Over the initial 4 years of this BRP proposal, our partnership has designed, developed, and demonstrated in animal models an array of diagnostic targeted perfluorocarbon nanoparticle approaches for use at 1.5T and 3T (clinical), and 4.7 and 11.7T (experimental) MRI field strengths for application in early, advanced, and unstable atherosclerotic plaque. The most significant translational outcome of these activities is the initiation of a Phase 1a/b clinical trial of an 1v23-integrin targeted gadolinium-loaded perfluorocarbon nanoemulsion for robust MRI (1H) delineation of pathological angiogenesis in cancer and cardiovascular disease, which is sponsored by our commercial BRP partner, Kereos, Inc. The anticipated outcome of this trial will be the first clinical proof-of-concept for a new molecularly targeted contrast agent, representing a specific and selective magnetic resonance image-based biomarker that is capable of detecting and quantifying angiogenesis-facilitated pathologies such as atherosclerosis. Our focus for the current BRP proposal (Yr 6-10) is: """""""" to develop new technologies for sensitive, quantitative, multicolor MRI/MRS using a proven targeted perfluorocarbon nanoparticle platform that can be adapted for use as novel diagnostic and therapeutic agents that provide image-based readouts of local biomarker concentration and measurable response to targeted therapeutics. These MRI/MRS signatures will emanate from unique 19F core materials that exhibit no background signal and can be imaged immediately and in real time after injection to provide pharmacokinetic analysis of serum levels and local tissue binding kinetics for drug dosing evaluation. """""""" to develop proof of concept data for a number of focused product concepts from which at least one diagnostic and one therapeutic can be transferred to our commercial partners within the next 5 years for entry into clinical trials. To achieve our translational endpoints, we will design, characterize, and demonstrate theranostic agents and their clinical applications using commercially available 3T MRI to generate quantitative temporal and spatial readouts of relevant biomarkers in response to conjunctive targeted nanoparticle-based therapeutics. These diagnostic readouts can be detected and coregistered immediately and directly with routine 1H images. The therapeutic moieties can be multiplexed in combination into the base particle, or be formulated as a mixture of monovalent constructs. The flexible multiplexing capability will rely on a recently developed and patent pending """"""""universal linker"""""""" strategy that takes advantage of a rationally designed amphipathic peptide core derived from the """"""""host defense"""""""" peptide melittin that has demonstrated wide-ranging functionality in our preliminary studies.

Public Health Relevance

Over the initial term of this BRP proposal, our partnership has designed, developed, and demonstrated in animal models an array of diagnostic targeted perfluorocarbon nanoparticle approaches for use at 1.5T and 3T (clinical), and 4.7 and 11.7T (experimental) MRI field strengths for application in early, advanced, and unstable atherosclerotic plaque. The anticipated outcome of this translational work will be the first clinical trial-based proof-of-concept for a new molecularly targeted contrast agent, representing a specific and selective magnetic resonance image-based biomarker that is capable of detecting and quantifying angiogenesis-facilitated pathologies such as atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL073646-06
Application #
7735487
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (50))
Program Officer
Buxton, Denis B
Project Start
2003-04-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
6
Fiscal Year
2010
Total Cost
$1,402,759
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Yan, Huimin; Zhou, Hui-Fang; Akk, Antonina et al. (2016) Neutrophil Proteases Promote Experimental Abdominal Aortic Aneurysm via Extracellular Trap Release and Plasmacytoid Dendritic Cell Activation. Arterioscler Thromb Vasc Biol 36:1660-1669
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Hou, Kirk K; Pan, Hua; Schlesinger, Paul H et al. (2015) A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin. Biotechnol Adv 33:931-40
Wagner, Elizabeth M; Jenkins, John; Schmieder, Anne et al. (2015) Angiogenesis and airway reactivity in asthmatic Brown Norway rats. Angiogenesis 18:1-11
Jallouk, Andrew P; Palekar, Rohun U; Pan, Hua et al. (2015) Modifications of natural peptides for nanoparticle and drug design. Adv Protein Chem Struct Biol 98:57-91

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