Macrophage-Targeted Therapeutics To Attenuate the Development of Ischemic Heart Failure Following MI
Thursday, September 7, 2023
10:00 AM-12:00 PM
BIOMED PhD Research Proposal
Title:
Macrophage-Targeted Therapeutics To Attenuate the Development of Ischemic Heart Failure Following Myocardial Infarction (MI)
Speaker:
Shreya Soni, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Advisor:
Christopher B. Rodell, PhD
Assistant Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University
Details:
Heart failure (HF) remains the leading cause of morbidity and mortality worldwide, projected to afflict over 8 million Americans by 2030. Nearly 70% of HF cases are the direct result of myocardial infarction (MI), causing a cascade of cell death, loss of muscle contraction, and maladaptive tissue remodeling. Inflammation has recently been recognized as a critical regulator of this left ventricular remodeling (LVR) process post-MI. After injury, classically activated (M1-like) macrophages (MF) initially dominate the immune microenvironment, necessary for early tissue remodeling. With injury resolution, alternatively activated (M2-like) MF are later required to mitigate inflammation and promote repair. In most cases, this transition is impeded by the establishment of a hyper-inflammatory milieu and chronic inflammation ensues. An appropriate functional shift from inflammatory to reparatory MF populations is often lacking post-MI. Yet, MF are highly plastic, able to shift between functional phenotypes in response to outside signals. Immunosuppressive therapies have been evaluated in clinical trials. These strategies have not specifically targeted MF phenotype, and translation has been stymied by moderate therapeutic efficacy and an increased risk of infection resulting from systemic immunosuppression. Therefore, phenotypic modulation of MF by small-molecule drugs remains under-explored, and delivery of these agents to immune cells at the injury site continues to be challenging.
To address these critical needs, we first seek to identify small-molecule drugs that directly combat the hyper-inflammatory environment by phenotypic modulation that includes attenuation of the destructive inflammatory (M1-like) MF and simultaneous promotion of reparatory (M2-like) MF. Second, the delivery of small molecule drugs is hampered by biodistribution challenges that include poor aqueous solubility, rapid renal clearance, and an inability to target specific cells or tissue. Therefore, we have developed two drug carrier systems that each enable drug solubilization and MF-targeted delivery. These include cyclodextrin nanoparticles for systemic delivery and polymer-nanoparticle hydrogels that enable local delivery to the injury site by direct injection. Our nanoparticle platform, which is the basis for both systems, has been optimized for rapid and cell-specific delivery of small molecule drugs, and has demonstrated desirable modulation of the inflammatory response with potential to attenuate the pathogenesis of HF. As it is increasingly recognized that a dysregulated immune response underlies a vast array of human diseases, vehicles that enable therapeutic manipulation of the immune system will continue to be of widespread impact, including in cardiovascular applications.
Contact Information
Natalia Broz
njb33@drexel.edu