Elucidating the kinetics of sodium fluorescein for fluorescence-guided surgery of glioma

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  • 1 Thayer School of Engineering and
  • 2 Geisel School of Medicine, Dartmouth College, Hanover; and
  • 3 Department of Surgery,
  • 4 Section of Neurosurgery, and
  • 5 Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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OBJECTIVE

The use of the optical contrast agent sodium fluorescein (NaFl) to guide resection of gliomas has been under investigation for decades. Although this imaging strategy assumes the agent remains confined to the vasculature except in regions of blood-brain barrier (BBB) disruption, clinical studies have reported significant NaFl signal in normal brain tissue, limiting tumor-to-normal contrast. A possible explanation arises from earlier studies, which reported that NaFl exists in both pure and protein-bound forms in the blood, the former being small enough to cross the BBB. This study aims to elucidate the kinetic binding behavior of NaFl in circulating blood and its effect on NaFl accumulation in brain tissue and tumor contrast. Additionally, the authors examined the blood and tissue kinetics, as well as tumor uptake, of a pegylated form of fluorescein selected as a potential optical analog of gadolinium-based MRI contrast agents.

METHODS

Cohorts of mice were administered one of the following doses/forms of NaFl: 1) high human equivalent dose (HED) of NaFl, 2) low HED of NaFl, or 3) pegylated form of fluorescein. In each cohort, groups of animals were euthanized 15, 30, 60, and 120 minutes after administration for ex vivo analysis of fluorescein fluorescence. Using gel electrophoresis and fluorescence imaging of blood and brain specimens, the authors quantified the temporal kinetics of bound NaFl, unbound NaFl, and pegylated fluorescein in the blood and normal brain tissue. Finally, they compared tumor-to-normal contrast for NaFl and pegylated-fluorescein in U251 glioma xenografts.

RESULTS

Administration of NaFl resulted in the presence of unbound and protein-bound NaFl in the circulation, with unbound NaFl constituting up to 70% of the signal. While protein-bound NaFl was undetectable in brain tissue, unbound NaFl was observed throughout the brain. The observed behavior was time and dose dependent. The pegylated form of fluorescein showed minimal uptake in brain tissue and improved tumor-to-normal contrast by 38%.

CONCLUSIONS

Unbound NaFl in the blood crosses the BBB, limiting the achievable tumor-to-normal contrast and undermining the inherent advantage of tumor imaging in the brain. Dosing and incubation time should be considered carefully for NaFl-based fluorescence-guided surgery (FGS) of glioma. A pegylated form of fluorescein showed more favorable normal tissue kinetics that translated to higher tumor-to-normal contrast. These results warrant further development of pegylated-fluorescein for FGS of glioma.

ABBREVIATIONS BBB = blood-brain barrier; FGS = fluorescence-guided surgery; HED = human equivalent dose; NaFl = sodium fluorescein; PBS = phosphate-buffered saline; ROI = region of interest.

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Contributor Notes

Correspondence Scott C. Davis: Thayer School of Engineering at Dartmouth College, Hanover, NH. scott.c.davis@dartmouth.edu.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

INCLUDE WHEN CITING Published online September 7, 2018; DOI: 10.3171/2018.4.JNS172644.

  • 1

    Acerbi F, Broggi M, Eoli M, Anghileri E, Cuppini L, Pollo B, : Fluorescein-guided surgery for grade IV gliomas with a dedicated filter on the surgical microscope: preliminary results in 12 cases. Acta Neurochir (Wien) 155:12771286, 2013

    • Search Google Scholar
    • Export Citation
  • 2

    Anderson CF, Cui H: Protease-sensitive nanomaterials for cancer therapeutics and imaging. Ind Eng Chem Res 56:57615777, 2017

  • 3

    Delori FC, Castany MA, Webb RH: Fluorescence characteristics of sodium fluorescein in plasma and whole blood. Exp Eye Res 27:417425, 1978

    • Search Google Scholar
    • Export Citation
  • 4

    Dimou S, Battisti RA, Hermens DF, Lagopoulos J: A systematic review of functional magnetic resonance imaging and diffusion tensor imaging modalities used in presurgical planning of brain tumour resection. Neurosurg Rev 36:205214, 2013

    • Search Google Scholar
    • Export Citation
  • 5

    Ding R, Frei E, Fardanesh M, Schrenk HH, Kremer P, Haefeli WE: Pharmacokinetics of 5-aminofluorescein-albumin, a novel fluorescence marker of brain tumors during surgery. J Clin Pharmacol 51:672678, 2011

    • Search Google Scholar
    • Export Citation
  • 6

    Elliott JT, Dsouza AV, Marra K, Pogue BW, Roberts DW, Paulsen KD: Microdose fluorescence imaging of ABY-029 on an operating microscope adapted by custom illumination and imaging modules. Biomed Opt Express 7:32803288, 2016

    • Search Google Scholar
    • Export Citation
  • 7

    Frangioni JV: The problem is background, not signal. Mol Imaging 8:303304, 2009

  • 8

    Hoffman HJ, Olszewski J: Spread of sodium fluorescein in normal brain tissue. A study of the mechanism of the blood-brain barrier. Neurology 11:10811085, 1961

    • Search Google Scholar
    • Export Citation
  • 9

    Ichioka T, Miyatake S, Asai N, Kajimoto Y, Nakagawa T, Hayashi H, : Enhanced detection of malignant glioma xenograft by fluorescein-human serum albumin conjugate. J Neurooncol 67:4752, 2004

