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

项目总结/摘要 该提案详细说明了John Stendahl博士的研究和临床科学家研究指导培训计划 职业发展奖。Stendahl博士的研究重点是可供移植的捐赠心脏的短缺。 移植他建议通过在体外使用常温机器灌注来解决这个问题。 移植前设置作为评估边缘供体心脏的平台， 纳米医学这项工作是基于这样的假设，即实现临床上显著的递送 离体供体心脏中的纳米药物需要：a）在损伤后恢复微血管灌注， 冷缺血，和B）纳米颗粒靶向的稳健方法。该提案的第一个目的是优化 进行离体常温机器灌注的心脏中的微血管血流。计划完成 这包括用显微镜和多模式心脏成像评估微血管系统， 应用药物治疗恢复血流。第二个目标是设计血管靶向 用于在离体常温机器灌注期间递送至人心脏的纳米颗粒。这涉及到强大的 纳米颗粒靶向的新方法和诊断成像评估纳米颗粒的进一步应用 交付.这些目标的成功完成将提供强大的，临床适用的技术，以改善 供体心脏的保存和实现边缘器官的更有效利用。 博士Stendahl是耶鲁大学医学院心血管医学部的讲师， 完成高级心血管成像的奖学金培训。他提出的研究建立在他的 有生物工程、器官移植和心脏成像的背景。他得到了一位杰出的 导师团队由多模式心脏成像专家Albert Sinusas（医学博士）和Gregory Tietjen组成， 博士，靶向纳米粒子输送和器官机器灌注方面的专家。拟议的工作利用了 耶鲁大学医学院拥有一流的设施，包括最先进的医学成像设备。博士 Stendahl的科学和专业发展的结构化培训计划包括讲座， 科学和伦理，与导师和顾问的个人会议，以及参加国家会议 与心脏成像、治疗递送和器官移植相关。他计划利用这些知识， 在指导培训期间获得的数据，以产生独立研究资金的申请。在 摘要，该提案概述了Stendahl博士的科学研究计划，并描述了指导和 机构支持，以促进他的发展，并为他作为一个成功的职业生涯做好准备， 独立调查员

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.