Abstract

The accumulation of potassium (K+) in the tumor microenvironment (TME) has been recently shown to inhibit immune cell efficacy, and thus immunotherapy. Despite the abundance of K+ in the body, few ways exist to measure it in vivo. To address this technology gap, we combine an optical K+ nanosensor with photoacoustic (PA) imaging. Using multi-wavelength deconvolution, we are able to quantitatively evaluate the TME K+ concentration in vivo, and its distribution. Significantly elevated K+ levels were found in the TME, with an average concentration of approximately 29 mM, compared to 19 mM found in muscle. These PA measurements were confirmed by extraction of the tumor interstitial fluid and subsequent measurement via inductively coupled plasma mass spectrometry.

© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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2019 (4)

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

J. Jo, C. H. Lee, J. Folz, J. W. Y. Tan, X. Wang, and R. Kopelman, “In Vivo Photoacoustic Lifetime Based Oxygen Imaging with Tumor Targeted G2 Polyacrylamide Nanosonophores,” ACS Nano 13(12), 14024–14032 (2019).
[Crossref]

W. Huang, R. Chen, Y. Peng, F. Duan, Y. Huang, W. Guo, X. Chen, and L. Nie, “In Vivo Quantitative Photoacoustic Diagnosis of Gastric and Intestinal Dysfunctions with a Broad pH-Responsive Sensor,” ACS Nano 13(8), 9561–9570 (2019).
[Crossref]

M. U. Arabul, M. C. M. Rutten, P. Bruneval, M. R. H. M. van Sambeek, F. N. van de Vosse, and R. G. P. Lopata, “Unmixing multi-spectral photoacoustic sources in human carotid plaques using non-negative independent component analysis,” Photoacoustics 15, 100140 (2019).
[Crossref]

2018 (1)

E. Merčep, X. L. Deán-Ben, and D. Razansky, “Imaging of blood flow and oxygen state with a multi-segment optoacoustic ultrasound array,” Photoacoustics 10, 48–53 (2018).
[Crossref]

2017 (2)

C. H. Lee, J. Folz, W. Zhang, J. Jo, J. W. Y. Tan, X. Wang, and R. Kopelman, “Ion-Selective Nanosensor for Photoacoustic and Fluorescence Imaging of Potassium,” Anal. Chem. 89(15), 7943–7949 (2017).
[Crossref]

J. Jo, C. H. Lee, R. Kopelman, and X. Wang, “In vivo quantitative imaging of tumor pH by nanosonophore assisted multispectral photoacoustic imaging,” Nat. Commun. 8(1), 471 (2017).
[Crossref]

2016 (2)

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

X. Xie, I. Szilagyi, J. Zhai, L. Wang, and E. Bakker, “Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation,” ACS Sens. 1(5), 516–520 (2016).
[Crossref]

2015 (3)

K. J. Cash, C. Li, J. Xia, L. V. Wang, and H. A. Clark, “Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo,” ACS Nano 9(2), 1692–1698 (2015).
[Crossref]

Q. Shao and S. Ashkenazi, “Photoacoustic lifetime imaging for direct in vivo tissue oxygen monitoring,” J. Biomed. Opt. 20(3), 036004 (2015).
[Crossref]

D. V. Dibrova, M. Y. Galperin, E. V. Koonin, and A. Y. Mulkidjanian, “Ancient Systems of Sodium/Potassium Homeostasis as Predecessors of Membrane Bioenergetics,” Biochemistry (Moscow) 80(5), 495–516 (2015).
[Crossref]

2014 (2)

I. A. Elabyad, R. Kalayciyan, N. C. Shanbhag, and L. R. Schad, “First In Vivo Potassium-39 (39 K) MRI at 9.4 T Using Conventional Copper Radio Frequency Surface Coil Cooled to 77 K,” IEEE Trans. Biomed. Eng. 61(2), 334–345 (2014).
[Crossref]

A. Pitto-Barry and N. P. E. Barry, “Pluronic® block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances,” Polym. Chem. 5(10), 3291–3297 (2014).
[Crossref]

2013 (4)

G. P. Luke, S. Y. Nam, and S. Y. Emelianov, “Optical wavelength selection for improved spectroscopic photoacoustic imaging,” Photoacoustics 1(2), 36–42 (2013).
[Crossref]

L. J. Steven, “Optical properties of biological tissues: a review,” Phys. Med. Biol. 58(11), R37–R61 (2013).
[Crossref]

R. Umathum, M. B. Rösler, and A. M. Nagel, “In Vivo 39 K MR Imaging of Human Muscle and Brain,” Radiology 269(2), 569–576 (2013).
[Crossref]

Q. Shao, E. Morgounova, C. Jiang, J. Choi, J. Bischof, and S. Ashkenazi, “In vivo photoacoustic lifetime imaging of tumor hypoxia in small animals,” J. Biomed. Opt. 18(7), 076019 (2013).
[Crossref]

2012 (2)

A. Ray, J. R. Rajian, Y.-E. K. Lee, X. Wang, and R. Kopelman, “Lifetime-based photoacoustic oxygen sensing in vivo,” J. Biomed. Opt. 17(5), 057004 (2012).
[Crossref]

K. Daoudi, A. Hussain, E. Hondebrink, and W. Steenbergen, “Correcting photoacoustic signals for fluence variations using acousto-optic modulation,” Opt. Express 20(13), 14117–14129 (2012).
[Crossref]

