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Purpose: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of 134Ce offer perspectives for developing innovative in vivo investigations that are not possible with 225Ac. In this work, 225Ac- and 134Ce-labelled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging. Methods: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225Ac and 134Ce-labelled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody. Results: In vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ce's PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging. Conclusion: When employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: Recent clinical advances with the approval of antibody-drug conjugates targeting Trop-2 such as sacituzumab-govitecan and datopotomab-deruxtecan have garnered tremendous interest for their therapeutic efficacy in numerous tumor types including breast and lung cancers. ImmunoPET can stratify tumor avidity, clarifying patient eligibility for ADC therapy as well as a diagnostic companion during therapy. Slow antibody circulation requires days to reach optimal imaging timepoints. To overcome this shortfall, bioorthogonal click chemistry for pretargeting can be employed, decoupling antibody circulation time and the delivery of the radionuclide., Experimental Design: Here we report the characterization of a new full-length Trop-2.2 antibody showing high affinity for Trop-2 positive cancers and leverage different site selective labeling and pretargeting radionuclide combinations to yield rapid imaging with minimal radionuclide footprint after imaging. Three pretargeting strategies for Fluorine-18, Copper-64, and Zirconium-89 were explored in addition to site specific bioconjugation., Results: We found pretargeting with [64Cu]Cu-Sar-Tz to yield the best images identifying Trop-2 positive tumors with optimal tumor-to-background ratios. Intriguingly we found the full-length antibody when directly conjugated, yielded rapid accumulation starting at 3 hours post injection and leading to over 50% injected activity per gram in the tumor before 24 hours., Conclusions: [89Zr]Zr-DFO-Trop-2 as well as pretargeting with [64Cu]Cu-Sar-Tz are viable imaging strategies to quickly identify Trop-2 positive tumors for subsequent Trop-2 therapies.

Purpose: The radionuclide pair cerium-134/lanthanum-134 ( 134 Ce/ 134 La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 ( 225 Ac). The unique properties of 134 Ce offer perspectives for developing innovative in vivo investigations not possible with 225 Ac. In this work, 225 Ac- and 134 Ce-labeled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134 Ce/ 134 La has limitations to the setting of quantitative positron emission tomography imaging., Methods: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG 8 -Tz) were radiolabelled with 225 Ac or 134 Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225 Ac and 134 Ce-labeled mcp-PEG 8 -Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody., Results: In vitro and in vivo studies with both 225 Ac and 134 Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134 Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134 Ce's PET-compatible daughter 134 La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225 Ac-labelled tracers are not quantitatively represented by 134 Ce PET imaging., Conclusion: When employing slow-internalizing vectors, 134 Ce might not be an ideal match for 225 Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134 La. However, this same characteristic makes it possible to estimate the redistribution of 225 Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.

Cerenkov (or Cherenkov) luminescence occurs when charged particles exceed the phase velocity of a given medium. Cerenkov has gained interest in preclinical space as well as in clinical trials for optical visualization of numerous radionuclides. However, Cerenkov intensity has to be inferred from alternative databases with energy emission spectra, or theoretical fluence estimates. Here we present the largest experimental dataset of Cerenkov emitting isotopes recorded using the IVIS optical imaging system. We report Cerenkov measurements spanning orders of magnitude normalized to the activity concentration for 21 Cerenkov emitting isotopes, covering electron, alpha, beta minus, and positron emissions. Isotopes measured include Carbon-11, Fluorine-18, Phosphorous-32, Scandium-47, Copper-64, Copper-67, Gallium-68, Arsenic-72, Bromine-76, Yttrium-86, Zirconium-89, Yttrium-90, Iodine-124, Iodine-131, Cerium-134, Lutetium-177, Lead-203, Lead-212, Radium-223, Actinium-225, and Thorium-227. We hope this updating resource will serve as a rank ordering for comparing isotopes for Cerenkov luminescence in the visible window and serve as a rule of thumb for comparing Cerenkov intensities in vitro and in vivo., Methods: All Cerenkov emitting radionuclides were either produced at Memorial Sloan Kettering Cancer Center (Carbon-11, 11 C; Fluorine-18, 18 F; Iodine-124, 124 I), from commercial sources such as Perkin Elmer (Phosphorous-32, 32 P; Yttrium-90, 90 Y), Bayer (Radium-223, 223 Ra, Xofigo), 3D-Imaging (Zirconium-89, 89 Zr), Nuclear Diagnostic Products (Iodine-131, 131 I), or from academic collaborators at Washington University at St. Louis (Copper-64, 64 Cu), University of Wisconsin (Bromine-76, 76 Br), MD Anderson Cancer Center (Yttrium-86, 86 Y), Brookhaven National Laboratory (Arsenic-72, 72 As; Thorium-227, 227 Th), or Oak Ridge National Laboratory (Cerium-134, 134 Ce, Actinium-225, 225 Ac), and Viewpoint Molecular Targeting (Lead-203, 203 Pb; Lead 212, 212 Pb). All isotopes were diluted in triplicate on a black bottomed corning 96 well plate to several activity concentrations ranging from 0.1-250 μCi in 100-200 μL of Phosphate Buffered Saline. Cerenkov imaging was acquired on a single Perkin-Elmer Spectrum In-Vivo Imaging System (IVIS) at field of view c with exposures ranging up to 15 minutes or lower provided no part of the image intensity was saturated, or that the activity significantly changed during the exposure. Experimental radiances on the IVIS were calculated from regions of interest drown over each 96 well, and then normalized for the activity present in the well, and the volume the isotope was diluted into.

