Development of Brain MRI Contrast Agents

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Alan  Koretsky
Organization: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Fiscal Year: 2024
Award: $145,123
Funding agency: National Institute of Neurological Disorders and Stroke

As originally planned when this project first started, it has now transitioned to be fully performed at the Uniformed Services University of the Health Sciences (USHSU).  David Brody is the PI of the project at USHSU and he has been successful at getting funding independent of NINDS intramural research program.

Therefore, this is the last report for this project under NINDS and intramural funding.

Personnel have all transitioned to new positions.
The project is successfully up and running and is extending the progress that was made at NIH
which was:

We have demonstrated that a mutant mouse transferrin receptor binding nanobody with strong pH dependent unbinding crosses the BBB in vivo approximately 500 times more effectively than a control nanobody.

We have demonstrated that the mutant mouse transferrin receptor binding nanobody can carry other nanobodies as cargo across the mouse BBB. A tandem dimer of nanobodies that bind to the P2X7 receptor has been used as a model cargo.

We have shown that cargo transported across the BBB can be detected in capillary depleted brain lysates and histochemically at their target sites between 1 and 16 hours after injection.

We have demonstrated that there is a strong nonlinearity in the dose-response curve for the BBB crossing nanobodies. At doses greater than 30 nmol/kg injected intravenously, there is no greater brain accumulation of cargo. The maximum brain concentration achieved was 4.5nM. This concentration is an order of magnitude too low for MRI detection of iron oxide nanoparticles. We therefore have decided to switch to PET imaging for further development molecular contrast imaging agents. 

We have developed methods to conjugate nanobodies to the positron emitting Copper-64 for PET scans.

Work on the SARS-COV-2 is continuing with collaborators.

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