In addition to small molecules and biomolecules, CLI is also compatible with
in vivo imaging of nanoparticles. Nanoparticles have gathered much attention in
biomedical research because of their unique properties, including ease of preparations and modifications, and better pharmacological properties than some conventional chemotherapeutic agents. Some nanoparticles are excitable by Cerenkov light
and emit in longer wavelengths. The imaging system utilizing this phenomenon is
called synonymously secondary Cerenkov-induced fluorescence imaging (SCIFI) or
Cerenkov radiation energy transfer (CRET). The higher optical cross section of
certain nanoparticles sometimes permits SCIFI or CRET [61]. For example, quantum nanoparticles (Qtracker 705) and quantum dots (QD605) have been shown to be
excited by CL to emit longer wavelengths of light, which is advantageous to
overcome the poor tissue permeability of UV light [63, 73]. However, the system
of SCIFI or CRET is not easily modulated because it can be activated regardless of
the surrounding environment. Hence, smart activatable agents, which could be
modulated by endogenous or exogenous stimuli when needed, may provide the
basis of a more accurate imaging system. Photoactivation of caged luciferin by CL is
one example of a smart activatable agent [74]. Luciferin is caged by an orthonitrobenzyl ether protecting group, which is known to be activated by UV light.
CL from
18
F-FDG successfully uncaged luciferin, the substrate of luciferase, and
induced bioluminescence from cancer cells expressing luciferase. Another example
of smart activatable agent is protease-activatable SCIFI, which can be turned on by
matrix metallopeptidase-2 enzyme activity [75]. Fluorescein is tethered with a
peptide to a gold nanoparticle and quenched due to the proximity of fluorescein
and a gold nanoparticle; once the enzyme cleaves the peptide, the gold nanoparticle
quencher is released and fluorescein becomes excitable by CL.
The major limitation of CLI is its low intensity of signal compared to conventional optical fluorescence imaging. The prolonged scanning time degrades image
quality due to confounding factors such as patient movement, and the duration of
imaging is limited because of the radionuclide half-life. The CL-activated “sticky
tag” strategy may potentially overcome these limitations by translating CL into
fluorescence (Fig. 3c) [76]. The sticky tag consists of a fluorescent dye tethered by
an aryl azide group. UV light irradiation from Cerenkov transforms the azide into a
singlet nitrene, which can be chemically incorporated into biomolecules on cellular
plasma membranes or proteins in the intracellular matrix. Therefore, radioactivity,
from, e.g.,
18 F-FDG or an
89 Zr-labeled antibody, is converted to fluorescence that is
attached to the side of the radioactive decay. The photoactivation of Cyanine 7-azide
is demonstrated in both in vitro and in vivo (Fig. 3d).
The first human CLI was performed in 2013. CL with 550 MBq of
131 I from the
thyroid gland of a patient treated for hyperthyroidism was detected using an electron
multiplied CCD camera [77]. In this study, photographic light and CL were successfully localized in the thyroid region. However, the first human study did not
provide quantification of the thyroid. A more rigorous study was performed in the
same year using
18 F-FDG in lymphoma patients, lung cancer, and breast cancer
[78]. Patients undergoing diagnostic
18 F-FDG PET/CT scans were tested for the
feasibility of CLI. A cooled CCD camera was used to monitor CL and quantification
The Present and Future of Optical Imaging Technologies in the Clinic:. . .
217
in vivo imaging of nanoparticles. Nanoparticles have gathered much attention in
biomedical research because of their unique properties, including ease of preparations and modifications, and better pharmacological properties than some conventional chemotherapeutic agents. Some nanoparticles are excitable by Cerenkov light
and emit in longer wavelengths. The imaging system utilizing this phenomenon is
called synonymously secondary Cerenkov-induced fluorescence imaging (SCIFI) or
Cerenkov radiation energy transfer (CRET). The higher optical cross section of
certain nanoparticles sometimes permits SCIFI or CRET [61]. For example, quantum nanoparticles (Qtracker 705) and quantum dots (QD605) have been shown to be
excited by CL to emit longer wavelengths of light, which is advantageous to
overcome the poor tissue permeability of UV light [63, 73]. However, the system
of SCIFI or CRET is not easily modulated because it can be activated regardless of
the surrounding environment. Hence, smart activatable agents, which could be
modulated by endogenous or exogenous stimuli when needed, may provide the
basis of a more accurate imaging system. Photoactivation of caged luciferin by CL is
one example of a smart activatable agent [74]. Luciferin is caged by an orthonitrobenzyl ether protecting group, which is known to be activated by UV light.
CL from
18
F-FDG successfully uncaged luciferin, the substrate of luciferase, and
induced bioluminescence from cancer cells expressing luciferase. Another example
of smart activatable agent is protease-activatable SCIFI, which can be turned on by
matrix metallopeptidase-2 enzyme activity [75]. Fluorescein is tethered with a
peptide to a gold nanoparticle and quenched due to the proximity of fluorescein
and a gold nanoparticle; once the enzyme cleaves the peptide, the gold nanoparticle
quencher is released and fluorescein becomes excitable by CL.
The major limitation of CLI is its low intensity of signal compared to conventional optical fluorescence imaging. The prolonged scanning time degrades image
quality due to confounding factors such as patient movement, and the duration of
imaging is limited because of the radionuclide half-life. The CL-activated “sticky
tag” strategy may potentially overcome these limitations by translating CL into
fluorescence (Fig. 3c) [76]. The sticky tag consists of a fluorescent dye tethered by
an aryl azide group. UV light irradiation from Cerenkov transforms the azide into a
singlet nitrene, which can be chemically incorporated into biomolecules on cellular
plasma membranes or proteins in the intracellular matrix. Therefore, radioactivity,
from, e.g.,
18 F-FDG or an
89 Zr-labeled antibody, is converted to fluorescence that is
attached to the side of the radioactive decay. The photoactivation of Cyanine 7-azide
is demonstrated in both in vitro and in vivo (Fig. 3d).
The first human CLI was performed in 2013. CL with 550 MBq of
131 I from the
thyroid gland of a patient treated for hyperthyroidism was detected using an electron
multiplied CCD camera [77]. In this study, photographic light and CL were successfully localized in the thyroid region. However, the first human study did not
provide quantification of the thyroid. A more rigorous study was performed in the
same year using
18 F-FDG in lymphoma patients, lung cancer, and breast cancer
[78]. Patients undergoing diagnostic
18 F-FDG PET/CT scans were tested for the
feasibility of CLI. A cooled CCD camera was used to monitor CL and quantification
The Present and Future of Optical Imaging Technologies in the Clinic:. . .
217