Targeted delivery of nanomedicines to the coronary microvasculature during ex vivo normothermic perfusion of marginal human hearts

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PROJECT SUMMARY/ABSTRACT This proposal details Dr. John Stendahl’s research and training plan for a Mentored Clinical Scientist Research Career Development Award. Dr. Stendahl’s research focuses on the shortage of donor hearts available for transplantation. He proposes to address this issue by utilizing ex vivo normothermic machine perfusion in the pretransplant setting as a platform to assess marginal donor hearts and treat them with vascular-targeted nanomedicines. This work is based on the hypothesis that achieving clinically significant delivery of nanomedicines in ex vivo donor hearts requires: a) restoration of microvascular perfusion following the insult of cold ischemia, and b) robust methods of nanoparticle targeting. The first aim of the proposal is to optimize microvascular blood flow in hearts undergoing ex vivo normothermic machine perfusion. The plan to accomplish this involves evaluation of the microvasculature with microscopy and multimodal cardiac imaging, and the application of pharmacologic treatments to restore flow. The second aim is to engineer vascular-targeted nanoparticles for delivery to human hearts during ex vivo normothermic machine perfusion. This involves potent new methods of nanoparticle targeting and further application of diagnostic imaging to assess nanoparticle delivery. Successful completion of these aims will provide powerful, clinically adaptable technologies to improve donor heart preservation and achieve more efficient usage of marginal organs. Dr. Stendahl is an instructor in the Yale School of Medicine’s Section of Cardiovascular Medicine and recently completed fellowship training in Advanced Cardiovascular Imaging. His proposed research builds upon his backgrounds in bioengineering, organ transplantation, and cardiac imaging. He is supported by an outstanding mentorship team consisting of Albert Sinusas, MD, an expert in multimodal cardiac imaging, and Gregory Tietjen, PhD, an expert in targeted nanoparticle delivery and machine perfusion of organs. The proposed work leverages outstanding facilities at the Yale School of Medicine, including state-of-the-art medical imaging equipment. Dr. Stendahl’s structured training plan for scientific and professional development includes lectures, coursework in science and ethics, personal meetings with mentors and consultants, and attendance at national meetings related to cardiac imaging, therapeutic delivery, and organ transplantation. He plans to utilize the knowledge and data gained during the mentored training period to generate applications for independent research funding. In summary, this proposal outlines Dr. Stendahl’s plan for scientific investigation and describes the mentoring and institutional support that is present to foster his development and prepare him for a successful career as an independent investigator.