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Purpose This study aimed to develop a chelate-free radiolabeled nanoparticle platform for simultaneous positron emission tomography (PET) and magnetic resonance (MR) imaging that provides contrast-enhanced diagnostic imaging and significant image quality gain by integrating the high spatial resolution of MR with the high sensitivity of PET. Methods A commercially available super-paramagnetic iron oxide nanoparticle (SPION) (Feraheme®, FH) was labeled with the [89Zr]Zr using a novel chelate-free radiolabeling technique, heat-induced radiolabeling (HIR). Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and radio-thin layer chromatography (radio-TLC). Characterization of the non-radioactive isotope 90Zr-labeled FH was performed by transmission electron microscopy (TEM). Simultaneous PET-MR phantom imaging was performed with different 89Zr-FH concentrations. The MR quantitative image analysis determined the contrast-enhancing properties of FH. The signal-to-noise ratio (SNR) and full-width half-maximum (FWHM) of the line spread function (LSF) were calculated before and after co-registering the PET and MR image data. Results High RCY (92%) and RCP (98%) of the [89Zr]Zr-FH product was achieved. TEM analysis confirmed the 90Zr atoms adsorption onto the SPION surface (≈ 10% average radial increase). Simultaneous PET-MR scans confirmed the capability of the [89Zr]Zr-FH nano-platform for this multi-modal imaging technique. Relative contrast image analysis showed that [89Zr]Zr-FH can act as a dual-mode T1/T2 contrast agent. For co-registered PET-MR images, higher spatial resolution (FWHM enhancement ≈ 3) and SNR (enhancement ≈ 8) was achieved at a clinical dose of radio-isotope and Fe. Conclusion Our results demonstrate FH is a highly suitable SPION-based platform for chelate-free labeling of PET tracers for hybrid PET-MR. The high RCY and RCP confirmed the robustness of the chelate-free HIR technique. An overall image quality gain was achieved compared to PET- or MR-alone imaging with a relatively low dosage of [89Zr]Zr-FH. Additionally, FH is suitable as a dual-mode T1/T2 MR image contrast agent., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: http://youtu.be/Me_QBfX7I3s

Purpose Using our chelate-free, heat-induced radiolabeling (HIR) method, we show that a wide range of metals, including those with radioactive isotopologues used for diagnostic imaging and radionuclide therapy, bind to the Feraheme (FH) nanoparticle (NP), a drug approved for the treatment of iron anemia. Material and methods FH NPs were heated (120°C) with nonradioactive metals, the resulting metal-FH NPs were characterized by inductively coupled plasma mass spectrometry (ICP-MS), dynamic light scattering (DLS), and r1 and r2 relaxivities obtained by nuclear magnetic relaxation spectrometry (NMRS). In addition, the HIR method was performed with [90Y]Y3+, [177Lu]Lu3+, and [64Cu]Cu2+, the latter with an HIR technique optimized for this isotope. Optimization included modifying reaction time, temperature, and vortex technique. Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and thin-layer chromatography (TLC). Results With ICP-MS, metals incorporated into FH at high efficiency were bismuth, indium, yttrium, lutetium, samarium, terbium and europium (>75% @ 120 oC). Incorporation occurred with a small (less than 20%) but statistically significant increases in size and the r2 relaxivity. An improved HIR technique (faster heating rate and improved vortexing) was developed specifically for copper and used with the HIR technique and [64Cu]Cu2+. Using SEC and TLC analyses with [90Y]Y3+, [177Lu]Lu3+ and [64Cu]Cu2+, RCYs were greater than 85% and RCPs were greater than 95% in all cases. Conclusion The chelate-free HIR technique for binding metals to FH NPs has been extended to a range of metals with radioisotopes used in therapeutic and diagnostic applications. Cations with f-orbital electrons, more empty d-orbitals, larger radii, and higher positive charges achieved higher values of RCY and RCP in the HIR reaction. The ability to use a simple heating step to bind a wide range of metals to the FH NP, a widely available approved drug, may allow this NP to become a platform for obtaining radiolabeled nanoparticles in many settings., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/_SYXGLeZuWM

