In vivo noninvasive preclinical tumor hypoxia imaging methods: a review

Technetium-99m has a rich coordination chemistry that offers many possibilities in terms of oxidation states and donor atom sets. Modifications in the structure of the technetium complexes could be very useful for fine tuning the physicochemical and biological properties of potential 99mTc radiopharmaceuticals. However, systematic study of the influence of the labelling strategy on the “in vitro” and “in vivo” behaviour is necessary for a rational design of radiopharmaceuticals. Herein we present a review of the influence of the Tc complexes’ molecular structure on the biodistribution and the interaction with the biological target of potential nitroimidazolic hypoxia imaging radiopharmaceuticals presented in the literature from 2010 to the present. Comparison with the gold standard [18F]Fluoromisonidazole (FMISO) is also presented.

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Assessment of Endothelin-A Receptor Expression in Subcutaneous and Orthotopic Thyroid Carcinoma Xenografts in Vivo Employing Optical Imaging Methods

Endocrinology ◽

10.1210/en.2011-2017 ◽

2012 ◽

Vol 153 (6) ◽

pp. 2907-2918 ◽

Cited By ~ 8

Author(s):

Katrin Büther ◽

Matthijs G. Compeer ◽

Jo G. R. De Mey ◽

Otmar Schober ◽

Michael Schäfers ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Optical Imaging ◽

Near Infrared ◽

Functional Performance ◽

Thyroid Tumor ◽

Receptor Expression ◽

Imaging Methods ◽

Carcinoma Cell Lines ◽

Isolated Artery

Endothelin (ET) receptor dysregulation has been described in a number of pathophysiological processes, including cardiovascular disorders, renal failure, and cancer. The aim of this study was to evaluate the expression of the ET-A receptor (ETAR) in murine models of thyroid carcinoma using optical imaging methods. A recently developed near-infrared fluorescent tracer was first assessed in isolated artery preparations for its functional performance in comparison with known ETAR antagonists BQ123 and PD156707. Before evaluation of the tracer in vivo, different thyroid carcinoma cell lines were characterized with respect to their ET receptor expression by RT-PCR and autoradiography. In vivo, sc and orthotopic papillary thyroid tumor xenografts were clearly visualized by fluorescence reflectance imaging and fluorescence-mediated tomography up to 48 h after injection of the tracer. Binding specificity of the probe was demonstrated by predosing with PD156707 as a competing inhibitor. In conclusion, optical imaging with a fluorescent ETAR tracer allows the noninvasive imaging of tumor-associated ETAR expression in vivo. In the future, this technique may help surgeons to evaluate lesion dimensions in intraoperative settings (e.g. thyroidectomy).

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Multimodal Functional Imaging for Cancer/Tumor Microenvironments Based on MRI, EPRI, and PET

Molecules ◽

10.3390/molecules26061614 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1614

Author(s):

Ken-ichiro Matsumoto ◽

James B. Mitchell ◽

Murali C. Krishna

Keyword(s):

Radiation Therapy ◽

Functional Imaging ◽

Imaging Techniques ◽

Biological Effects ◽

Tumor Hypoxia ◽

Redox Status ◽

Blood Oxygen Level Dependent ◽

Oxygen Level ◽

Cancer Tumor

Radiation therapy is one of the main modalities to treat cancer/tumor. The response to radiation therapy, however, can be influenced by physiological and/or pathological conditions in the target tissues, especially by the low partial oxygen pressure and altered redox status in cancer/tumor tissues. Visualizing such cancer/tumor patho-physiological microenvironment would be a useful not only for planning radiotherapy but also to detect cancer/tumor in an earlier stage. Tumor hypoxia could be sensed by positron emission tomography (PET), electron paramagnetic resonance (EPR) oxygen mapping, and in vivo dynamic nuclear polarization (DNP) MRI. Tissue oxygenation could be visualized on a real-time basis by blood oxygen level dependent (BOLD) and/or tissue oxygen level dependent (TOLD) MRI signal. EPR imaging (EPRI) and/or T1-weighted MRI techniques can visualize tissue redox status non-invasively based on paramagnetic and diamagnetic conversions of nitroxyl radical contrast agent. 13C-DNP MRI can visualize glycometabolism of tumor/cancer tissues. Accurate co-registration of those multimodal images could make mechanisms of drug and/or relation of resulted biological effects clear. A multimodal instrument, such as PET-MRI, may have another possibility to link multiple functions. Functional imaging techniques individually developed to date have been converged on the concept of theranostics.

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Corrigendum to Ellerbrock et al. (2018) “Four in vivo g-ratio-weighted imaging methods: Comparability and repeatability at the group level”

Human Brain Mapping ◽

10.1002/hbm.23980 ◽

2018 ◽

Vol 39 (3) ◽

pp. 1467-1467

Keyword(s):

Group Level ◽

Imaging Methods ◽

G Ratio

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Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01034-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Simeng Wang ◽

Xinrui Zhou ◽

Zekun Zeng ◽

Mengjun Sui ◽

Lihong Chen ◽

...

