Monday, April 29, 2024
4/29/2024
Summary. High resolution imaging in deep tissue (> 1 cm) environments can address a swathe of funda- mental and applied problems in the elucidation of mechanisms of disease origin and progression. While fluores- cence imaging is a workhorse technique for the cellular imaging of biological molecular markers, it suffers from light scattering, and aberration distortions at tissue depths >1 mm. On the opposite end of the spectrum, mag- netic resonance imaging (MRI) is a well-established and broadly employed pre-clinical and clinical imaging method that has no practical limitations with respect to tissue depth, but it suffers from low resolution. In this project we will innovate a new class of hyperpolarized 13C nanoparticle probes that can serve as efficient deep tissue markers in MRI. Our central idea is to dramatically boost 13C NMR signal by means of (i) optical hyperpo- larization that can be carried out at low magnetic fields and (ii) significant extension of 13C coherence times. Specifically, we propose to develop MRI probes based on fluorescent nanodiamonds (FNDs) endowed with nitrogen-vacancy (NV) centers. The electronic spins associated with NVs can be optically “hyperpolarized” and that polarization to be effectively transferred to the diamond 13C nuclear spins, resulting in NMR signal enhance- ment over three orders of magnitude vs. 13C thermal polarization at the fields of clinical MRI. In conjunction, by implementing effective decoupling schemes we propose significantly extend the 13C spin coherences to be able to interrogate them for second-long periods. The latter yields enormous signal gains, a multiplicative factor of another 103- fold. Combining the gains due to hyperpolarization and spin coherence extensions permits a total signal gain of ca. 106 for MRI, and will enable a significant improvement in spatial resolution. Moreover, since the polarization is optically generated, this 13C photo-MRI (PMRI), can be carried out at low-field at a much lower cost vs. conventional MRI infrastructure. In our method the spin polarization is regenerated optically, allowing for acquiring MRI data repeatedly and enabling longitudinal studies. Furthermore, the FND particles are inherently biocompatible, and their surfaces are amenable to a versatile set of targeting ligands. With this basis, we propose to develop targetable fluorescent nanoparticle MRI probes that can be imaged with high fidelity with resolution better than 20 um in deep tissue (>1 cm) settings. In addition to being bright MRI agents, the particles are also bright fluorescent providing an option for a cross-examination of the agent biodistribution in histopathological analysis. In order to realize the prospects of this novel technology, we propose to further develop the hyperpo- larization and MR imaging methodologies, as well as boost hyperpolarizability of nanosized particles by optimiz- ing their structure through synthesis and processing developments. We aim at transferring the PMRI technology we demonstrated for micron-sized particles to the nanosized FND suitable for in vivo MRI. As a part of the technology demonstration, we will construct a simple prototype PMRI imaging set-up on the benchtop (low-field) and image FNDs in tissue phantoms, characterizing achievable metrics of resolution and imaging depth.
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