2011 (3)

A. Bauer, R. Nothdurft, J. Culver, T. Erpelding, and L. Wang, “Quantitative photoacoustic imaging: correcting for heterogeneous light fluence distributions using diffuse optical tomography,” J. Biomed. Opt. 16(9), 096016 (2011).
[Crossref]

S. Kim, Y.-S. Chen, G. P. Luke, and S. Y. Emelianov, “In vivo three-dimensional spectroscopic photoacoustic imaging for monitoring nanoparticle delivery,” Biomed. Opt. Express 2(9), 2540–2550 (2011).
[Crossref]

I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunotherapy comes of age,” Nature 480(7378), 480–489 (2011).
[Crossref]

2009 (2)

M. Augath, P. Heiler, S. Kirsch, and L. R. Schad, “In vivo 39 K, 23Na and 1H MR imaging using a triple resonant RF coil setup,” J. Magn. Reson. 200(1), 134–136 (2009).
[Crossref]

L. V. Wang, “Multiscale photoacoustic microscopy and computed tomography,” Nat. Photonics 3(9), 503–509 (2009).
[Crossref]

2007 (1)

K. Maslov, H. F. Zhang, and L. V. Wang, “Effects of wavelength-dependent fluence attenuation on the noninvasive photoacoustic imaging of hemoglobin oxygen saturation in subcutaneous vasculaturein vivo,” Inverse Probl. 23(6), S113–S122 (2007).
[Crossref]

2006 (1)

M. Xu and L. Wang, “Photoacoustic Imaging in Biomedicine,” Rev. Sci. Instrum. 77(4), 041101 (2006).
[Crossref]

2003 (2)

H. Wiig, K. Aukland, and O. Tenstad, “Isolation of interstitial fluid from rat mammary tumors by a centrifugation method,” Am J Physiol-Heart C 284(1), H416–H424 (2003).
[Crossref]

M. G. Brasuel, T. J. Miller, R. Kopelman, and M. A. Philbert, “Liquid polymer nano-PEBBLEs for Cl- analysis and biological applications,” Analyst 128(10), 1262–1267 (2003).
[Crossref]

1998 (1)

S. L. R. Barker, B. A. Thorsrud, and R. Kopelman, “Nitrite- and Chloride-Selective Fluorescent Nano-Optodes and in Vitro Application to Rat Conceptuses,” Anal. Chem. 70(1), 100–104 (1998).
[Crossref]

1997 (1)

C. D. Bortner, F. M. Hughes, and J. A. Cidlowski, “A Primary Role for K and Na Efflux in the Activation of Apoptosis,” J. Biol. Chem. 272(51), 32436–32442 (1997).
[Crossref]

1996 (1)

M. Shortreed, E. Bakker, and R. Kopelman, “Miniature Sodium-Selective Ion-Exchange Optode with Fluorescent pH Chromoionophores and Tunable Dynamic Range,” Anal. Chem. 68(15), 2656–2662 (1996).
[Crossref]

1995 (1)

W. D. Stein, “The Sodium Pump in the Evolution of Animal Cells,” Philos. Trans. R. Soc., B 349(1329), 263–269 (1995).
[Crossref]

Arabul, M. U.

M. U. Arabul, M. C. M. Rutten, P. Bruneval, M. R. H. M. van Sambeek, F. N. van de Vosse, and R. G. P. Lopata, “Unmixing multi-spectral photoacoustic sources in human carotid plaques using non-negative independent component analysis,” Photoacoustics 15, 100140 (2019).
[Crossref]

Ashkenazi, S.

Q. Shao and S. Ashkenazi, “Photoacoustic lifetime imaging for direct in vivo tissue oxygen monitoring,” J. Biomed. Opt. 20(3), 036004 (2015).
[Crossref]

Q. Shao, E. Morgounova, C. Jiang, J. Choi, J. Bischof, and S. Ashkenazi, “In vivo photoacoustic lifetime imaging of tumor hypoxia in small animals,” J. Biomed. Opt. 18(7), 076019 (2013).
[Crossref]

S. Ashkenazi, S. W. Huang, T. Horvath, Y. E. L. Koo, and R. Kopelman, “Oxygen sensing for in vivo imaging by photoacoustic lifetime probing,” in 2008), 68560D-68560D-68565.

Augath, M.

M. Augath, P. Heiler, S. Kirsch, and L. R. Schad, “In vivo 39 K, 23Na and 1H MR imaging using a triple resonant RF coil setup,” J. Magn. Reson. 200(1), 134–136 (2009).
[Crossref]

Aukland, K.

H. Wiig, K. Aukland, and O. Tenstad, “Isolation of interstitial fluid from rat mammary tumors by a centrifugation method,” Am J Physiol-Heart C 284(1), H416–H424 (2003).
[Crossref]

Bakker, E.

X. Xie, I. Szilagyi, J. Zhai, L. Wang, and E. Bakker, “Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation,” ACS Sens. 1(5), 516–520 (2016).
[Crossref]

M. Shortreed, E. Bakker, and R. Kopelman, “Miniature Sodium-Selective Ion-Exchange Optode with Fluorescent pH Chromoionophores and Tunable Dynamic Range,” Anal. Chem. 68(15), 2656–2662 (1996).
[Crossref]

Barker, S. L. R.

