[R01] Enabling systemic delivery of europium-containing contrast agents for magnetic resonance imaging
Ente: National Institute of Biomedical Imaging and Bioengineering
Scadenza: 2029-03-31
Importo max: 73.092 EUR
Paese: US
Descrizione
The ability to image the presence or absence of oxygen is of paramount importance to the study of biochemistry,
medicine, and multiple diseases. Hypoxia is linked to a variety of diseases including kidney disease; hepatic and
neurological toxicities; and the progression, proliferation, and therapy resistance of many cancers, making
hypoxia an important diagnostic and therapeutic target. This proposal describes plans to study a new class of
phosphonate-containing complexes of EuII that are compatible with systemic delivery, where the lack of systemic
delivery is the largest obstacles to the widespread use of EuII for imaging hypoxia in multiple diseases.
Specifically, we propose to address the two greatest challenges preventing systemic delivery: persistence time
and relaxivity. With the advent of hypoxia-responsive contrast agents for magnetic resonance imaging (MRI),
including the recent development and characterization by our team of a novel EuII-based agent that persists in
blood, the ability to systemically deliver EuII for imaging hypoxia is expected to become a reality for the stud of
multiple diseases. Our overarching goal is to develop hypoxia-sensing probes for MRI to target unmet needs in
diagnostic medicine relevant to a range of diseases. We will build on our discovery from the previous funding
period of the first EuII-based molecule compatible with systemic delivery by increasing the persistence and
relaxivity of EuII through control of the phosphonate arms that are at the center of kinetic resistance to O2 and
through conjugation to macromolecules. Our hypothesis is that new phosphonate complexes of EuII based on
our lead complex will enable systemic delivery of EuII by increasing the persistence time and relaxivity of EuII in
vivo. Aim 1 studies the properties of new derivatives of our initial discovery that contain electron-withdrawing
groups. Aim 2 studies dendrimeric conjugates of our original phosphonate complex. Aim 3 defines the toxicity
and biodistribution of Eu-containing phosphonate complexes in mice. The expected outcome of this proposal is
an understanding of the design criteria of phosphonate complexes of EuII that enable systemic delivery and make
the complexes compatible with bioconjugation to enable study of a wide-range of hypoxia-related diseases. We
envision that our results will serve as the basis for future translation for monitoring new and existing therapies
for hypoxia-related diseases.
Istituzione: WAYNE STATE UNIVERSITY
PI: MATTHEW J ALLEN, ROBIA G PAUTLER
Progetto: 3R01EB035631-02S1
Settori: National Institute of Biomedical Imaging and Bioengineering
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