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Ultrasound-Stimulated Phase-Change Contrast Agents for Sonothrombolysis.

Award Number: R43HL152819
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/17/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2021

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Ultrasound-Stimulated Phase-Change Contrast Agents for Sonothrombolysis. - ABSTRACT Cardiovascular disease is the leading cause of death and disability worldwide accounting for 840,678 deaths in the US in 2016. Acute myocardial infarction caused by thrombus within the coronary arteries is the major culprit in cardiovascular disease. ST-Elevation Myocardial Infarction (STEMI), results in death and disability due to damage to cardiac myocytes and decreased cardiac function. Despite advancements in restoring epicardial artery patency via reperfusion therapy, microvascular obstruction (MVO) limits cardiovascular recovery at the tissue level and results in poorer prognosis, including death. While the prevalence of MVO ranges from 10% to >70%, there is no consensus on how to safely and effectively prevent or treat MVO. Efforts to remove occlusive thrombi via thrombectomy, mechanical disruption, and/or biochemical dissolution have demonstrated efficacy; however, these are time consuming, show mixed results in improving clinical outcomes, and are accompanied by substantial risk of hemorrhagic complications. Efforts to enhance the safety and efficacy of thrombus removal have high potential clinical impact. Ultrasound has been shown to disrupt thrombi and microbubbles (MB) can locally amplify and accelerate ultrasound-enhanced thrombolysis at a lower energy level. A caveat to the use of MBs stems from their size (1-3 microns), which may limit their access to the interior of the microthrombi responsible for MVO. Smaller acoustically active materials, including phase change nanodroplets (ND, ~100- 200 nm), should more easily penetrate thrombus to increase sonothrombolytic efficiency and clinical efficacy. Microvascular Therapeutics (MVT) has developed a safe and more stable lipid-based MB (MVT-100) less likely to induce anaphylactoid reactions as compared to Definity® and is developing MVT-100 via the 505(b)(2) pathway. Moreover, MVT has subsequently made ND from MVT-100 (Patent, US 9,427,410B2) and conjugated ND with a peptide ligand with high affinity for fibrin (FTND). Electron microscopy of fibrin clots shows that that FTND permeate clot > non-targeted ND >> MB. Preliminary studies performed in our laboratory as well as by our collaborators at the University of Pittsburgh Center for Ultrasound Molecular Imaging and Therapeutics in an in vitro model of MVO show that fibrin micro-clots are disrupted by US with ND >> MB. In this Phase I SBIR, our combined groups propose to characterize fibrin targeted NDs (FTND) and evaluate their effectiveness in vivo in disrupting the microvascular thrombi in a biologically relevant model reflective of MVO during acute myocardial infarction. After production of bioconjugate and FTNDs, we will evaluate their binding to the fibrin target. We hypothesize that FTND will improve fibrin clot detection and achieve superior dissolution of thrombi upon ultrasound activation as compared to MBs. The overall goal of this Phase I program is to obtain proof of concept for the usage of FTNDs and perform feasibility studies which will if successful, support further preclinical development and IND-enabling studies of ND for a Phase II SBIR grant application in STEMI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	MICROVASCULAR THERAPEUTICS LLC	1635 E 18TH ST	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	1	7/1/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $378,190 )
2020	2020	MICROVASCULAR THERAPEUTICS LLC	1635 E 18TH ST	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	1	7/17/2020	NEW	$378,190
														Subtotal = $378,190

Grand Total All Awards = $378,190

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Ultrasound-Stimulated Phase-Change Contrast Agents for Sonothrombolysis.

Award Number: R43HL152819

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/17/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2021

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