S. L. R. Barker, B. A. Thorsrud, and R. Kopelman, “Nitrite- and Chloride-Selective Fluorescent Nano-Optodes and in Vitro Application to Rat Conceptuses,” Anal. Chem. 70(1), 100–104 (1998).
[Crossref]

Barry, N. P. E.

A. Pitto-Barry and N. P. E. Barry, “Pluronic® block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances,” Polym. Chem. 5(10), 3291–3297 (2014).
[Crossref]

Bauer, A.

A. Bauer, R. Nothdurft, J. Culver, T. Erpelding, and L. Wang, “Quantitative photoacoustic imaging: correcting for heterogeneous light fluence distributions using diffuse optical tomography,” J. Biomed. Opt. 16(9), 096016 (2011).
[Crossref]

Bischof, J.

Q. Shao, E. Morgounova, C. Jiang, J. Choi, J. Bischof, and S. Ashkenazi, “In vivo photoacoustic lifetime imaging of tumor hypoxia in small animals,” J. Biomed. Opt. 18(7), 076019 (2013).
[Crossref]

Bortner, C. D.

C. D. Bortner, F. M. Hughes, and J. A. Cidlowski, “A Primary Role for K and Na Efflux in the Activation of Apoptosis,” J. Biol. Chem. 272(51), 32436–32442 (1997).
[Crossref]

Brasuel, M.

E. M. Y. E. Koo Lee, M. Brasuel, M. Philbert, and R. Kopelman, “PEBBLE Nanosensors for In Vitro Bioanalysis,” in CRC Biomedical Photonics Handbook, 2nd ed., T. Vo-Dinh, ed. (CRC Press, Boca Raton, 2014), p. 767.

Brasuel, M. G.

M. G. Brasuel, T. J. Miller, R. Kopelman, and M. A. Philbert, “Liquid polymer nano-PEBBLEs for Cl- analysis and biological applications,” Analyst 128(10), 1262–1267 (2003).
[Crossref]

Bruneval, P.

M. U. Arabul, M. C. M. Rutten, P. Bruneval, M. R. H. M. van Sambeek, F. N. van de Vosse, and R. G. P. Lopata, “Unmixing multi-spectral photoacoustic sources in human carotid plaques using non-negative independent component analysis,” Photoacoustics 15, 100140 (2019).
[Crossref]

Carbonaro, V.

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Cash, K. J.

K. J. Cash, C. Li, J. Xia, L. V. Wang, and H. A. Clark, “Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo,” ACS Nano 9(2), 1692–1698 (2015).
[Crossref]

Chen, R.

W. Huang, R. Chen, Y. Peng, F. Duan, Y. Huang, W. Guo, X. Chen, and L. Nie, “In Vivo Quantitative Photoacoustic Diagnosis of Gastric and Intestinal Dysfunctions with a Broad pH-Responsive Sensor,” ACS Nano 13(8), 9561–9570 (2019).
[Crossref]

Chen, X.

W. Huang, R. Chen, Y. Peng, F. Duan, Y. Huang, W. Guo, X. Chen, and L. Nie, “In Vivo Quantitative Photoacoustic Diagnosis of Gastric and Intestinal Dysfunctions with a Broad pH-Responsive Sensor,” ACS Nano 13(8), 9561–9570 (2019).
[Crossref]

Q. Yu, S. Huang, Z. Wu, J. Zheng, X. Chen, and L. Nie, “Label-free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-guided Surgery by Photoacoustic Imaging,” J. Nucl. Med. (2019).

Chen, Y.-S.

Choi, J.

Q. Shao, E. Morgounova, C. Jiang, J. Choi, J. Bischof, and S. Ashkenazi, “In vivo photoacoustic lifetime imaging of tumor hypoxia in small animals,” J. Biomed. Opt. 18(7), 076019 (2013).
[Crossref]

Cidlowski, J. A.

C. D. Bortner, F. M. Hughes, and J. A. Cidlowski, “A Primary Role for K and Na Efflux in the Activation of Apoptosis,” J. Biol. Chem. 272(51), 32436–32442 (1997).
[Crossref]

Clark, H. A.

K. J. Cash, C. Li, J. Xia, L. V. Wang, and H. A. Clark, “Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo,” ACS Nano 9(2), 1692–1698 (2015).
[Crossref]

Clever, D.

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Coukos, G.

I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunotherapy comes of age,” Nature 480(7378), 480–489 (2011).
[Crossref]

Culver, J.

A. Bauer, R. Nothdurft, J. Culver, T. Erpelding, and L. Wang, “Quantitative photoacoustic imaging: correcting for heterogeneous light fluence distributions using diffuse optical tomography,” J. Biomed. Opt. 16(9), 096016 (2011).
[Crossref]

Daoudi, K.

Deán-Ben, X. L.

E. Merčep, X. L. Deán-Ben, and D. Razansky, “Imaging of blood flow and oxygen state with a multi-segment optoacoustic ultrasound array,” Photoacoustics 10, 48–53 (2018).
[Crossref]

Dibrova, D. V.

D. V. Dibrova, M. Y. Galperin, E. V. Koonin, and A. Y. Mulkidjanian, “Ancient Systems of Sodium/Potassium Homeostasis as Predecessors of Membrane Bioenergetics,” Biochemistry (Moscow) 80(5), 495–516 (2015).
[Crossref]

Dranoff, G.

