Abstract
This paper describes functional fluorinated bioactivatable molecules to study cancer metabolism using Cerenkov imaging. Resazurin (RA), or Alamar Blue, is a commonly used viability dye and redox sensor. Under reductive conditions or by the action of NADH dehydrogenases, RA is reduced into resorufin (RAred), a highly fluorescent molecule. Cold- and radiolabeled monofluorinated resazurin (MFRA) and difluorinated resazurin (DFRA) were synthesized using electrophilic fluorination. The fluorescence of the reduced probes allowed for the detection of Cerenkov Radiation Energy Transfer (CRET). Cerenkov imaging of MFRAred showed a 4-fold increase in signal at 640 nm relative to MFRA, demonstrating the ability to differentiate between oxidized and reduced species via optical imaging. CRET allows the measurement of signal at longer wavelengths closer to the near infrared (NIR) window, ideal for in vivo imaging. MFRA reduction showed different rates in two breast cancer cell lines: MDA-MB-231, a triple-negative breast cancer, and 4175-Luc+, an aggressive MDA-MB-231 variant, isolated from murine lung metastases. 4175-Luc + cells showed a more rapid reduction of RA and MFRAox than MDA-MB-231 cells. Intratumoral injections of 18F-FDG/MFRA showed a faster reduction of the probe in 4175-Luc + tumors than in MDA-MB-231, suggesting that the metabolic feature observed in the cells is maintained in the tumors. MFRA is a promising probe to determine tumor energy imbalance, reductive environments and assess metastatic potential of tumors. Furthermore, the use of 18F-labeled probes allows for dual modality PET/Cerenkov imaging for probe localization and biodistribution while assessing probe reduction simultaneously.
Highlights
Cerenkov radiation is a photon emission arising from a beta particle emitted with kinetic energy greater than the phase velocity of the speed of light in its surrounding solution [1]
Metabolic Cerenkov Imaging rays arising from this annihilation can be detected by positron emission tomography (PET), but gamma rays are not affected by the structure of the molecule containing the radioisotope
The successful application of 18F-monofluorinated resazurin (MFRA) probe, the best candidate, will require higher specific activity, which could be achieved through higher specific labeling of the probe or by improvement of the synthetic pathway of the probe
Summary
Cerenkov radiation is a photon emission arising from a beta particle emitted with kinetic energy greater than the phase velocity of the speed of light in its surrounding solution [1]. Metabolic Cerenkov Imaging rays arising from this annihilation can be detected by positron emission tomography (PET), but gamma rays are not affected by the structure of the molecule containing the radioisotope. As with optical imaging techniques, the Cerenkov photons emitted can be differentially absorbed by bioactive contrast agents that act as molecular switches depending on the effect of the tissue environment on its molecular structure. Investigations into the physical and chemical properties of this new technique demonstrated that the number of Cerenkov photons produced by beta-emitting radionuclides and the brightness of the isotopes, was directly correlated to the kinetic energy of the beta emission of each isotope [3, 4]. While fluorine is a widely used radioisotope for Cerenkov imaging, other isotopes such as iodine-124 and gallium-68 produce more photons due to their higher energy, with yttrium-90 being the highest producer of Cerenkov photons
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