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MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound

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Abstract

Purpose

A wide variety of hydrophilic imaging and therapeutic agents are unable to gain access to the central nervous system (CNS) due to the blood-brain barrier (BBB). In particular, unless a particular transporter exists that may transport the agent across the BBB, most agents that are larger than 500 Da or that are hydrophilic will be excluded by the BBB. Glutamate carboxypeptidase II (GCPII), also known as the prostate-specific membrane antigen (PSMA) in the periphery, has been implicated in various neuropsychiatric conditions. As all agents that target GCPII are hydrophilic and thereby excluded from the CNS, we used GCPII as a platform for demonstrating our MR-guided focused ultrasound (MRgFUS) technique for delivery of GCPII/PSMA-specific imaging agents to the brain.

Procedures

Female rats underwent MRgFUS-mediated opening of the BBB. After opening of the BBB, either a radio- or fluorescently labeled ureido-based ligand for GCPII/PSMA was administered intravenously. Brain uptake was assessed for 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([18F]DCFPyL) and YC-27, two compounds known to bind GCPII/PSMA with high affinity, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging, respectively. Specificity of ligand binding to GCPII/PSMA in the brain was determined with co-administration of a molar excess of ZJ-43, a compound of the same chemical class but different structure from either [18F]DCFPyL or YC-27, which competes for GCPII/PSMA binding.

Results

Dynamic PET imaging using [18F]DCFPyL demonstrated that target uptake reached a plateau by ∼1 h after radiotracer administration, with target/background ratios continuing to increase throughout the course of imaging, from a ratio of ∼4:1 at 45 min to ∼7:1 by 80 min. NIRF imaging likewise demonstrated delivery of YC-27 to the brain, with clear visualization of tracer in the brain at 24 h. Tissue uptake of both ligands was greatly diminished by ZJ-43 co-administration, establishing specificity of binding of each to GCPII/PSMA. On gross and histological examination, animals showed no evidence for hemorrhage or other deleterious consequences of MRgFUS.

Conclusions

MRgFUS provided safe opening of the BBB to enable specific delivery of two hydrophilic agents to target tissues within the brain. This platform might facilitate imaging and therapy using a variety of agents that have heretofore been excluded from the CNS.

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Acknowledgments

The authors are grateful for grant and in-kind support for this research from Philips Healthcare, the Walter and Mary Ciceric Foundation, and the National Institutes of Health (grant numbers: CA134675, CA184228). The authors also wish to acknowledge the Johns Hopkins Cyclotron Lab for the provision of surplus cGMP [18F]DCFPyL during these studies.

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Authors and Affiliations

  1. The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Raag D. Airan, Catherine A. Foss, Nicholas P. K. Ellens, Yuchuan Wang, Ronnie C. Mease, Keyvan Farahani & Martin G. Pomper

  2. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Keyvan Farahani

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  1. Raag D. Airan
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  2. Catherine A. Foss
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  3. Nicholas P. K. Ellens
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  4. Yuchuan Wang
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  7. Martin G. Pomper
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Correspondence to Martin G. Pomper.

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Conflict of Interest

The authors (RDA, NPKE, KF, MGP) received limited grant funding and support in kind for this work from Philips Healthcare. Under a licensing agreement between Progenics and the Johns Hopkins University, Dr. Pomper is entitled to royalties on an invention described in this article. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

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Airan, R.D., Foss, C.A., Ellens, N.P.K. et al. MR-Guided Delivery of Hydrophilic Molecular Imaging Agents Across the Blood-Brain Barrier Through Focused Ultrasound. Mol Imaging Biol 19, 24–30 (2017). https://doi.org/10.1007/s11307-016-0985-2

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