Trametinib is an extremely potent allosteric inhibitor of mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) (MEK) 1/2, which has been approved for treatment of metastatic melanoma and anaplastic thyroid cancer in patients with confirmed BRAF V600E /K mutations. Though trametinib is highly efficacious, adverse side effects, including skin, gastrointestinal, and hepatic toxicity, are dose-limiting and can lead to treatment termination. Development of a noninvasive tool to visualize and quantify the delivery and distribution of trametinib (either as a single agent or in combination with other therapeutics) to tumors and organs would be helpful in assessing therapeutic index, personalizing individual dose, and potentially predicting resistance to therapy. Methods: To address these issues, we have developed a radiolabeled trametinib and evaluated the in vitro and in vivo properties. 123 I-, 124 I-, and 131 I-trametinib, pure tracer analogs to trametinib, were synthesized in more than 95% purity, with an average yield of 69.7% and more than 100 GBq/μmol specific activity. Results: Overall, 124 I-trametinib uptake in a panel of cancer cell lines can be blocked with cold trametinib, confirming specificity of the radiotracer in vitro and in vivo. 124 I-trametinib was taken up at higher rates in KRAS and BRAF mutant cell lines than in wild-type KRAS cancer cell lines. In vivo, biodistribution revealed high uptake in the liver 2 h after injection, followed by clearance through the gastrointestinal tract over 4 d. Importantly, uptake higher than expected was observed in the lung and heart for up to 24 h. Peak uptake in the skin and gastrointestinal tract was observed between 6 and 24 h, whereas in B16F10 melanoma-bearing mice peak tumor concentrations were achieved between 24 and 48 h. Tumor uptake relative to muscle and skin was relatively low, peaking at 3.4- to 8.1-fold by 72 h, respectively. The biodistribution of 124 I-trametinib was significantly reduced in mice on trametinib therapy, providing a quantitative method to observe MEK inhibition in vivo. Conclusion: 124 I-trametinib serves as an in vivo tool to personalize the dose instead of using the current single-fixed-dose scheme and, when combined with radiomic data, to monitor the emergence of therapy resistance. In addition, the production of iodinated trametinib affords researchers the ability to measure drug distribution for improved drug delivery studies., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Optoacoustic imaging offers the promise of high spatial resolution and, at the same time, penetration depths well beyond the conventional optical imaging technologies, advantages that would be favorable for a variety of clinical applications. However, similar to optical fluorescence imaging, exogenous contrast agents, known as sonophores, need to be developed for molecularly targeted optoacoustic imaging. Despite numerous optoacoustic contrast agents that have been reported, there is a need for more rational design of sonophores. Here, using a library screening approach, we systematically identified and evaluated twelve commercially available near-infrared (690-900 nm) and highly absorbing dyes for multi-spectral optoacoustic tomography (MSOT). In order to achieve more accurate spectral deconvolution and precise data quantification, we sought five practical mathematical methods, namely direct classical least squares based on UV-Vis (UV/Vis-DCLS) or optoacoustic (OA-DCLS) spectra, non-negative LS (NN-LS), independent component analysis (ICA) and principal component analysis (PCA). We found that OA-DCLS is the most suitable method, allowing easy implementation and sufficient accuracy for routine analysis. Here, we demonstrate for the first time that our biocompatible nanoemulsions (NEs), in combination with near-infrared and highly absorbing dyes, enable non-invasive in vivo MSOT detection of tumors. Specifically, we found that NE-IRDye QC1 offers excellent optoacoustic performance and detection compared to related near-infrared NEs. We demonstrate that when loaded with low fluorescent or dark quencher dyes, NEs represent a flexible and new class of exogenous sonophores suitable for non-invasive pre-clinical optoacoustic imaging.

In this study, we cover the convergence of radiochemistry for imaging and therapy with advances in nanoparticle (NP) design for biomedical applications. We first explore NP properties relevant for therapy and theranostics and emphasize the need for biocompatibility. We then explore radionuclide-imaging modalities such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and Cerenkov luminescence (CL) with examples utilizing radiolabeled NP for imaging. PET and SPECT have served as diagnostic workhorses in the clinic, while preclinical NP design examples of multimodal imaging with radiotracers show promise in imaging and therapy. CL expands the types of radionuclides beyond PET and SPECT tracers to include high-energy electrons (β - ) for imaging purposes. These advances in radionanomedicine will be discussed, showing the potential for radiolabeled NPs as theranostic agents. WIREs Nanomed Nanobiotechnol 2016, 8:872-890. doi: 10.1002/wnan.1402 For further resources related to this article, please visit the WIREs website., Competing Interests: statement The authors declare no competing financial interests., (© 2016 Wiley Periodicals, Inc.)