15th European Molecular Imaging Meeting
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Industry Lunch Symposium by MILabs

Session chair: Freek Beekman (Utrecht, Netherlands)
 
Shortcut: LS 01
Date: Wednesday, 26 August, 2020, 1:45 p.m. - 2:30 p.m.
Session type: Lunch Symposium

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Contents

Abstract/Video opens by clicking at the talk title.

1:45 p.m. LS 01-01

Synergetic Ultra-high Definition PET, SPECT, X-ray and Optical CT

Freek Beekman1, 3, 2

1 MILabs B.V., Utrecht, Netherlands
2 University Medical Center Utrecht, Translational Neuroscience, Utrecht, Netherlands
3 Delft University of Technology, Radiation, Detection and Medical Imaging, Delft, Netherlands

Content

In 2018, for the second time, MILabs won the Innovation of the Year from the World Molecular Imaging Society with its newly launched VECTor6 PET, SPECT, X-ray & Optical CT imaging platform, utilizing for 3D/4D imaging of photon energies from 1 eV up to 1 MeV. Using a unique positron range free imaging technology VECTor-6  enables to produce < 0.75 mm resolution PET images of difficult isotopes like  82Rb, 86Y, 76Br, 89Zr  and 124I as well as of multiple co-injected PET tracers or mixed PET SPECT tracers and 0.6 mm resolution for 18F while SPECT reaches down to 0.25 mm resolution in vivo and 0.12 mm ex vivo (Exirad Option). The U-OI optical unit performs Bioluminescence Tomography and Fluorescence Tomography. U-OI can be used integrated with any combination of the other 3 modalities or used in parallel using an optical docking station on the bench. The adaptive ultra-low-dose and ultra-high resolution X-ray CT (U-OI) is utilized used for attenuation correction in both nuclear and optical tomography top arrive at highly quantitative molecular imaging. Several unique applications of the VECTor 6 technology will be presented, performed by many labs across the globe.

Figure
Keywords: VECTor6 PET, SPECT, X-ray & Optical CT
1:55 p.m. LS 01-02

MILabs VECTor/CT: Applications at the University of British Columbia (UBC)

Vesna Sossi1

1 University of British Columbia, Physics and Astronomy, Vancouver, Canada

Content

UBC was one of the first sites in North America to acquire a Milabs VECTor/CT; following an early scanner characterization, the instrument has been predominantly used to image non-conventional radiotracers, and compounds where dual labelling is advantageous to the understanding of their mechanism of action. The unique detector/collimator combinations allow for a much broader range of radiation emitting isotopes to be imaged thus enabling a wide range of radiolabelling choices. Building on these characteristics, our program now includes includes applications in α-emitters imaging, theranostics, nanomedicine, quantitative imaging of novel dual isotope combinations, such as 111In and 67Ga, investigations of  mechanisms of delivery and pharmacokinetics of antibiotics and antimicrobials, investigation of metal chelators and their use as radiopharmaceuticals, studies in immunologies and vaccines, and macromolecular conjugates and lipid based formulations. This talk will review some of the technical methodology that enabled the acquisition of some of the ‘first of its kind’ images, such as  those obtained from the a-emitter 225Ac [1] and 209At as theranostic companion the a-emitter 211At [2], as well as images obtained from simultaneous injection of 67Ga-NOTA- hyperbranched polycerol  (HPG) and IP injection of 111In-DTPA HPG [3]. Two novel applications of more traditional imaging  will also be discussed: use of monosized polymeric microspheres designed for localized antibiotic delivery via lung targeting [4] and investigation of the effect of delivery on the inhalable nanoparticle distribution (Milabs SNMMI image of the year), which informs both on experimental designs as well as optimal delivery methods of possible treatments [5].

References
1 Robertson, A.K.H., et al., Multi-isotope SPECT imaging of the (225)Ac decay chain: feasibility studies. Phys Med Biol, 2017. 62(11): p. 4406-4420.
2 Crawford, J.R., et al., Evaluation of (209)At as a theranostic isotope for (209)At-radiopharmaceutical development using high-energy SPECT. Phys Med Biol, 2018. 63(4): p. 045025.
3 Esquinas, P.L., et al., Dual SPECT imaging of (111)In and (67)Ga to simultaneously determine in vivo the pharmacokinetics of different radiopharmaceuticals: a quantitative tool in pre-clinical research. Phys Med Biol, 2018. 63(23): p. 235029
4 Agnoletti, M., et al., Monosized Polymeric Microspheres Designed for Passive Lung Targeting: Biodistribution and Pharmacokinetics after Intravenous Administration. ACS Nano, 2020. 14(6): p. 6693-6706
5 Wu, L., et al., Quantitative comparison of three widely-used pulmonary administration methods in vivo with radiolabeled inhalable nanoparticles. Eur J Pharm Biopharm, 2020. 152: p. 108-115.
Keywords: MIlabs VECT/or/CT, dual-isotope imaging, theranostic, alpha-emitters, novel pre-clinical imaging applications
2:05 p.m. LS 01-03

