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Toward a Nanoencapsulated EPR Imaging Agent for Clinical Use

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Abstract

Purpose

Progress toward developing a novel radiocontrast agent for determining pO2 in tumors in a clinical setting is described. The imaging agent is designed for use with electron paramagnetic resonance imaging (EPRI), in which the collision of a paramagnetic probe molecule with molecular oxygen causes a spectroscopic change which can be calibrated to give the real oxygen concentration in the tumor tissue.

Procedures

The imaging agent is based on a nanoscaffold of aluminum hydroxide (boehmite) with sizes from 100 to 200 nm, paramagnetic probe molecule, and encapsulation with a gas permeable, thin (10–20 nm) polymer layer to separate the imaging agent and body environment while still allowing O2 to interact with the paramagnetic probe. A specially designed deuterated Finland trityl (dFT) is covalently attached on the surface of the nanoparticle through 1,3-dipolar addition of the alkyne on the dFT with an azide on the surface of the nanoscaffold. This click-chemistry reaction affords 100% efficiency of the trityl attachment as followed by the complete disappearance of the azide peak in the infrared spectrum. The fully encapsulated, dFT-functionalized nanoparticle is referred to as RADI-Sense.

Results

Side-by-side in vivo imaging comparisons made in a mouse model made between RADI-Sense and free paramagnetic probe (OX-071) showed oxygen sensitivity is retained and RADI-Sense can create 3D pO2 maps of solid tumors

Conclusions

A novel encapsulated nanoparticle EPR imaging agent has been described which could be used in the future to bring EPR imaging for guidance of radiotherapy into clinical reality.

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Data Availability

The data needed to evaluate the conclusions of the paper are present in the paper.

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Acknowledgements

We would like to thank Dr. Brian Gorman, Colorado School of Mines for help with the SEM of nanoparticles.

Funding

This work was funded under a National Cancer Institute (NCI) Small-Business-Innovation and Research (SBIR) Phase I Award (Contract #75N91010C00032 “Encapsulated Nanoparticle Oxygen Imaging Agents for Radiotherapy Guidance”, with TDA Research as the primary grant awardee and sub-contracts to WVU, DU and O2M Technologies, LLC. The alkyne-functionalized trityl (dFT) was synthesized by Dr. Driesschaert at West Virginia University (WVU), RADI-Sense imaging agent was synthesized at TDA Research Inc. under the direction of Dr. Biller. EPR measurements were performed at the University of Denver under Dr. Gareth Eaton. Mouse imaging comparisons between RADI-Sense and OX-071 were carried out under the direction of Dr. Kotecha, founder and CEO of O2M Technologies. All applicable institutional and/or national guidelines for the care and use of animals were followed.

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Authors and Affiliations

  1. TDA Research Inc., Golden, CO, 80403, USA

    Rhia M. Martin, Samantha Diaz & Joshua R. Biller

  2. Department of Pharmaceutical Sciences, School of Pharmacy & In-Vivo Multifunctional Magnetic Resonance Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, 26506, USA

    Martin Poncelet & Benoit Driesschaert

  3. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, 60637, USA

    Eugene Barth & Boris Epel

  4. Oxygen Measurement Core, O2M Technologies, Chicago, IL, 60612, USA

    Mrignayani Kotecha & Boris Epel

  5. Department of Chemistry, University of Denver, Denver, CO, 80210, USA

    Gareth R. Eaton

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  1. Rhia M. Martin
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Correspondence to Joshua R. Biller.

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Conflict of Interest

Dr. Biller reports grants from National Cancer Institute, during the conduct of the study; In addition, Dr. Biller has patents “Encapsulated Nanoparticle Imaging Agents for Radiotherapy Guidance” 63/352249, filed 06/15/23 pending.

Dr. Kotecha reports other from TDA Research, Inc., during the conduct of the study; other from O2M Technologies, LLC, outside the submitted work.

Dr. Driesschaert reports grants from National Cancer Institute, during the conduct of the study.

Dr. Eaton reports grants from National Cancer Institute, during the conduct of the study.

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Martin, R.M., Diaz, S., Poncelet, M. et al. Toward a Nanoencapsulated EPR Imaging Agent for Clinical Use. Mol Imaging Biol (2023). https://doi.org/10.1007/s11307-023-01863-0

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