    • Search Google Scholar
    • Export Citation
  • 10

    Kozler P, Pokorný J: Altered blood-brain barrier permeability and its effect on the distribution of Evans blue and sodium fluorescein in the rat brain applied by intracarotid injection. Physiol Res 52:607614, 2003

    • Search Google Scholar
    • Export Citation
  • 11

    Kremer P, Fardanesh M, Ding R, Pritsch M, Zoubaa S, Frei E: Intraoperative fluorescence staining of malignant brain tumors using 5-aminofluorescein-labeled albumin. Neurosurgery 64 (3 Suppl):ons53ons61, 2009

    • Search Google Scholar
    • Export Citation
  • 12

    Lamberts LE, Koch M, de Jong JS, Adams ALL, Glatz J, Kranendonk MEG, : Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study. Clin Cancer Res 23:27302741, 2017

    • Search Google Scholar
    • Export Citation
  • 13

    Lieto E, Galizia G, Cardella F, Mabilia A, Basile N, Castellano P, : Indocyanine green fluorescence imaging-guided surgery in primary and metastatic liver tumors. Surg Innov 25:6268, 2018

    • Search Google Scholar
    • Export Citation
  • 14

    Moore GE, Peyton WT, Hunter SW, French L: The clinical use of sodium fluorescein and radioactive diiodofluorescein in the localization of tumors of the central nervous system. Minn Med 31:10731076, 1948

    • Search Google Scholar
    • Export Citation
  • 15

    Roberts DW, Olson J: Fluorescein guidance in glioblastoma resection. N Engl J Med 376:e36, 2017

  • 16

    Rosenthal EL, Warram JM, de Boer E, Chung TK, Korb ML, Brandwein-Gensler M, : Safety and tumor specificity of cetuximab-IRDye800 for surgical navigation in head and neck cancer. Clin Cancer Res 21:36583666, 2015

    • Search Google Scholar
    • Export Citation
  • 17

    Samkoe KS, Gibbs-Strauss SL, Yang HH, Khan Hekmatyar S, Hoopes PJ, O’Hara JA, : Protoporphyrin IX fluorescence contrast in invasive glioblastomas is linearly correlated with Gd enhanced magnetic resonance image contrast but has higher diagnostic accuracy. J Biomed Opt 16:096008, 2011

    • Search Google Scholar
    • Export Citation
  • 18

    Samkoe KS, Gunn JR, Marra K, Hull SM, Moodie KL, Feldwisch J, : Toxicity and pharmacokinetic profile for single-dose injection of ABY-029: a fluorescent anti-EGFR synthetic affibody molecule for human use. Mol Imaging Biol 19:512521, 2017

    • Search Google Scholar
    • Export Citation
  • 19

    Schebesch KM, Brawanski A, Hohenberger C, Hohne J: Fluorescein sodium-guided surgery of malignant brain tumors: history, current concepts, and future project. Turk Neurosurg 26:185194, 2016

    • Search Google Scholar
    • Export Citation
  • 20

    Segal MB: The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cell Mol Neurobiol 20:183196, 2000

  • 21

    Stummer W: Poor man’s fluorescence? Acta Neurochir (Wien) 157:13791381, 2015

  • 22

    Stummer W, Suero Molina E: Fluorescence imaging/agents in tumor resection. Neurosurg Clin N Am 28:569583, 2017

  • 23

    Suero Molina E, Wölfer J, Ewelt C, Ehrhardt A, Brokinkel B, Stummer W: Dual-labeling with 5-aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note. J Neurosurg 128:399405, 2018

    • Search Google Scholar
    • Export Citation
  • 24

    Tichauer KM, Samkoe KS, Sexton KJ, Hextrum SK, Yang HH, Klubben WS, : In vivo quantification of tumor receptor binding potential with dual-reporter molecular imaging. Mol Imaging Biol 14:584592, 2012

    • Search Google Scholar
    • Export Citation
  • 25

    Tichauer KM, Wang Y, Pogue BW, Liu JT: Quantitative in vivo cell-surface receptor imaging in oncology: kinetic modeling and paired-agent principles from nuclear medicine and optical imaging. Phys Med Biol 60:R239R269, 2015

    • Search Google Scholar
    • Export Citation
  • 26

    Wallace MB, Meining A, Canto MI, Fockens P, Miehlke S, Roesch T, : The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract. Aliment Pharmacol Ther 31:548552, 2010

    • Search Google Scholar
    • Export Citation
  • 27

    Wang LL, Leach JL, Breneman JC, McPherson CM, Gaskill-Shipley MF: Critical role of imaging in the neurosurgical and radiotherapeutic management of brain tumors. Radiographics 34:702721, 2014

    • Search Google Scholar
    • Export Citation
  • 28

    Xi L, Jiang H: Image-guided surgery using multimodality strategy and molecular probes. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:4660, 2016

    • Search Google Scholar
    • Export Citation
  • 29

    Yen LF, Wei VC, Kuo EY, Lai TW: Distinct patterns of cerebral extravasation by Evans blue and sodium fluorescein in rats. PLoS One 8:e68595, 2013

    • Search Google Scholar
    • Export Citation
  • 30

    Zhang ZZ, Shields LB, Sun DA, Zhang YP, Hunt MA, Shields CB: The art of intraoperative glioma identification. Front Oncol 5:175, 2015

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