Project Details
Projekt
Localized and bioresponsive delivery of therapeutics from injectable hydrogel/coacervate composites for the treatment of heart failure
Applicant
Dr. Rosario Manuela Garay Sarmiento
Subject Area
Biomaterials
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 551186431
Heart failure (HF) poses a significant global health challenge, contributing to substantial morbidity, mortality, and healthcare costs. The development of new therapies for HF has faced considerable limitations, largely due to the pronounced pathophysiologic heterogeneity of HF. Namely, the etiology and phenotype of HF can differ largely, with differences observed in each patient based on age, sex, genetic factors and comorbidities. Identifying common molecular pathways underlying HF progression and customizing drug delivery to release drugs only when needed and in response to local biological stimuli can address HF heterogeneity. However, such therapies have yet to be efficiently translated into clinical practice. Faced with this challenge, in this project I aim to develop a novel and upstream biomaterial-based therapeutic avenue to counteract HF. The guiding hypothesis is rooted in the cell biology of myocardial fibrosis, which is identified as a hallmark of HF regardless of its etiology. Specifically, the condition of “maladaptive” myocardial fibrosis resulting in HF has been linked to the emergence of an activated fibroblast population, which expresses the protease, fibroblast activation protein α (FAP). This fibroblast phenotype contributes to adverse cardiac remodeling and the progression of HF, rationalizing FAP as an innovative, strategic and upstream therapeutic target to counteract HF. For the safe and efficient delivery of FAP inhibitors to the cardiac tissue, I aim to develop a bioresponsive drug-loaded hydrogel/nanoparticle composite matrix that serves as both a drug carrier (nanoparticle) and an injectable material (hydrogel). Importantly, FAP inhibitor release will be designed to occur only in response to the local level of FAP expression. Thus, this biomaterial approach not only enables minimally-invasive application but also addresses FAP heterogeneity among patients. I will evaluate the safety and therapeutic efficacy of this approach using advanced in vitro cardiac tissue models. Particular attention will be paid to the controlled and sustained delivery of the FAP inhibitor, with therapeutic outcomes monitored over the course of one month. Upon positive results, I will translate these studies to a rodent model to demonstrate that localized targeting of FAP through an innovative FAP inhibitor-loaded hydrogel/coacervate composite approach can halt HF progression safely and efficiently. Specially, I aim to demonstrate that this approach can minimize the emergence of the "malignant" fibroblast phenotype, thereby interrupting HF progression and offering a breakthrough therapeutic approach. The deliverable from this project will be the establishment of a novel therapeutic direction for the prevention and treatment of HF. These results will significantly advance the cardiovascular field by confirming the role of fibroblast activation in HF and opening an entirely new treatment direction through innovative, smart biomaterials.
DFG Programme
WBP Fellowship
International Connection
USA
