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Catheter-injectable system for local drug delivery after myocardial infarct

Award Number: K99HL169844
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/14/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Catheter-injectable system for local drug delivery after myocardial infarct - PROJECT SUMMARY Myocardial infarction (MI) is a leading cause of cardiovascular disease and death. After an MI, limited regeneration occurs, and instead, inflammation and scarring cause the affected myocardial tissue to turn fibrotic and thin. This tissue remodeling results in abnormal tissue mechanics and impaired cardiac function, often leading to heart failure and death. Therefore, a promising therapeutic approach is to reduce inflammation and the adverse tissue remodeling of the infarct zone. Unfortunately, many emerging drug candidates to achieve these goals require prolonged dosing over multiple weeks, greatly limiting their clinical translation. To overcome this challenge, I propose the development of a hydrogel that is catheter-injectable and enables the one-time injection of a drug payload into the myocardium for long-term release. This multidisciplinary project merges my expertise in drug delivery, polymeric materials, and cardiovascular bioengineering. Specifically, I propose a nanoparticle-based, therapy-eluting gel that will be retained within the contractile myocardium to locally deliver the chosen therapy at a controlled rate. This hydrogel will address two challenges in cardiovascular therapies 1) retention in the myocardium due to the mechanically active heart and 2) delivery of a sustained therapeutic dose that preserves the bioactivity in the harsh environment of the infarct zone. In this project, I propose to deliver two potential therapeutics investigated in clinical trials to address inflammation and adverse remodeling. Anakinra delivered daily through subcutaneous injection has emerged as a promising candidate to reduce inflammation and prevent cardiomyocyte apoptosis after MI. Fresolimumab has potential to mitigate heart failure after MI by preventing fibroblast activation into myofibroblasts and thereby limiting fibrosis. However, to elicit a therapeutic effect, these drugs must be present for an extended duration via multiple daily injections. Therefore, novel therapeutics like Anakinra and Fresolimumab are limited in efficacy and clinical use and would greatly benefit from materials science approaches that would reduce the need for painful daily injections by enabling them to be delivered locally within the myocardium in a reservoir that can protect their bioactivity, limit their off-target effects, and offer tunable release kinetics that can match the therapeutic window of the chosen drugs. In the K99 mentored phase of this grant, I will develop the catheter-injectable hydrogel and demonstrate retention within the myocardium (Aim 1), tailor the release kinetics of the nanoparticles to achieve both rapid and sustained payload delivery of Anakinra (Aims 2), and demonstrate the therapeutic effect in a preclinical rat model of MI (Aim 3). In the R00 phase, the modular hydrogel technology will be expanded to include a second type of nanoparticle to enable the combinatorial release of Anakinra and Fresolimumab (hydrophobic and hydrophilic drugs, respectively) (Aim 4) and improve heart function quantitatively after an MI by preventing adverse remodeling in a rat preclinical model (Aim 5).


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: 2026 ( Subtotal = $0 )
2026	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	1/18/2026	NON-COMPETING CONTINUATION	$8,387,975
2026	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	2	1/21/2026	NON-COMPETING CONTINUATION	-$8,387,975
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	8/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $156,708 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	7/2/2024	NON-COMPETING CONTINUATION	$156,708
														Subtotal = $156,708

Issue Date FY: 2023 ( Subtotal = $156,708 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	7/14/2023	NEW	$156,708
														Subtotal = $156,708

Grand Total All Awards = $313,416

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Catheter-injectable system for local drug delivery after myocardial infarct

Award Number: K99HL169844

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/14/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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