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Principal Investigator: Renato Samuel Navarro
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $156,708
Funding agency: National Heart Lung and Blood Institute
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).
Terms: <Address><Affect><Aldehydes><Anterior><Apoptosis><Apoptosis Pathway><Arteries><Assay><Bioassay><Biological Assay><Biomedical Engineering><Biopolymers><Blood capillaries><Body Tissues><Bolus><Bolus Infusion><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac infarction><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Catheters><Cessation of life><Chemistry><Cicatrix><Clinical><Clinical Research><Clinical Study><Clinical Trials><Closure by Ligation><Co-culture><Cocultivation><Coculture><Coculture Techniques><Common Rat Strains><Complex><Contracting Opportunities><Contracts><Death><Development><Diffusion><Dose><Drug Delivery><Drug Delivery Systems><Drugs><Echocardiogram><Echocardiography><Elastin><Emulsions><Encapsulated><Environment><Female><Fibroblasts><Fibrosis><Gel><Geometry><Goals><Grant><Heart><Heart Muscle Cells><Heart Muscle tissue><Heart Vascular><Heart failure><Heart myocyte><Histologic><Histologically><Hydrogels><Hydrogen Oxide><Hydrophobicity><IL-1ra><IL1 febrile inhibitor><IL1RN><Impairment><In Situ><In Vitro><Infarction><Inflammation><Injectable><Injections><Interleukin-1 Receptor Antagonist><Kinetics><Leanness><Left><Ligation><Light><Liquid substance><Lytotoxicity><Measurement><Mechanics><Medication><Mentors><Methods><Modality><Modeling><Modification><Molecular><Molecular Weight><Myocardial><Myocardial Infarct><Myocardial Infarction><Myocardial tissue><Myocardium><Myofibroblast><Natural regeneration><Oils><Outcome><Output><Pain><Painful><Performance><Pharmaceutical Preparations><Pharmacology><Phase><Photoradiation><Polymers><Pre-Clinical Model><Preclinical Models><Pressure Transducers><Prevention><Programmed Cell Death><Proteins><Rat><Rats Mammals><Rattus><Reaction><Regeneration><Rheology><Saline><Saline Solution><Scars><Stress><Subcutaneous Injections><System><Technology><Therapeutic><Therapeutic Effect><Thinness><Time><Tissues><Toxic effect><Toxicities><Transthoracic Echocardiography><Ventricular><Water><Wistar Rats><Work><anakinra><bio-engineered><bio-engineers><bioengineering><biological engineering><capillary><cardiac failure><cardiac function><cardiac infarct><cardiac muscle><cardiomyocyte><cardiovascular disorder><circulatory system><clinical translation><clinically translatable><combinatorial><coronary attack><coronary infarct><coronary infarction><crosslink><cytotoxic><cytotoxicity><density><design><designing><developmental><diffused><diffuses><diffusing><diffusions><dosage><drug candidate><drug/agent><experimental group><fluid><function of the heart><healing><heart attack><heart function><heart infarct><heart infarction><heart muscle><heart sonography><hydrophilicity><improved><infarct><interleukin 1 receptor antagonist protein><light scattering><lipid based nanoparticle><lipid nanoparticle><liquid><local drug delivery><male><materials science><mechanic><mechanical><mortality><multidisciplinary><nano particle><nano-sized particle><nanoparticle><nanoparticle therapy><nanosized particle><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><polymer><polymeric><power analysis><pre-clinical><preclinical><preservation><pressure><prevent><preventing><regenerate><site targeted delivery><subdermal injection><targeted delivery><therapeutic nanoparticles><therapeutically effective><urine IL-1 inhibitor><urine interleukin 1 inhibitor><urine-derived IL1 inhibitor>