Airway Remodeling in Ferrets with Cigarette Smoke Induced COPD using µCT Imaging

Denise Stanford1, 2, Harrison Kim4, Sandeep Bodduluri2, 3, Jennifer LaFontaine1, 2, Stephen Byzek2, 1, Trenton Schoeb6, Elex Harris2, 1, Hrudaya Nath3, 4, Surya Bhatt1, 3, S. Vamsee Raju1, 2, Steven Rowe2, 1, 5

1 University of Alabama at Birmingham, Department of Medicine, Birmingham, United States of America
2 University of Alabama at Birmingham, Cystic Fibrosis Research Center, Birmingham, United States of America
3 University of Alabama at Birmingham, UAB Lung Imaging Core, Birmingham, United States of America
4 University of Alabama at Birmingham, Department of Radiology, Birmingham, United States of America
5 University of Alabama at Birmingham, Department of Pediatrics and Department of Cell Developmental and Integrative Biology, Birmingham, United States of America
6 University of Alabama at Birmingham, Genetics and Animal Resources Program, Birmingham, United States of America

Content

RATIONALE: Structural changes to airway morphology such as increased bronchial wall thickness (BWT) and airway wall area are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis.

OBJECTIVES: Develop a µCT method for evaluating structural changes to the airways in ferrets, and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans.

METHODS: Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 months.  µCT was conducted in vivo at 6 months; a longitudinal cohort was imaged monthly.  Manual measurements of BWT, luminal diameter (LD), and BWT:LD ratio were conducted, and confirmed by a semi-automated algorithm.  The square root of bronchial wall area ( WA) vs. luminal perimeter was determined on an individual ferret basis.

MEASUREMENTS AND MAIN RESULTS: Smoke exposed ferrets reproducibly demonstrated 34% increased BWT (P<0.001); along with increased LD, and BWT:LD ratio vs. air controls.  Regression indicated the effect of smoking on BWT persisted despite controlling for covariates.  Semi-automated measurements replicated findings.   WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke exposed ferrets (P=0.015).  Increased BWT and Pi4 developed steadily over time.

CONCLUSIONS: µCT-based airway measurements in ferrets are feasible and reproducible.  Smoke exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis.  µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

Acknowledgment

The authors acknowledge institutional support through the University of Alabama Health Services Foundation Institutional Endowment to purchase the µCT instrument.

References
Mr. Bodduluri S, Reinhardt JM, Hoffman EA, Newell JD, Jr., and Bhatt SP. Recent Advances in Computed Tomography Imaging in Chronic Obstructive Pulmonary Disease. Annals of the American Thoracic Society 15: 281-289, 2018.
Mr. Raju SV, Kim H, Byzek SA, Tang LP, Trombley JE, Jackson P, Rasmussen L, Wells JM, Libby EF, Dohm E, Winter L, Samuel SL, Zinn KR, Blalock JE, Schoeb TR, Dransfield MT, and Rowe SM. A ferret model of COPD-related chronic bronchitis. JCI Insight 1: e87536, 2016.
Structural analysis of smoke exposed ferret airways using µCT
(A) Representative image of ferret lung µCT scan. Red arrows show the locations where airway measurements were taken. (B) Representative coronal and axial projections of air control and 6 month smoke-exposed  ferrets. Lower insets are magnified views of a representative airway selected for measurements.  Yellow line indicates airway luminal diameter and red line represents BWT. Upper insets demonstrate the same measurements by histopathological analysis for comparison. (C) Manual BWT. (D) Manual Mean luminal diameter. (E) Manual Mean BWT/Luminal Diameter ratio (23 smoke, 19 control ferrets).
Semi-automated analysis of airway wall anatomy in smoke exposed and air control ferrets.
(A) Semi-Automated image processing for measurement of bronchial wall thickness illustrated. (B) Box plots of the Semi-Automated bronchial wall thickness (BWT).  N=6648 airways. (C) Semi-Automated probability density function of the luminal perimeter, when the 4-6th generations of the apical airway were analyzed in the control group. (D) Semi-Automated scatter plots of √WA vs. airway luminal perimeter in representative ferrets. (E, F) Semi-Automated linear regression lines of √WA vs. airway luminal perimeters. (G) Semi-Automated calculated WA of the theoretical 4 mm perimeter airway (Pi4).
Keywords: COPD, chronic bronchitis, bronchial wall thickness
2:15 p.m. LS 01-04