I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunotherapy comes of age,” Nature 480(7378), 480–489 (2011).
[Crossref]

Duan, F.

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A. Ray, J. R. Rajian, Y.-E. K. Lee, X. Wang, and R. Kopelman, “Lifetime-based photoacoustic oxygen sensing in vivo,” J. Biomed. Opt. 17(5), 057004 (2012).
[Crossref]

Ray, A.

A. Ray, J. R. Rajian, Y.-E. K. Lee, X. Wang, and R. Kopelman, “Lifetime-based photoacoustic oxygen sensing in vivo,” J. Biomed. Opt. 17(5), 057004 (2012).
[Crossref]

Razansky, D.

E. Merčep, X. L. Deán-Ben, and D. Razansky, “Imaging of blood flow and oxygen state with a multi-segment optoacoustic ultrasound array,” Photoacoustics 10, 48–53 (2018).
[Crossref]

Restifo, N. P.

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Rösler, M. B.

R. Umathum, M. B. Rösler, and A. M. Nagel, “In Vivo 39 K MR Imaging of Human Muscle and Brain,” Radiology 269(2), 569–576 (2013).
[Crossref]

Roychoudhuri, R.

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Rutten, M. C. M.

M. U. Arabul, M. C. M. Rutten, P. Bruneval, M. R. H. M. van Sambeek, F. N. van de Vosse, and R. G. P. Lopata, “Unmixing multi-spectral photoacoustic sources in human carotid plaques using non-negative independent component analysis,” Photoacoustics 15, 100140 (2019).
[Crossref]

Schad, L. R.

I. A. Elabyad, R. Kalayciyan, N. C. Shanbhag, and L. R. Schad, “First In Vivo Potassium-39 (39 K) MRI at 9.4 T Using Conventional Copper Radio Frequency Surface Coil Cooled to 77 K,” IEEE Trans. Biomed. Eng. 61(2), 334–345 (2014).
[Crossref]

M. Augath, P. Heiler, S. Kirsch, and L. R. Schad, “In vivo 39 K, 23Na and 1H MR imaging using a triple resonant RF coil setup,” J. Magn. Reson. 200(1), 134–136 (2009).
[Crossref]

Schrump, D. S.

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Shanbhag, N. C.

I. A. Elabyad, R. Kalayciyan, N. C. Shanbhag, and L. R. Schad, “First In Vivo Potassium-39 (39 K) MRI at 9.4 T Using Conventional Copper Radio Frequency Surface Coil Cooled to 77 K,” IEEE Trans. Biomed. Eng. 61(2), 334–345 (2014).
[Crossref]

Shao, Q.

Q. Shao and S. Ashkenazi, “Photoacoustic lifetime imaging for direct in vivo tissue oxygen monitoring,” J. Biomed. Opt. 20(3), 036004 (2015).
[Crossref]

Q. Shao, E. Morgounova, C. Jiang, J. Choi, J. Bischof, and S. Ashkenazi, “In vivo photoacoustic lifetime imaging of tumor hypoxia in small animals,” J. Biomed. Opt. 18(7), 076019 (2013).
[Crossref]

Shin, M.

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

Shortreed, M.

M. Shortreed, E. Bakker, and R. Kopelman, “Miniature Sodium-Selective Ion-Exchange Optode with Fluorescent pH Chromoionophores and Tunable Dynamic Range,” Anal. Chem. 68(15), 2656–2662 (1996).
[Crossref]

Sigel, A.

A. Sigel, H. Sigel, and R. K. Sigel, Interrelations between essential metal ions and human diseases, 1 ed. (Springer).

Sigel, H.

A. Sigel, H. Sigel, and R. K. Sigel, Interrelations between essential metal ions and human diseases, 1 ed. (Springer).

Sigel, R. K.

A. Sigel, H. Sigel, and R. K. Sigel, Interrelations between essential metal ions and human diseases, 1 ed. (Springer).

Steenbergen, W.

Stein, W. D.

W. D. Stein, “The Sodium Pump in the Evolution of Animal Cells,” Philos. Trans. R. Soc., B 349(1329), 263–269 (1995).
[Crossref]

Steven, L. J.

L. J. Steven, “Optical properties of biological tissues: a review,” Phys. Med. Biol. 58(11), R37–R61 (2013).
[Crossref]

Sukumar, M.

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Szilagyi, I.

X. Xie, I. Szilagyi, J. Zhai, L. Wang, and E. Bakker, “Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation,” ACS Sens. 1(5), 516–520 (2016).
[Crossref]

Tan, J. W. Y.

J. Jo, C. H. Lee, J. Folz, J. W. Y. Tan, X. Wang, and R. Kopelman, “In Vivo Photoacoustic Lifetime Based Oxygen Imaging with Tumor Targeted G2 Polyacrylamide Nanosonophores,” ACS Nano 13(12), 14024–14032 (2019).
[Crossref]

C. H. Lee, J. Folz, W. Zhang, J. Jo, J. W. Y. Tan, X. Wang, and R. Kopelman, “Ion-Selective Nanosensor for Photoacoustic and Fluorescence Imaging of Potassium,” Anal. Chem. 89(15), 7943–7949 (2017).
[Crossref]

Tenstad, O.

