Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5

Amanda Shanks Huynh, Veronica Estrella, Valerie E. Stark, Allison S. Cohen, Tingan Chen, Todd J. Casagni, Jatinder S. Josan, Mark C. Lloyd, Joseph Johnson, Jongphil Kim, Victor J Hruby, Josef Vagner, David L. Morse

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Fluorescence molecular imaging can be employed for the development of novel cancer targeting agents. Herein, we investigated the pharmacokinetics (PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (δOR) antagonist-fluorescent dye conjugate, as a tumor-targeting molecular imaging agent. δOR expression is observed normally in the CNS, and pathologically in some tumors, including lung liver and breast cancers. In vitro, in vivo, and ex vivo experiments were conducted to image and quantify the fluorescence signal associated with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence microscopy and small animal fluorescence imaging of tumor-bearing mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with maximum uptake in δOR-expressing positive tumors at 3 h and observable persistence for >96 h; clearance from δOR nonexpressing negative tumors by 6 h; and systemic clearance from normal organs by 24 h. Live-cell and intravital fluorescence microscopy demonstrated that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least 24 h with gradual internalization over the initial 6 h following administration. Dmt-Tic-Cy5 is a δOR-targeted agent that exhibits long-lasting and specific signal in δOR-expressing tumors, is rapidly cleared from systemic circulation, and is not retained in non-δOR-expressing tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging agent.

Original languageEnglish (US)
Pages (from-to)534-544
Number of pages11
JournalMolecular Pharmaceutics
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2016

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Narcotic Antagonists
Pharmacokinetics
Opioid Receptors
Neoplasms
Molecular Imaging
Optical Imaging
Fluorescence Microscopy
2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
cyanine dye 5
delta Opioid Receptor
Liver Neoplasms
Fluorescent Dyes
Lung Neoplasms
Fluorescence
Breast Neoplasms

Keywords

  • biodistribution
  • cancer
  • cancer imaging
  • delta opioid receptor antagonist
  • dorsal window chamber
  • fluorescence imaging agent
  • intravital microscopy
  • live cell imaging
  • pharmacokinetics
  • tumor targeting
  • uptake

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5. / Huynh, Amanda Shanks; Estrella, Veronica; Stark, Valerie E.; Cohen, Allison S.; Chen, Tingan; Casagni, Todd J.; Josan, Jatinder S.; Lloyd, Mark C.; Johnson, Joseph; Kim, Jongphil; Hruby, Victor J; Vagner, Josef; Morse, David L.

In: Molecular Pharmaceutics, Vol. 13, No. 2, 01.02.2016, p. 534-544.

Research output: Contribution to journalArticle

Huynh, AS, Estrella, V, Stark, VE, Cohen, AS, Chen, T, Casagni, TJ, Josan, JS, Lloyd, MC, Johnson, J, Kim, J, Hruby, VJ, Vagner, J & Morse, DL 2016, 'Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5', Molecular Pharmaceutics, vol. 13, no. 2, pp. 534-544. https://doi.org/10.1021/acs.molpharmaceut.5b00760
Huynh, Amanda Shanks ; Estrella, Veronica ; Stark, Valerie E. ; Cohen, Allison S. ; Chen, Tingan ; Casagni, Todd J. ; Josan, Jatinder S. ; Lloyd, Mark C. ; Johnson, Joseph ; Kim, Jongphil ; Hruby, Victor J ; Vagner, Josef ; Morse, David L. / Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5. In: Molecular Pharmaceutics. 2016 ; Vol. 13, No. 2. pp. 534-544.
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