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

在人类边缘心脏离体常温灌注过程中将纳米药物靶向输送至冠状动脉微血管

• 批准号: 10543861
• 负责人: John C Stendahl
• 金额: $ 16.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543861
• 关键词: Address; Affect; Allogenic; Antibodies; Biomedical Engineering; Blood Vessels; Blood flow; Cardiac; Cardiopulmonary Bypass; Cardiovascular system; Clinical; Collaborations; Coronary; Coronary artery; Data; Development; Diagnostic Imaging; Doctor of Philosophy; Documentation; Drug Carriers; Echocardiography; Engineering; Equipment; Ethics; Evaluation; Exposure to; Family suidae; Fellowship; Fluorescence Microscopy; Formulation; Fostering; Foundations; Funding; Goals; Heart; Heart Transplantation; Human; Imaging Device; Imaging Techniques; Immunologics; Impairment; Institution; Intervention; Investigation; Ischemia; K-Series Research Career Programs; Kidney; Knowledge; Life; Link; Liver; Medical Imaging; Medicine; Mentors; Mentorship; Methods; Microscopy; Myocardial Infarction; Myocardial perfusion; Obstruction; Organ; Organ Procurements; Organ Transplantation; Patients; Perfusion; Pharmacological Treatment; Predisposition; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Science; Scientist; Small Interfering RNA; Structure; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Training; Translational Research; Transplantation; Vascular Endothelium; Work; X-Ray Computed Tomography; cardiovascular imaging; career; clinically significant; coronary vasculature; design; ex vivo imaging; experience; heart function; heart imaging; heart preservation; high risk; imaging facilities; imaging modality; improved; innovation; instructor; lectures; medical schools; meetings; mouse model; multimodality; nanomedicine; nanoparticle; nanoparticle delivery; nanoparticle drug; novel strategies; particle; receptor; restoration; risk mitigation; severe injury; single photon emission computed tomography; targeted delivery; targeted treatment

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.

项目概要/摘要 该提案详细介绍了 John Stendahl 博士的指导临床科学家研究的研究和培训计划 职业发展奖。 Stendahl 博士的研究重点是可用于捐赠心脏的短缺问题 移植。他建议通过利用离体常温机器灌注来解决这个问题 移植前环境作为评估边缘供体心脏并对其进行血管靶向治疗的平台 纳米药物。这项工作基于以下假设：实现具有临床意义的交付 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，b）稳健的纳米颗粒靶向方法。该提案的首要目标是优化 进行离体常温机器灌注的心脏中的微血管血流。计划要完成的事 这涉及利用显微镜和多模态心脏成像评估微血管系统，以及 应用药物治疗以恢复血流。第二个目标是设计针对血管的 用于在离体常温机器灌注期间递送至人类心脏的纳米颗粒。这涉及到强效 纳米颗粒靶向的新方法以及诊断成像的进一步应用来评估纳米颗粒 送货。成功完成这些目标将提供强大的、临床适用的技术来改善 保存供体心脏并实现边缘器官的更有效利用。 Stendahl 博士是耶鲁大学医学院心血管医学科的讲师，最近 完成了高级心血管成像的进修培训。他提出的研究建立在他的 具有生物工程、器官移植和心脏成像背景。他得到了杰出人士的支持 导师团队由多模态心脏成像专家 Albert Sinusas 医学博士和 Gregory Tietjen 组成， 博士，靶向纳米颗粒输送和器官机器灌注方面的专家。拟议的工作利用 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 的科学和专业发展结构化培训计划包括讲座、课程作业 科学和道德、与导师和顾问的个人会议以及出席国家会议 与心脏成像、治疗实施和器官移植有关。他计划利用这些知识和 在指导培训期间获得的数据用于生成独立研究资金的申请。在 总之，该提案概述了 Stendahl 博士的科学研究计划，并描述了指导和 为促进他的发展并为他作为一名成功的职业生涯做好准备而提供的机构支持 独立调查员。