H. Wiig, K. Aukland, and O. Tenstad, “Isolation of interstitial fluid from rat mammary tumors by a centrifugation method,” Am J Physiol-Heart C 284(1), H416–H424 (2003).
[Crossref]

Thorsrud, B. A.

S. L. R. Barker, B. A. Thorsrud, and R. Kopelman, “Nitrite- and Chloride-Selective Fluorescent Nano-Optodes and in Vitro Application to Rat Conceptuses,” Anal. Chem. 70(1), 100–104 (1998).
[Crossref]

Umathum, R.

R. Umathum, M. B. Rösler, and A. M. Nagel, “In Vivo 39 K MR Imaging of Human Muscle and Brain,” Radiology 269(2), 569–576 (2013).
[Crossref]

van de Vosse, F. N.

M. U. Arabul, M. C. M. Rutten, P. Bruneval, M. R. H. M. van Sambeek, F. N. van de Vosse, and R. G. P. Lopata, “Unmixing multi-spectral photoacoustic sources in human carotid plaques using non-negative independent component analysis,” Photoacoustics 15, 100140 (2019).
[Crossref]

van Sambeek, M. R. H. M.

M. U. Arabul, M. C. M. Rutten, P. Bruneval, M. R. H. M. van Sambeek, F. N. van de Vosse, and R. G. P. Lopata, “Unmixing multi-spectral photoacoustic sources in human carotid plaques using non-negative independent component analysis,” Photoacoustics 15, 100140 (2019).
[Crossref]

Vodnala, S. K.

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Wang, L.

X. Xie, I. Szilagyi, J. Zhai, L. Wang, and E. Bakker, “Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation,” ACS Sens. 1(5), 516–520 (2016).
[Crossref]

A. Bauer, R. Nothdurft, J. Culver, T. Erpelding, and L. Wang, “Quantitative photoacoustic imaging: correcting for heterogeneous light fluence distributions using diffuse optical tomography,” J. Biomed. Opt. 16(9), 096016 (2011).
[Crossref]

M. Xu and L. Wang, “Photoacoustic Imaging in Biomedicine,” Rev. Sci. Instrum. 77(4), 041101 (2006).
[Crossref]

Wang, L. V.

K. J. Cash, C. Li, J. Xia, L. V. Wang, and H. A. Clark, “Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo,” ACS Nano 9(2), 1692–1698 (2015).
[Crossref]

L. V. Wang, “Multiscale photoacoustic microscopy and computed tomography,” Nat. Photonics 3(9), 503–509 (2009).
[Crossref]

K. Maslov, H. F. Zhang, and L. V. Wang, “Effects of wavelength-dependent fluence attenuation on the noninvasive photoacoustic imaging of hemoglobin oxygen saturation in subcutaneous vasculaturein vivo,” Inverse Probl. 23(6), S113–S122 (2007).
[Crossref]

Wang, X.

J. Jo, C. H. Lee, J. Folz, J. W. Y. Tan, X. Wang, and R. Kopelman, “In Vivo Photoacoustic Lifetime Based Oxygen Imaging with Tumor Targeted G2 Polyacrylamide Nanosonophores,” ACS Nano 13(12), 14024–14032 (2019).
[Crossref]

J. Jo, C. H. Lee, R. Kopelman, and X. Wang, “In vivo quantitative imaging of tumor pH by nanosonophore assisted multispectral photoacoustic imaging,” Nat. Commun. 8(1), 471 (2017).
[Crossref]

C. H. Lee, J. Folz, W. Zhang, J. Jo, J. W. Y. Tan, X. Wang, and R. Kopelman, “Ion-Selective Nanosensor for Photoacoustic and Fluorescence Imaging of Potassium,” Anal. Chem. 89(15), 7943–7949 (2017).
[Crossref]

A. Ray, J. R. Rajian, Y.-E. K. Lee, X. Wang, and R. Kopelman, “Lifetime-based photoacoustic oxygen sensing in vivo,” J. Biomed. Opt. 17(5), 057004 (2012).
[Crossref]

Wiig, H.

H. Wiig, K. Aukland, and O. Tenstad, “Isolation of interstitial fluid from rat mammary tumors by a centrifugation method,” Am J Physiol-Heart C 284(1), H416–H424 (2003).
[Crossref]

Wu, Z.

Q. Yu, S. Huang, Z. Wu, J. Zheng, X. Chen, and L. Nie, “Label-free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-guided Surgery by Photoacoustic Imaging,” J. Nucl. Med. (2019).

Xia, J.

K. J. Cash, C. Li, J. Xia, L. V. Wang, and H. A. Clark, “Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo,” ACS Nano 9(2), 1692–1698 (2015).
[Crossref]

Xie, X.

X. Xie, I. Szilagyi, J. Zhai, L. Wang, and E. Bakker, “Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation,” ACS Sens. 1(5), 516–520 (2016).
[Crossref]

Xu, M.

M. Xu and L. Wang, “Photoacoustic Imaging in Biomedicine,” Rev. Sci. Instrum. 77(4), 041101 (2006).
[Crossref]

Yamamoto, T. N.

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Yu, Q.

Q. Yu, S. Huang, Z. Wu, J. Zheng, X. Chen, and L. Nie, “Label-free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-guided Surgery by Photoacoustic Imaging,” J. Nucl. Med. (2019).

Yu, Z.

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Zhai, J.