The aim of this project was to develop and evaluate a theranostic nano-platform to enable Radionuclide Therapy (RNT) and multimodal imaging to improve the therapy and diagnosis of lymph node metastases. The work presented in this thesis consists of four main studies. First, Feraheme (FH) and two other superparamagnetic iron-oxide nanoparticles (SPIONs) were radiolabelled with radioisotopes commonly used in the clinic (89Zr, 177Lu and 90Y) for imaging and therapy utilising a novel chelate-free technique, which produced a high radiochemical yield and purity (up to 98%). FH nanoparticles were successfully radiolabelled with 90Y and 177Lu which was the first experimental demonstration that the HIR technique can be extended to radiolabel FH with these isotopes. In the second study, a series of phantom experiments were performed and results demonstrated that 89Zr-FH is a novel nanotechnology for simultaneous PET/MR imaging providing the capability of integrating the spatial resolution and tissue contrast provided by MR imaging with the high sensitivity of PET. An additional phantom study demonstrated the ability to image 177Lu-FH using Single Photon Emission Computed Tomography. The third study was a proof of concept for 90Y RNT. Results revealed that in RNT, the kinetics of DNA double strand break (DSB) induction, repair and misrepair must be considered when deriving radiobiological parameters. The fourth study, a Monte Carlo simulation study, was performed to study the subcellular mechanisms of dose delivery of the radionuclide 223Ra when treating metastases. These simulations showed that indirect cell damage may play an important role in RNT with alpha emitters due to the stochastic nature of alpha particle energy deposition. In conclusion, these results open a pathway towards a novel nuclear nanoplatform for multimodal imaging and RNT of lymph node metastases.

International audience; The validity of isotropic approximation to perform acoustic full waveform inversion (FWI) of real wide-aperture anisotropic data can be questioned due to the intrinsic kinematic inconsistency between short- and large-aperture components of the data. This inconsistency is mainly related to the differences between the vertical and horizontal velocities in vertical-transverse isotropic (VTI) media. The footprint of VTI anisotropy on 2-D acoustic isotropic FWI is illustrated on a hydrophone data set of an ocean-bottom cable that was collected over the Valhall field in the North Sea. Multiscale FWI is implemented in the frequency domain by hierarchical inversions of increasing frequencies and decreasing aperture angles. The FWI models are appraised by local comparison with well information, seismic modelling, reverse-time migration (RTM) and source-wavelet estimation. A smooth initial VTI model parameterized by the vertical velocity V0 and the Thomsen parameters δ and ε were previously developed by anisotropic reflection traveltime tomography. The normal moveout (inline image) and horizontal (inline image) velocity models were inferred from the anisotropic models to perform isotropic FWI. The VNMO models allows for an accurate match of short-spread reflection traveltimes, whereas the Vh model, after updating by first-arrival traveltime tomography (FATT), allows for an accurate match of first-arrival traveltimes. Ray tracing in the velocity models shows that the first 1.5 km of the medium are sampled by both diving waves and reflections, whereas the deeper structure at the reservoir level is mainly controlled by short-spread reflections. Starting from the initial anisotropic model and keeping fixed δ and ε models, anisotropic FWI allows us to build a vertical velocity model that matches reasonably well the well-log velocities. Isotropic FWI is performed using either the NMO model or the FATT model as initial model. In both cases, horizontal velocities are mainly reconstructed in the first 1.5 km of the medium. This suggests that the wide-aperture components of the data have a dominant control on the velocity estimation at these depths. These high velocities in the upper structure lead to low values of velocity in the underlying gas layers (either equal or lower than vertical velocities of the well log), and/or a vertical stretching of the structure at the reservoir level below the gas. This bias in the gas velocities and the mispositioning in depth of the deep reflectors, also shown in the RTM images, are required to match the deep reflections in the isotropic approximation and highlight the footprint of anisotropy in the isotropic FWI of long-offset data. Despite the significant differences between the anisotropic and isotropic FWI models, each of these models produce a nearly-equivalent match of the data, which highlights the ill-posedness of acoustic anisotropic FWI. Hence, we conclude with the importance of considering anisotropy in FWI of wide-aperture data to avoid bias in the velocity reconstructions and mispositioning in depth of reflectors. Designing a suitable parameterization of the VTI acoustic FWI is a central issue to manage the ill-posedness of the FWI.