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Published on: January 19, 2018
Targeting tumor hypoxia with 2-nitroimidazole-indocyanine green dye conjugates
Yan Xu1, Saeid Zanganeh, Innus Mohammad
1University of Connecticut, Electrical and Computer Engineering Department, Storrs, Connecticut 06269, USA.
Abstract:
Tumor hypoxia is a major indicator of treatment resistance to chemotherapeutic drugs, and fluorescence optical tomography has tremendous potential to provide clinically useful, functional information by identifying tumor hypoxia. The synthesis of a 2-nitroimidazole-indocyanine green conjugate using a piperazine linker (piperazine-2-nitroimidazole-ICG) capable of robust fluorescent imaging of tumor hypoxia is described. In vivo mouse tumor imaging studies were completed and demonstrate an improved imaging capability of the new dye relative to an earlier version of the dye that was synthesized with an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG). Mouse tumors located at imaging depths of 1.5 and 2.0 cm in a turbid medium were imaged at various time points after intravenous injection of the dyes. On average, the reconstructed maximum fluorescence concentration of the tumors injected with piperazine-2-nitroimidazole-ICG was twofold higher than that injected with ethanolamine-2-nitroimidazole-ICG within 3 h postinjection period and 1.6 to 1.7 times higher beyond 3 h postinjection. The untargeted bis-carboxylic acid ICG completely washed out after 3 h postinjection. Thus, the optimal window to assess tumor hypoxia is beyond 3 h postinjection. These findings were supported with fluorescence images of histological sections of tumor samples and an immunohistochemistry technique for identifying tumor hypoxia.
Insights
A new fluorescent dye, piperazine-2-nitroimidazole-indocyanine green (ICG), effectively images tumor hypoxia in mice. This dye shows improved performance over older versions, aiding in assessing treatment resistance.
Area of Science:
- Biomedical Imaging
- Chemical Synthesis
- Cancer Research
Background:
- Tumor hypoxia is a key factor in chemotherapy resistance.
- Fluorescence optical tomography offers valuable functional insights into tumor microenvironments.
- Developing targeted imaging agents is crucial for cancer diagnostics.
Purpose of the Study:
- To synthesize and evaluate a novel 2-nitroimidazole-indocyanine green (ICG) conjugate for fluorescent imaging of tumor hypoxia.
- To compare the in vivo imaging performance of a piperazine-linked ICG conjugate against an ethanolamine-linked version.
- To determine the optimal time window for assessing tumor hypoxia using the new fluorescent probe.
Main Methods:
- Synthesis of piperazine-2-nitroimidazole-ICG conjugate.
- In vivo fluorescence optical tomography imaging in mouse tumor models.
- Comparison of imaging signal intensity and washout kinetics between different ICG conjugates.
- Histological analysis and immunohistochemistry to validate hypoxia imaging.
Main Results:
- The piperazine-2-nitroimidazole-ICG conjugate demonstrated significantly higher fluorescence signal in mouse tumors compared to the ethanolamine-linked conjugate.
- Enhanced imaging capability was observed at depths of 1.5 and 2.0 cm.
- The optimal imaging window for assessing tumor hypoxia was determined to be beyond 3 hours post-injection.
- Untargeted ICG showed rapid washout, highlighting the importance of the targeted conjugate.
Conclusions:
- Piperazine-2-nitroimidazole-ICG is a superior fluorescent probe for robust in vivo imaging of tumor hypoxia.
- This advanced imaging agent can improve the assessment of treatment resistance in cancer patients.
- The findings provide a basis for further development of targeted fluorescent probes for clinical applications.