X. Xie, I. Szilagyi, J. Zhai, L. Wang, and E. Bakker, “Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation,” ACS Sens. 1(5), 516–520 (2016).
[Crossref]

Zhang, H. F.

K. Maslov, H. F. Zhang, and L. V. Wang, “Effects of wavelength-dependent fluence attenuation on the noninvasive photoacoustic imaging of hemoglobin oxygen saturation in subcutaneous vasculaturein vivo,” Inverse Probl. 23(6), S113–S122 (2007).
[Crossref]

Zhang, W.

C. H. Lee, J. Folz, W. Zhang, J. Jo, J. W. Y. Tan, X. Wang, and R. Kopelman, “Ion-Selective Nanosensor for Photoacoustic and Fluorescence Imaging of Potassium,” Anal. Chem. 89(15), 7943–7949 (2017).
[Crossref]

Zheng, J.

Q. Yu, S. Huang, Z. Wu, J. Zheng, X. Chen, and L. Nie, “Label-free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-guided Surgery by Photoacoustic Imaging,” J. Nucl. Med. (2019).

ACS Nano (3)

K. J. Cash, C. Li, J. Xia, L. V. Wang, and H. A. Clark, “Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium in Vivo,” ACS Nano 9(2), 1692–1698 (2015).
[Crossref]

J. Jo, C. H. Lee, J. Folz, J. W. Y. Tan, X. Wang, and R. Kopelman, “In Vivo Photoacoustic Lifetime Based Oxygen Imaging with Tumor Targeted G2 Polyacrylamide Nanosonophores,” ACS Nano 13(12), 14024–14032 (2019).
[Crossref]

W. Huang, R. Chen, Y. Peng, F. Duan, Y. Huang, W. Guo, X. Chen, and L. Nie, “In Vivo Quantitative Photoacoustic Diagnosis of Gastric and Intestinal Dysfunctions with a Broad pH-Responsive Sensor,” ACS Nano 13(8), 9561–9570 (2019).
[Crossref]

ACS Sens. (1)

X. Xie, I. Szilagyi, J. Zhai, L. Wang, and E. Bakker, “Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation,” ACS Sens. 1(5), 516–520 (2016).
[Crossref]

Am J Physiol-Heart C (1)

H. Wiig, K. Aukland, and O. Tenstad, “Isolation of interstitial fluid from rat mammary tumors by a centrifugation method,” Am J Physiol-Heart C 284(1), H416–H424 (2003).
[Crossref]

Anal. Chem. (3)

M. Shortreed, E. Bakker, and R. Kopelman, “Miniature Sodium-Selective Ion-Exchange Optode with Fluorescent pH Chromoionophores and Tunable Dynamic Range,” Anal. Chem. 68(15), 2656–2662 (1996).
[Crossref]

S. L. R. Barker, B. A. Thorsrud, and R. Kopelman, “Nitrite- and Chloride-Selective Fluorescent Nano-Optodes and in Vitro Application to Rat Conceptuses,” Anal. Chem. 70(1), 100–104 (1998).
[Crossref]

C. H. Lee, J. Folz, W. Zhang, J. Jo, J. W. Y. Tan, X. Wang, and R. Kopelman, “Ion-Selective Nanosensor for Photoacoustic and Fluorescence Imaging of Potassium,” Anal. Chem. 89(15), 7943–7949 (2017).
[Crossref]

Analyst (1)

M. G. Brasuel, T. J. Miller, R. Kopelman, and M. A. Philbert, “Liquid polymer nano-PEBBLEs for Cl- analysis and biological applications,” Analyst 128(10), 1262–1267 (2003).
[Crossref]

Biochemistry (Moscow) (1)

D. V. Dibrova, M. Y. Galperin, E. V. Koonin, and A. Y. Mulkidjanian, “Ancient Systems of Sodium/Potassium Homeostasis as Predecessors of Membrane Bioenergetics,” Biochemistry (Moscow) 80(5), 495–516 (2015).
[Crossref]

Biomed. Opt. Express (1)

IEEE Trans. Biomed. Eng. (1)

I. A. Elabyad, R. Kalayciyan, N. C. Shanbhag, and L. R. Schad, “First In Vivo Potassium-39 (39 K) MRI at 9.4 T Using Conventional Copper Radio Frequency Surface Coil Cooled to 77 K,” IEEE Trans. Biomed. Eng. 61(2), 334–345 (2014).
[Crossref]

Inverse Probl. (1)

K. Maslov, H. F. Zhang, and L. V. Wang, “Effects of wavelength-dependent fluence attenuation on the noninvasive photoacoustic imaging of hemoglobin oxygen saturation in subcutaneous vasculaturein vivo,” Inverse Probl. 23(6), S113–S122 (2007).
[Crossref]

J. Biol. Chem. (1)

C. D. Bortner, F. M. Hughes, and J. A. Cidlowski, “A Primary Role for K and Na Efflux in the Activation of Apoptosis,” J. Biol. Chem. 272(51), 32436–32442 (1997).
[Crossref]

J. Biomed. Opt. (4)

A. Ray, J. R. Rajian, Y.-E. K. Lee, X. Wang, and R. Kopelman, “Lifetime-based photoacoustic oxygen sensing in vivo,” J. Biomed. Opt. 17(5), 057004 (2012).
[Crossref]