Quantitative Multimodal Fluorescence and Bioluminescence Tomography with the MILabs OI-CT System

Felix Gremse1, 2

1 Gremse-IT GmbH, Aachen, Germany
2 RWTH Aachen University, Experimental Molecular Imaging, Aachen, Germany

Content

Introduction: Hybrid fluorescence tomography and x-ray computed tomography (FLT-CT) provided by the MILabs OI-CT system allows non-invasive longitudinal volumetric assessment of fluorescent probes in mice in vivo. The 3D fluorescence reconstruction uses many transillumination images to resolve fluorescence in depth to overcome quantification problems with in vivo 2D fluorescence reflectance imaging. Polymeric micelles like core-cross-linked polymeric micelles (CCL-PMs) are nanomedicines with potential for clinical applications due to their improved tumor uptake by means of long blood circulation and EPR-based passive targeting. Experimental biodistribution assessment with in vivo experiments is important during development of such nanomedicines to confirm their predicted biodistribution and tumor uptake and exclude unwanted accumulation sites. The aim of this study was to evaluate if the FLT-CT can be used to quantitatively determine the biodistribution of such NIRF-labeled probes. Furthermore, we wanted to test the functionality for multimodal bioluminescence tomography (BLT-CT) which uses multispectral images to identify deep luminescent sources such as luciferase-expressing tumors and metastases.

Methods: CCL-PMs were labelled with the fluorescent near-infrared dye Cy7. To compare organ and tumor uptake, we also used cationic micelles (CatMic) with fast liver uptake and free dye (Cy7). 4T1 orthotopic tumor-bearing mice (3 to 5 mice per group) were scanned at time points (pre, 15 min, 4h, 24h, 48h) before and after i.v. injection of the three fluorescent probes. FLT-CT scans were acquired with approximately 3 mm spacing and 120 laser points covering the whole body. The fluorescence reconstruction used shape information as well as scattering and absorption maps derived from the μCT and optical data. Using the anatomical µCT data, we segmented organs and tumors to assign the reconstructed fluorescence and derive the longitudinal biodistribution and tumor uptake. After the last of the scans, we excised organs and tumors and performed ex vivo 2D fluorescence reflectance imaging. For bioluminescence tomography, a 3D-printed mouse phantom with an inserted break light stick was scanned in a 3-mouse bed.

Results: Significantly (P<0.05) higher tumor accumulation was found 48h post injection in CCL-PMs (18.6±10.8%ID/g) compared to cationic micelles (1.4±0.8%ID/g) and Cy7 (0.76±0.77%ID/g). Cationic micelles had significantly (P<0.05) higher liver and spleen concentrations compared to CCL-PMs and Cy7. Some kidney retention was found for CCL-PMs and Cy7 at 48 h but none of the probes showed high signal in the urinary bladder indicative for fast renal clearance. 2D fluorescence imaging of excised organs and tumors confirmed the in vivo results at 48 h with a strong correlation (r=0.95, P<0.01) between in vivo concentrations and ex vivo mean fluorescence intensities. The BLT-CT scans of the bioluminescence phantom showed correct localization of the reconstructed signal near the break light stick.

Conclusions: Strong tumor accumulation was found for the NIRF-labelled CCL-PMs whereas CatMic and Cy7 showed only marginal tumor accumulation. The CT-FLT technology identifies presence and absence of accumulation and retention in liver, spleen and kidneys, which are important elimination organs. The strong correlation between the FLT-based in vivo concentrations and mean fluorescence intensities of excised organs shows the capability of FLT-CT for quantitative in vivo biodistribution assessment of NIRF-labelled probes. BLT-CT can be performed to identify deep bioluminescent lesions for up to three mice at the same time.

AcknowledgmentI would like to thank the teams of MILabs, Cristal Therapeutics, ExMI, STCE and Gremse-IT for the good cooperation.
References
1 Hu, Q. et al. 2016 J. Control Release, 244:314-325
2 Gremse, F. et al. 2014 Theranostics;4(10):960-71
3 Gremse, F. et al. 2016 Theranostics;6(3):328-41
In vivo FLT-CT vs. ex vivo 2D FRI
We used in vivo fluorescence tomography with computed tomography (FLT-CT) to determine the biodistribution of three i.v. injected fluorescent probes: free dye (Cy7), core-cross-linked micelles (Cripec) and cationic micelles (CatMic). Organ segmentations were performed for quantification. After the last scan at 48h, organs were excised and imaged by 2D reflectance imaging. In vivo concentrations and ex vivo means showed similar results, e.g. high tumor uptake for Cripec and high liver and spleen uptake for CatMic. In vivo and ex vivo values correlated strongly (P<0.05).
Keywords: Fluorescence tomography, Multimodal imaging, Bioluminescence Tomography