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

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 hrs 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 hours 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 moeity, 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.

PET/CT features of a novel gallium-68 labelled hypoxia seeking agent in patients diagnosed with tuberculosis: a proof-of-concept study

“…Since 68 Ga-nitroimidazoles are more hydrophilic [9,13], compared with 18 F-FMISO, it was anticipated that the LMR would be higher in the current study and that uptake would be more intense [13]. However, the findings align with Wu et al [14], who raised the concern that the hydrophilicity may lead to insufficient retention and accumulation in hypoxic cells [14]. Furthermore, hypoxia PET/CT is known to have inherently low signal-to-noise ratios [56].…”

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

“…HBED-CC has been successfully applied in the theranostics of prostate cancer when conjugated to the prostate-specific membrane antigen (PSMA) (Virgolini et al, 2017 ) but the combination with oxygen sensitive groups is yet to been investigated. Gallium-68 labeled nitroimidazole complexes were studied in mice models with induced (xenografted) tumors for CT26 (colon cancer) (Seelam et al, 2015 ), A549 (Wu et al, 2015 ) or 3LL (Fernández et al, 2013 ) (lung cancer cell lines). The comparison with [ 18 F]F-FMISO revealed successful hypoxia imaging and improved clearance properties.…”

Imaging of Tumor Hypoxia With Radionuclide-Labeled Tracers for PET

“…also confirmed that the 68 Ga marker could help in the visualization of tumor tissues and hypoxic areas within 2 h of intravenous injection ( 195 ). In short, studies on lung ( 196 ) and colon cancers ( 197 , 198 ) show that on the basis of the ease in production, 68 Ga-labeled hypoxia tracers are comparable to traditional 18 F-labeled tracers.…”