MMP responsive polymeric materials for treating acute myocardial infarction

MMP响应性高分子材料治疗急性心肌梗死

基本信息

批准号：
10734728
负责人：
Karen L Christman
金额：
$ 59.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734728
关键词：
Acute myocardial infarction Alternative Therapies American Animal Model Antioxidants Biocompatible Materials Biodistribution Catheters Cause of Death Development Diameter Drug Carriers Drug Kinetics Enzyme Induction Enzymes Evaluation Exhibits Flow Cytometry Future Gene Expression Goals Heart Heart failure Histology Immune response Immunohistochemistry Infarction Inflammation Inhibition of Matrix Metalloproteinases Pathway Injectable Injections Kidney Left Ventricular Remodeling Liver MMP2 gene Magnetic Resonance Imaging Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Methods Modality Molecular Weight Myocardial Myocardial Infarction Myocardium NF-E2-related factor 2 Operative Surgical Procedures Pathway interactions Patients Peptides Pharmacologic Substance Phase Transition Polymers Procedures Process Property Proteins Recovery Recurrence Rest Safety Site Spleen Stress Structure System Testing Therapeutic Translating Translations Vertebral column Western World aqueous biomaterial compatibility controlled release copolymer cost effective design heart function hemocompatibility immunoregulation improved inhibitor therapy innovation minimally invasive nano-string nanomaterials nanoparticle nanopattern nanoscale novel novel strategies particle patient population peptide drug protein protein interaction repaired response scaffold success targeted delivery therapeutic protein therapeutic target

项目摘要

Summary Heart failure (HF) remains the leading cause of death in the U.S., and the rest of the western world. Approximately 37% of myocardial infarction (MI) patients will die from HF within 1 year, and of those who do survive, two-thirds do not make a complete recovery. Each year it is estimated that ~550K Americans will have a new MI, and ~200K will have a recurrent MI, leading to a large body of patients suffering from HF.1 Therefore, our long-term goal is the development of new, minimally invasive, targeted biomaterial based therapies for the treatment of acute MI (AMI), thereby limiting the number of patients that progress to HF. Over the past two decades, there has been significant progress in the development injectable biomaterials that stimulate endogenous repair on their own or through the controlled release of additional therapeutics. This approach is attractive since potential therapies could be delivered minimally invasively via catheter, would be off the shelf and cost-effective, and in the case of therapeutic delivery, would provide targeted delivery limiting systemic off- target effects that plague traditional pharmaceuticals. However, direct injection of these biomaterials, either through minimally invasive surgery or percutaneous transendocardial injection, is unlikely to be translated to AMI patients because of serious safety concerns with the injection procedures, thereby missing the critical therapeutic window immediately post-MI. Together, the PIs developed enzyme-responsive, injectable nanoparticles (NPs), capable of responding to matrix metalloproteinases (MMPs) associated with AMI. The particles accumulate efficiently in infarcted myocardium following systemic administration, by virtue of an enzyme-induced phase transition from small NP to micron-sized scaffold. While we had initial success with this system and observed better targeting compared to traditional modalities, this system suffers the same drawback as most nanoparticles, which have significant off-target accumulation, as they are phagocytosed and transported to the liver following opsonization. Leveraging our success with the general MMP responsive targeting strategy, we propose that a new MMP responsive material comprised of a completely aqueous soluble polymer displaying therapeutic peptides at high densities will have superior biodistribution patterns nanoparticles. Upon systemic administration, these polymers exhibit exceptionally favorable pharmacokinetics (week-long half-lives) and biodistribution characterized by kidney clearance combined with very little liver/spleen accumulation. These polymers are protein like in molecular weight (MW), physicochemical properties and size. They are therapeutic proteomimetic polymers, designed to accumulate at the site of AMI. Here, we aim to develop new MMP responsive polymeric systems (termed protein-like polymers, PLPs) and demonstrate proof-of-concept for using these novel biomaterials for the targeted delivery of therapeutics for AMI.

