Autonomously Assembling Nanomaterial Scaffolds for Treating Myocardial Infarction

自主组装纳米材料支架治疗心肌梗塞

• 批准号: 9109001
• 负责人: Karen L Christman
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109001
• 关键词: Acute; Acute myocardial infarction; Address; American; Angioplasty; Animal Model; Animals; Architecture; Area; Award; Biocompatible Materials; Cardiac; Catheters; Cells; Complication; Country; Data; Detection; Development; Disadvantaged; Early treatment; Enzymes; Extracellular Matrix; Fluorescence; Healed; Heart; Heart Transplantation; Heart failure; Home environment; Hour; In Situ; In Vitro; Infarction; Infiltration; Inflammatory; Injection of therapeutic agent; Innovative Therapy; Knowledge; Left Ventricular Remodeling; Magnetic Resonance Imaging; Matrix Metalloproteinases; Modeling; Myocardial Infarction; Myocardial dysfunction; Operative Surgical Procedures; Patients; Process; Quality of life; Rattus; Recovery; Recurrence; Research; Risk; Rupture; Staging; Structure; Syringes; Testing; Therapeutic; Time; Tissues; Translations; Ventricular; Work; base; design; experience; healing; high reward; high risk; improved; in vivo; innovation; intravenous injection; left ventricular assist device; minimally invasive; nanomaterials; nanoparticle; novel; novel therapeutics; particle; patient population; pre-clinical; prevent; programs; research clinical testing; response; scaffold; statistics; therapy design

DESCRIPTION (provided by applicant): Each year approximately three quarters of a million Americans will have a new myocardial infarction (MI), and approximately half a million will have a recurrent MI. Approximately 37% of these patients will die from the MI within one year, and of those who do survive, two-thirds do not make a complete recovery, leading to an extremely large patient population that progresses to heart failure. No current therapies exist that directly address the negative left ventricular (LV) remodeling process that occurs post-MI and results in heart failure. These staggering statistics necessitate the development of new innovative therapies for MI. This research program will establish a new paradigm in the design of treatments for healing heart tissue post-MI. Specifically our plan is to develop self-assembling materials programmed to form a healing scaffold in damaged heart tissue immediately following MI. Currently, such early treatment is not possible because it would require direct injection of materials into inflamed tissue constituting an unacceptable risk. In the proposed, unprecedented approach, the materials are designed to be injected intravenously rather than directly into heart tissue. They will circulate, and assemble into the healing scaffold in response to inflammatory enzymes present in damaged heart tissue (matrix metalloproteinases, MMPs). We hypothesize that, if such a material could be delivered to a patient's heart within the first day post-MI, this could prevent significant damage by immediately stabilizing the extracellular matrix framework, and then promoting cell infiltration to alter the typical infarct process. The proposed research program will develop novel nanoparticles capable of forming a scaffold material architecture in response to MMPs in damaged heart tissue. This process of enzyme-directed assembly has been proven in vitro in preliminary studies. We aim to optimize and test these nanoparticles in established in vivo animal models. Our overarching aim is therefore to develop autonomously assembling nanomaterial scaffolds, which can be delivered via IV injection, target the area of acute MI, prevent and/or slow negative left ventricular remodeling, and improve cardiac function post-MI.

描述（由申请人提供）：每年约有四分之三百万的美国人将有一个新的心肌梗塞（MI），大约有50万人将有一个经常性的MI。这些患者中约有37％会在一年内死于MI，而在生存的患者中，三分之二的患者没有完全康复，导致患者人数非常大，发展为心力衰竭。目前没有直接存在的疗法 解决发生在MI后发生并导致心力衰竭的负左心室（LV）重塑过程。这些惊人的统计数据需要开发MI的新创新疗法。 该研究计划将建立一个新的范式，以设计MI后治疗心脏组织的治疗方法。具体而言，我们的计划是开发编程的自组装材料，以在MI后立即在受损的心脏组织中形成愈合脚手架。目前，这种早期治疗是不可能的，因为它需要将材料直接注入发炎的组织，从而构成不可接受的风险。在提出的前所未有的方法中，这些材料被设计为静脉注射而不是直接进入心脏组织。它们将响应受损的心脏组织中存在的炎症酶（基质金属蛋白酶，MMP），并将其组装成愈合支架。我们假设，如果在MI之后的第一天内可以将这种材料递送给患者的心脏，那么 通过立即稳定细胞外基质框架，然后促进细胞浸润以改变典型的梗塞过程，可以防止重大损害。 拟议的研究计划将开发出能够响应受损心脏组织中MMP的脚手架材料结构的新型纳米颗粒。在初步研究中，已证明了酶导向组装的过程。我们旨在在既定的体内动物模型中优化和测试这些纳米颗粒。因此，我们的总体目的是开发自主组装纳米材料支架，可以通过静脉注射递送，靶向急性MI的面积，预防和/或缓慢的负阴性左心室重塑，并在MI后改善心脏功能。

项目成果

Bioactive Peptide Brush Polymers via Photoinduced Reversible-Deactivation Radical Polymerization.

• DOI: 10.1002/anie.201908634
• 发表时间: 2019-10
• 期刊: Angewandte Chemie
• 作者: Hao Sun;Wonmin Choi;Nanzhi Zang;Claudia Battistella;M. Thompson;Wei Cao;Xuhao Zhou;C. Forman;N. Gianneschi

Micro- and Nanoparticles for Treating Cardiovascular Disease.

• DOI: 10.1039/c4bm00441h
• 发表时间: 2015-04
• 期刊: Biomaterials science
• 影响因子: 6.6
• 作者: Suarez S;Almutairi A;Christman KL
• 通讯作者: Christman KL

Enzyme-Responsive Nanoparticles for Targeted Accumulation and Prolonged Retention in Heart Tissue after Myocardial Infarction.

• DOI: 10.1002/adma.201502003
• 发表时间: 2015-10-07
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Nguyen MM;Carlini AS;Chien MP;Sonnenberg S;Luo C;Braden RL;Osborn KG;Li Y;Gianneschi NC;Christman KL
• 通讯作者: Christman KL

Biosynthetic Polymers as Functional Materials.

• DOI: 10.1021/acs.macromol.6b00439
• 发表时间: 2016-06-28
• 期刊: Macromolecules
• 影响因子: 5.5
• 作者: Carlini AS;Adamiak L;Gianneschi NC
• 通讯作者: Gianneschi NC