Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia

Our plain-English summary of Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia, by M.S. Ali, F.L. Kong, A. Rollo, et al (Journal of Biomedicine & Biotechnology, 2012).

The study

• Authors: M.S. Ali, F.L. Kong, A. Rollo, R. Mendez, S. Kohanim, D.L. Smith, D.J. Yang
• Journal: Journal of Biomedicine & Biotechnology
• Published: 2012;2012:828139
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11-tetraazacyclotetradecane (N4) has shown to be a stable chelator for (99m)Tc. The present study was aimed to develop (99m)Tc-cyclam-2-nitroimidazole ((99m)Tc-N4-NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4-oxalate and 1,3-dibromopropane-NIM, yielded 14% (total synthesis). Cell uptake of (99m)Tc-N4-NIM and (99m)Tc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of (99m)Tc-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5-4 hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of (99m)Tc-N4-NIM was >96% by HPLC. Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines. Biodistribution of (99m)Tc-N4-NIM showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6-10 mmHg compared to 40-50 mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with (99m)Tc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy.

In plain English

This was a laboratory and animal study of a cancer imaging agent, not a study of asbestos exposure. The authors, at MD Anderson Cancer Center, made a new radioactive tracer, 99mTc-N4-NIM, designed to show tumor areas that are low in oxygen (hypoxia). They labeled it with radiochemical purity above 96%. In cell cultures, uptake of the tracer by rat mammary tumor cells and by mesothelioma cells (IL-45) rose up to 240 minutes, while uptake of a comparison compound, 99mTc-N4, did not. In rats with mammary tumors (3 rats per time point), tumor-to-muscle ratios were 2.86 at 30 minutes, 5.69 at 2 hours and 4.88 at 4 hours. Oxygen probe readings showed that the rat tumors were hypoxic. On scans taken 60 to 120 minutes after injection, tumor-to-muscle ratios were 4.1 to 4.2 in rats and 2.52 to 2.98 in rabbits with VX-2 tumors. No mesothelioma tumors were scanned in animals. The authors concluded that the tracer was feasible for imaging tumor hypoxia. They noted that the cell tests were run under normal oxygen conditions and that anemia was not examined.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory chemistry, cell culture and animal experiments (biodistribution in rats, oxygen probe measurements, planar scintigraphic imaging in rats and rabbits) developing a technetium-99m imaging agent for tumor hypoxia
• Who was studied: 13762 rat mammary cancer cells and mesothelioma cells (IL-45) in culture. Female Fischer 344 rats with 13762 mammary tumors (3 rats per time point for biodistribution, 3 rats for oxygen measurements). Male New Zealand white rabbits with VX-2 tumors in the thigh for imaging.
• Exposure: No asbestos exposure was studied. The material studied was the radiotracer 99mTc-N4-NIM (a 2-nitroimidazole joined to an N4 chelator and labeled with technetium-99m), compared with 99mTc-N4.
• Main results:
  • The precursor N4-NIM was labeled with technetium-99m with radiochemical purity above 96%.
  • In rat mammary tumor cells and mesothelioma cells, uptake of 99mTc-N4-NIM increased up to 240 minutes; uptake of 99mTc-N4 did not.
  • In mammary tumor-bearing rats (n = 3 per time point) given 99mTc-N4-NIM, tumor/blood ratios were 0.69, 1.01 and 0.98, and tumor/muscle ratios were 2.86, 5.69 and 4.88, at 30 minutes, 2 hours and 4 hours (Table 2). The authors described these ratios as gradually increasing.
  • With the comparison compound 99mTc-N4, there was almost no tumor uptake in rats (tumor 0.09, 0.03 and 0.02 percent of injected dose per gram at 30, 120 and 240 minutes, Table 1).
  • Oxygen tension in the rat mammary tumors was 4.6 ± 1.4 mmHg, compared with 35 ± 10 mmHg in normal muscle. The authors took this to mean the tumors were hypoxic. The article gives other figures elsewhere (see text problems).
  • Tumors were clearly seen on planar scans. Tumor-to-muscle ratios at 60 to 120 minutes were 4.1 to 4.2 in tumor-bearing rats and 2.52 to 2.98 in tumor-bearing rabbits.
  • From rat data converted to human estimates, the authors stated that a proposed single 20 mCi dose would be within radiation dose limits for humans.
• The authors' conclusion: The authors concluded that N4-NIM kits could be labeled with technetium-99m easily and with high purity, and that the cell and imaging studies showed it was feasible to use 99mTc-N4-NIM for tumor hypoxia imaging.
• Limitations the authors state:
  • The cell uptake tests were done under normal oxygen (normoxic) conditions, not hypoxic ones.
  • Other factors such as anemia may have influenced tumor hypoxia, and these were not investigated.

Topics

Medical terms in this study, explained in our Lexicon: Hypoxia, Mesothelioma.

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