Keyword(s):

Tumor Microenvironment ◽

Disulfide Bonds ◽

Tumor Targeting ◽

Tumor Hypoxia ◽

Animal Experiments ◽

Complex Iii ◽

Mitochondrial Activity ◽

Hypoxic Tumor

Abstract Background Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. Methods We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. Results Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. Conclusions Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment. Graphic abstract

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Water-soluble cyclometalated platinum(ii) and iridium(iii) complexes: synthesis, tuning of the photophysical properties, and in vitro and in vivo phosphorescence lifetime imaging

RSC Advances ◽

10.1039/c8ra02742k ◽

2018 ◽

Vol 8 (31) ◽

pp. 17224-17236 ◽

Cited By ~ 10

Author(s):

Anastasia I. Solomatina ◽

Shih-Hao Su ◽

Maria M. Lukina ◽

Varvara V. Dudenkova ◽

Vladislav I. Shcheslavskiy ◽

...

Keyword(s):

Photophysical Properties ◽

Water Soluble ◽

Iridium Complexes ◽

Hypoxia Imaging ◽

Phosphorescence Lifetime ◽

Lifetime Imaging ◽

Phosphorescence Lifetime Imaging

Novel water-soluble iridium complexes with sulfonated diphosphine allow in vitro and in vivo lifetime hypoxia imaging.

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2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging—Investigation of Nucleoside Transporter Interaction, 18F-Labeling and Preclinical PET Imaging

Pharmaceuticals ◽

10.3390/ph12010031 ◽

2019 ◽

Vol 12 (1) ◽

pp. 31

Author(s):

Florian Maier ◽

Anna Schweifer ◽

Vijaya Damaraju ◽

Carol Cass ◽

Gregory Bowden ◽

...

Keyword(s):

Pet Imaging ◽

Tumor Hypoxia ◽

Radiochemical Yield ◽

Nucleoside Transporters ◽

Nucleoside Transporter ◽

Hypoxia Imaging ◽

Molar Activity ◽

Slow Kinetics ◽

Sugar Derivatives

The benefits of PET imaging of tumor hypoxia in patient management has been demonstrated in many examples and with various tracers over the last years. Although, the optimal hypoxia imaging agent has yet to be found, 2-nitroimidazole (azomycin) sugar derivatives—mimicking nucleosides—have proven their potential with [18F]FAZA ([18F]fluoro-azomycin-α-arabinoside) as a prominent representative in clinical use. Still, for all of these tracers, cellular uptake by passive diffusion is postulated with the disadvantage of slow kinetics and low tumor-to-background ratios. We recently evaluated [18F]fluoro-azomycin-β-deoxyriboside (β-[18F]FAZDR), with a structure more similar to nucleosides than [18F]FAZA and possible interaction with nucleoside transporters. For a deeper insight, we comparatively studied the interaction of FAZA, β-FAZA, α-FAZDR and β-FAZDR with nucleoside transporters (SLC29A1/2 and SLC28A1/2/3) in vitro, showing variable interactions of the compounds. The highest interactions being for β-FAZDR (IC50 124 ± 33 µM for SLC28A3), but also for FAZA with the non-nucleosidic α-configuration, the interactions were remarkable (290 ± 44 µM {SLC28A1}; 640 ± 10 µM {SLC28A2}). An improved synthesis was developed for β-FAZA. For a PET study in tumor-bearing mice, α-[18F]FAZDR was synthesized (radiochemical yield: 15.9 ± 9.0% (n = 3), max. 10.3 GBq, molar activity > 50 GBq/µmol) and compared to β-[18F]FAZDR and [18F]FMISO, the hypoxia imaging gold standard. We observed highest tumor-to-muscle ratios (TMR) for β-[18F]FAZDR already at 1 h p.i. (2.52 ± 0.94, n = 4) in comparison to [18F]FMISO (1.37 ± 0.11, n = 5) and α-[18F]FAZDR (1.93 ± 0.39, n = 4), with possible mediation by the involvement of nucleoside transporters. After 3 h p.i., TMR were not significantly different for all 3 tracers (2.5–3.0). Highest clearance from tumor tissue was observed for β-[18F]FAZDR (56.6 ± 6.8%, 2 h p.i.), followed by α-[18F]FAZDR (34.2 ± 7.5%) and [18F]FMISO (11.8 ± 6.5%). In conclusion, both isomers of [18F]FAZDR showed their potential as PET hypoxia tracers. Differences in uptake behavior may be attributed to a potential variable involvement of transport mechanisms.

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