van der Wal, Steffen and Van Malderen, Stijn and M{\"u}ller, Larissa and Kuil, Joeri and van Unen, Vincent and Peters, Ruud JB and van Bemmel, Margaretha EM and McDonnell, Liam A and Velders, Aldrik H and Koning, Frits and Vanhaecke, Frank and van Leeuwen, Fijs WB},
  issn         = {1838-7640},
  journal      = {THERANOSTICS },
  keyword      = {bimodal,fluorescence,molecular imaging,molecular pathology,mass spectrometry,mass cytometry,LA-ICP-MS imaging,radioisotopes,SPECT,CHEMOKINE RECEPTOR CXCR4,MULTIPLE-MYELOMA,BREAST-CANCER,EXPRESSION,CYTOMETRY,BIOASSAYS,THERAPY,POLYMER,TISSUES,DESIGN},
  language     = {eng},
  number       = {3},
  pages        = {624--633},
  title        = {Hybrid imaging labels : providing the link between mass spectrometry-based molecular pathology and theranostics},
  url          = {http://dx.doi.org/10.7150/thno.17484},
  volume       = {7},
  year         = {2017},
}

Chicago
Buckle, Tessa, Steffen van der Wal, Stijn Van Malderen, Larissa Müller, Joeri Kuil, Vincent van Unen, Ruud JB Peters, et al. 2017. “Hybrid Imaging Labels : Providing the Link Between Mass Spectrometry-based Molecular Pathology and Theranostics.” Theranostics 7 (3): 624–633.
APA
Buckle, T., van der Wal, S., Van Malderen, S., Müller, L., Kuil, J., van Unen, V., Peters, R. J., et al. (2017). Hybrid imaging labels : providing the link between mass spectrometry-based molecular pathology and theranostics. THERANOSTICS , 7(3), 624–633.
Vancouver
1.
Buckle T, van der Wal S, Van Malderen S, Müller L, Kuil J, van Unen V, et al. Hybrid imaging labels : providing the link between mass spectrometry-based molecular pathology and theranostics. THERANOSTICS . 2017;7(3):624–33.
MLA
Buckle, Tessa, Steffen van der Wal, Stijn Van Malderen, et al. “Hybrid Imaging Labels : Providing the Link Between Mass Spectrometry-based Molecular Pathology and Theranostics.” THERANOSTICS 7.3 (2017): 624–633. Print.