[68Ga]-HP-DO3A-nitroimidazole: A promising agent for PET detection of tumor hypoxia

Yunkou Wu, Guiyang Hao, Saleh Ramezani, Debabrata Saha, Dawen Zhao, Xiankai Sun, A. Dean Sherry

Research output: Contribution to journalArticle

Abstract

The goal of this study is to evaluate a new 68Ga-based imaging agent for detecting tumor hypoxia using positron emission tomography (PET). The new hypoxia targeting agent reported here, [68Ga]-HP-DO3A-nitroimidazole ([68Ga]-HP-DO3A-NI), was constructed by linking a nitroimidazole moiety with the macrocyclic ligand component of ProHance®, HP-DO3A. The hypoxia targeting capability of this agent was evaluated in A549 lung cancer cells in vitro and in SCID mice bearing subcutaneous A549 tumor xenografts. The cellular uptake assays showed that significantly more [68Ga]-HP-DO3A-NI accumulates in hypoxic tumor cells at 30, 60 and 120 min than in the same cells exposed to 21% O2. The agent also accumulated in hypoxic tumors in vivo to give a tumor/muscle ratio (T/M) of 5.0 ± 1.2 (n = 3) as measured by PET at 2 h post-injection (p.i.). This was further confirmed by ex vivo biodistribution data. In addition, [68Ga]-HP-DO3A-NI displayed very favorable pharmacokinetic properties, as it was cleared largely through the kidneys with little to no accumulation in liver, heart or lung (%ID/g < 0.5%) at 2 h p.i. The specificity of the agent for hypoxic tissues was further validated in a comparative study with a control compound, [68Ga]-HP-DO3A, which lacks the nitroimidazole moiety, and by PET imaging of tumor-bearing mice breathing air versus 100% O2. Given the commercial availability of cGMP 68Ge/68Ga generators and the ease of 68Ga labeling, the new agent could potentially be widely applied for imaging tumor hypoxia prior to radiation therapy.

Original languageEnglish (US)
Pages (from-to)465-472
Number of pages8
JournalContrast Media and Molecular Imaging
Volume10
Issue number6
DOIs
StatePublished - Nov 1 2015
Externally publishedYes

Fingerprint

Nitroimidazoles
Positron-Emission Tomography
Neoplasms
Injections
SCID Mice
Heterografts
Tumor Hypoxia
10-(2-hydroxypropyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid
Lung Neoplasms
Respiration
Radiotherapy
Pharmacokinetics
Air
Ligands
Kidney
Muscles
Lung
Liver

Keywords

  • Ga
  • Nitroimidazole
  • PET
  • Tumor hypoxia

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

[68Ga]-HP-DO3A-nitroimidazole : A promising agent for PET detection of tumor hypoxia. / Wu, Yunkou; Hao, Guiyang; Ramezani, Saleh; Saha, Debabrata; Zhao, Dawen; Sun, Xiankai; Sherry, A. Dean.

In: Contrast Media and Molecular Imaging, Vol. 10, No. 6, 01.11.2015, p. 465-472.

Research output: Contribution to journalArticle

Wu, Yunkou ; Hao, Guiyang ; Ramezani, Saleh ; Saha, Debabrata ; Zhao, Dawen ; Sun, Xiankai ; Sherry, A. Dean. / [68Ga]-HP-DO3A-nitroimidazole : A promising agent for PET detection of tumor hypoxia. In: Contrast Media and Molecular Imaging. 2015 ; Vol. 10, No. 6. pp. 465-472.
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AU - Wu, Yunkou

AU - Hao, Guiyang

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AU - Saha, Debabrata

AU - Zhao, Dawen

AU - Sun, Xiankai

AU - Sherry, A. Dean

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AB - The goal of this study is to evaluate a new 68Ga-based imaging agent for detecting tumor hypoxia using positron emission tomography (PET). The new hypoxia targeting agent reported here, [68Ga]-HP-DO3A-nitroimidazole ([68Ga]-HP-DO3A-NI), was constructed by linking a nitroimidazole moiety with the macrocyclic ligand component of ProHance®, HP-DO3A. The hypoxia targeting capability of this agent was evaluated in A549 lung cancer cells in vitro and in SCID mice bearing subcutaneous A549 tumor xenografts. The cellular uptake assays showed that significantly more [68Ga]-HP-DO3A-NI accumulates in hypoxic tumor cells at 30, 60 and 120 min than in the same cells exposed to 21% O2. The agent also accumulated in hypoxic tumors in vivo to give a tumor/muscle ratio (T/M) of 5.0 ± 1.2 (n = 3) as measured by PET at 2 h post-injection (p.i.). This was further confirmed by ex vivo biodistribution data. In addition, [68Ga]-HP-DO3A-NI displayed very favorable pharmacokinetic properties, as it was cleared largely through the kidneys with little to no accumulation in liver, heart or lung (%ID/g < 0.5%) at 2 h p.i. The specificity of the agent for hypoxic tissues was further validated in a comparative study with a control compound, [68Ga]-HP-DO3A, which lacks the nitroimidazole moiety, and by PET imaging of tumor-bearing mice breathing air versus 100% O2. Given the commercial availability of cGMP 68Ge/68Ga generators and the ease of 68Ga labeling, the new agent could potentially be widely applied for imaging tumor hypoxia prior to radiation therapy.

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