Q. Shao, E. Morgounova, C. Jiang, J. Choi, J. Bischof, and S. Ashkenazi, “In vivo photoacoustic lifetime imaging of tumor hypoxia in small animals,” J. Biomed. Opt. 18(7), 076019 (2013).
[Crossref]

Q. Shao and S. Ashkenazi, “Photoacoustic lifetime imaging for direct in vivo tissue oxygen monitoring,” J. Biomed. Opt. 20(3), 036004 (2015).
[Crossref]

A. Bauer, R. Nothdurft, J. Culver, T. Erpelding, and L. Wang, “Quantitative photoacoustic imaging: correcting for heterogeneous light fluence distributions using diffuse optical tomography,” J. Biomed. Opt. 16(9), 096016 (2011).
[Crossref]

J. Magn. Reson. (1)

M. Augath, P. Heiler, S. Kirsch, and L. R. Schad, “In vivo 39 K, 23Na and 1H MR imaging using a triple resonant RF coil setup,” J. Magn. Reson. 200(1), 134–136 (2009).
[Crossref]

Nat. Commun. (1)

J. Jo, C. H. Lee, R. Kopelman, and X. Wang, “In vivo quantitative imaging of tumor pH by nanosonophore assisted multispectral photoacoustic imaging,” Nat. Commun. 8(1), 471 (2017).
[Crossref]

Nat. Photonics (1)

L. V. Wang, “Multiscale photoacoustic microscopy and computed tomography,” Nat. Photonics 3(9), 503–509 (2009).
[Crossref]

Nature (2)

I. Mellman, G. Coukos, and G. Dranoff, “Cancer immunotherapy comes of age,” Nature 480(7378), 480–489 (2011).
[Crossref]

R. Eil, S. K. Vodnala, D. Clever, C. A. Klebanoff, M. Sukumar, J. H. Pan, D. C. Palmer, A. Gros, T. N. Yamamoto, S. J. Patel, G. C. Guittard, Z. Yu, V. Carbonaro, K. Okkenhaug, D. S. Schrump, W. M. Linehan, R. Roychoudhuri, and N. P. Restifo, “Ionic immune suppression within the tumour microenvironment limits T cell effector function,” Nature 537(7621), 539–543 (2016).
[Crossref]

Opt. Express (1)

Philos. Trans. R. Soc., B (1)

W. D. Stein, “The Sodium Pump in the Evolution of Animal Cells,” Philos. Trans. R. Soc., B 349(1329), 263–269 (1995).
[Crossref]

Photoacoustics (3)

E. Merčep, X. L. Deán-Ben, and D. Razansky, “Imaging of blood flow and oxygen state with a multi-segment optoacoustic ultrasound array,” Photoacoustics 10, 48–53 (2018).
[Crossref]

M. U. Arabul, M. C. M. Rutten, P. Bruneval, M. R. H. M. van Sambeek, F. N. van de Vosse, and R. G. P. Lopata, “Unmixing multi-spectral photoacoustic sources in human carotid plaques using non-negative independent component analysis,” Photoacoustics 15, 100140 (2019).
[Crossref]

G. P. Luke, S. Y. Nam, and S. Y. Emelianov, “Optical wavelength selection for improved spectroscopic photoacoustic imaging,” Photoacoustics 1(2), 36–42 (2013).
[Crossref]

Phys. Med. Biol. (1)

L. J. Steven, “Optical properties of biological tissues: a review,” Phys. Med. Biol. 58(11), R37–R61 (2013).
[Crossref]

Polym. Chem. (1)

A. Pitto-Barry and N. P. E. Barry, “Pluronic® block-copolymers in medicine: from chemical and biological versatility to rationalisation and clinical advances,” Polym. Chem. 5(10), 3291–3297 (2014).
[Crossref]

Radiology (1)

R. Umathum, M. B. Rösler, and A. M. Nagel, “In Vivo 39 K MR Imaging of Human Muscle and Brain,” Radiology 269(2), 569–576 (2013).
[Crossref]

Rev. Sci. Instrum. (1)

M. Xu and L. Wang, “Photoacoustic Imaging in Biomedicine,” Rev. Sci. Instrum. 77(4), 041101 (2006).
[Crossref]

Science (1)

S. K. Vodnala, R. Eil, R. J. Kishton, M. Sukumar, T. N. Yamamoto, N.-H. Ha, P.-H. Lee, M. Shin, S. J. Patel, Z. Yu, D. C. Palmer, M. J. Kruhlak, X. Liu, J. W. Locasale, J. Huang, R. Roychoudhuri, T. Finkel, C. A. Klebanoff, and N. P. Restifo, “T cell stemness and dysfunction in tumors are triggered by a common mechanism,” Science 363(6434), eaau0135 (2019).
[Crossref]

Other (5)

A. Sigel, H. Sigel, and R. K. Sigel, Interrelations between essential metal ions and human diseases, 1 ed. (Springer).

S. Ashkenazi, S. W. Huang, T. Horvath, Y. E. L. Koo, and R. Kopelman, “Oxygen sensing for in vivo imaging by photoacoustic lifetime probing,” in 2008), 68560D-68560D-68565.

M. Kroll, “Tietz Textbook of Clinical Chemistry, 3 Edition. Carl A. Burtis and Edward R. Ashwood, eds. WB Saunders, Philadelphia, PA 1998, 1917 pp., ${\$}$$195.00. ISBN 0-7216-5610-2,” Clinical Chemistry 45, 913-914 (1999).

E. M. Y. E. Koo Lee, M. Brasuel, M. Philbert, and R. Kopelman, “PEBBLE Nanosensors for In Vitro Bioanalysis,” in CRC Biomedical Photonics Handbook, 2nd ed., T. Vo-Dinh, ed. (CRC Press, Boca Raton, 2014), p. 767.

Q. Yu, S. Huang, Z. Wu, J. Zheng, X. Chen, and L. Nie, “Label-free Visualization of Early Cancer Hepatic Micrometastasis and Intraoperative Image-guided Surgery by Photoacoustic Imaging,” J. Nucl. Med. (2019).

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Figures (12)

Fig. 1.
Fig. 1. General PA setup for in vitro and in vivo imaging. For acoustic coupling, in vitro tube experiments were conducted in water, while in vivo mice experiments were conducted using ultrasound gel. A partial reflector (glass slide) was used to reflect part (<20%) of the laser beam energy to the power meter for energy monitoring. The PA signal was acquired using an ultrasound transducer (CL15-7) connected to a research ultrasound acquisition system (Vantage 256, Verasonics, Kirkland, WA, USA).
Fig. 2.
Fig. 2. Absorption spectra and PA K+ calibrations compared to UV-Vis K+ calibrations. (a) Absorption spectra of SDKNP for various K+ concentrations, oxyhemoglobin (HbO2), and deoxyhemoglobin (Hb). PA and UV-Vis ratio measurements for (b) 625 nm/560 nm, (c) 605 nm/560 nm, (d) 584 nm/560 nm, (e) 576 nm/560 nm, and (f) 545 nm/560 nm. There is excellent agreement between the PA and UV-Vis calibrations.
Fig. 3.
Fig. 3. PA multi-wavelength unmixing for SDKNP samples in a tube for determining total hemoglobin concentration ([THb]), SDKNP concentration ([SDKNP]), and K+ concentration ([K+]). All samples contain a constant 10 mg/mL SDKNP and 1% blood v/v at the specified K+ concentrations, with exception of “Blank”, which only contains saline solution. Sample values of K+ are provided at the top of the figure, while the measured values obtained via deconvolution are given at the bottom of the figure. Measured values pertain to the average K+ in the region of interest outlined by the white box.
Fig. 4.
Fig. 4. In vivo PA imaging with overlaid ultrasound images of subcutaneous tumors and thigh muscles (control) in nude mice. (a) Multi-wavelength unmixing performed to identify the hemoglobin oxygenation saturation (%SO2), SDKNP concentration ([SDKNP]), and K+ concentration ([K+]). With exception of [K+], images do not show 0 concentration values for better image clarity. Additionally, [K+] concentrations are only shown where [SDKNP] are also present. The average value across all mice (n=6) in the tumor and the muscle for (b) %SO2, (c) [SDKNP], and (d) [K+], as determined by multi-wavelength unmixing. ‘N.S.’ indicates no significance, ‘*’ indicates p < 0.05.
Fig. 5.
Fig. 5. Average [K+] measurement in the tumor from PACI vs ICP. Average [K+] in the tumor for (a) individual mouse measurements, and (b) across all mouse samples (n=6). ‘N.S.’ indicates no significance. (c) Correlation analysis between the ICP and the PACI measurements.
Fig. 6.
Fig. 6. Further analysis of the measured K+ within the tumor core vs the tumor periphery. (a) An overlaid PA and ultrasound image showing the regions of interest of the core and the periphery, outlined in red. (b) Measured K+ concentrations for each mouse for the tumor core and the tumor periphery.
Fig. 7.
Fig. 7. Mass spectrum of the synthesized and purified dye using the protocol described in the methods section. Measurements were made using positive ion electronspray mass spectrometry and performed by the University of Michigan’s Mass Spectrometry Core. The reported mass of the dye was 559.5 Da; we measured a mass of 559.4 Da.
Fig. 8.
Fig. 8. Dynamic Light Scattering measurements of SDKNP diameter. The average nanosensor size is 90 nm, with a PDI of 0.107.
Fig. 9.
Fig. 9. TEM images of the SDKNP taken at 5 mg/mL in water. An average diameter of approximately 50 nm is observed.
Fig. 10.
Fig. 10. A comparison of two calibration curves taken of the SDKNP, both in MBS, and one containing 5 mg/mL human serum albumin. As the figure shows, HSA has no influence on the SDKNP’s function in the biologically relevant concentration ranges (HSA– 5 mg/mL [38]; K+ 1-50 mM).
Fig. 11.
Fig. 11. Results of an MTT assay evaluating the toxicity of the SDKNP. We observe limited toxicity over the first two hours of incubation, but prolonged exposure results in significant cell death. Error bars represent the standard deviation of 4 measurements.
Fig. 12.
Fig. 12. Results of a photostability study of the SDKNP. The normalized PA intensity of the SDKNP is measured as a function of the cumulative light dose and shows a linear decrease with increasing light dose. The black dotted line indicates the expected cumulative light dose in the in vivo imaging (6 wavelengths × 80 images), which corresponds to 88% of the original PA signal at the end of the imaging protocol.

Equations (1)

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P A λ = k ( [ S D K N P ] ε S D K N P ( λ , [ K + ] ) + [ H b O 2 ] ε H b O 2 ( λ ) + [ H b ] ε H b ( λ ) )

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