概括心力衰竭 (HF) 仍然是美国和西方世界其他国家死亡的主要原因。大约 37% 的心肌梗塞 (MI) 患者将在 1 年内死于心力衰竭，其中幸存下来，三分之二的人没有完全康复。据估计，每年约有 55 万美国人将一个新的心梗，约 20 万将有复发的心梗，导致大量患者患有心力衰竭。1 因此，我们的长期目标是开发新的、微创的、基于靶向生物材料的疗法治疗急性心肌梗死（AMI），从而限制进展为心力衰竭的患者数量。过去两年几十年来，可注射生物材料的开发取得了重大进展，可刺激自行修复或通过额外治疗药物的控制释放进行内源修复。这种方法是有吸引力，因为潜在的治疗方法可以通过导管以微创方式进行，并且是现成的且具有成本效益，并且在治疗递送的情况下，将提供有针对性的递送，限制系统性关闭困扰传统药物的目标效应。然而，直接注射这些生物材料，要么通过微创手术或经皮心内膜注射，不太可能转化为 AMI 患者由于注射程序存在严重的安全问题，从而错过了关键的治疗 MI 后立即窗口。 PI 共同开发了酶响应型可注射纳米颗粒 (NP)、能够响应与 AMI 相关的基质金属蛋白酶 (MMP)。颗粒堆积凭借酶诱导阶段，全身给药后可有效地作用于梗塞心肌从小纳米颗粒到微米级支架的转变。虽然我们在这个系统上取得了初步成功并观察到与传统方式相比，该系统具有更好的靶向性，但该系统具有与大多数纳米粒子相同的缺点，它们具有显着的脱靶积累，因为它们被吞噬并转运至肝脏调理作用。利用我们在通用 MMP 响应式目标策略方面的成功，我们建议新型 MMP 响应材料由完全水溶性聚合物组成，具有治疗作用高密度的肽将具有优异的纳米颗粒生物分布模式。全身给药后，这些聚合物表现出极其有利的药代动力学（半衰期为一周）和生物分布其特点是肾脏清除，且肝脏/脾脏积聚极少。这些聚合物是蛋白质的分子量 (MW)、理化性质和大小。它们是治疗性蛋白质模拟物聚合物，旨在在 AMI 部位积聚。在这里，我们的目标是开发新的 MMP 响应性聚合物系统（称为类蛋白质聚合物，PLP）并展示了使用这些新颖的概念验证用于 AMI 靶向治疗的生物材料。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Degradable polymers via olefin metathesis polymerization.

通过烯烃复分解聚合可降解聚合物。

DOI：
10.1016/j.progpolymsci.2021.101427
发表时间：
2021-09-01
期刊：
Progress in polymer science
影响因子：
27.1
作者：
Hao Sun;Yifei Liang;M. Thompson;N. Gianneschi
通讯作者：
N. Gianneschi

Enzyme-responsive progelator cyclic peptides for minimally invasive delivery to the heart post-myocardial infarction.

用于心肌梗塞后微创递送至心脏的酶响应性促凝胶剂环肽。

DOI：
发表时间：
2019-04-15
期刊：
影响因子：
16.6
作者：
Carlini, Andrea S;Gaetani, Roberto;Braden, Rebecca L;Luo, Colin;Christman, Karen L;Gianneschi, Nathan C
通讯作者：
Gianneschi, Nathan C

Poly(peptide): Synthesis, Structure, and Function of Peptide-Polymer Amphiphiles and Protein-like Polymers.

聚（肽）：肽聚合物两亲物和类蛋白聚合物的合成、结构和功能。

DOI：
10.1021/acs.accounts.9b00518
发表时间：
2020-01-22
期刊：
Accounts of chemical research
影响因子：
18.3
作者：
Cass;ra E. Callmann;ra;M. Thompson;N. Gianneschi
通讯作者：
N. Gianneschi

Innovations in Disease State Responsive Soft Materials for Targeting Extracellular Stimuli Associated with Cancer, Cardiovascular Disease, Diabetes, and Beyond.

针对与癌症、心血管疾病、糖尿病等相关的细胞外刺激的疾病状态响应软材料的创新。

DOI：
发表时间：
2021-11
期刊：
影响因子：
0
作者：
Battistella, Claudia;Liang, Yifei;Gianneschi, Nathan C
通讯作者：
Gianneschi, Nathan C

Enzyme-Responsive Nanoparticles for Dexamethasone Targeted Delivery to Treat Inflammation in Diabetes.

用于地塞米松靶向递送以治疗糖尿病炎症的酶响应纳米颗粒。

DOI：
发表时间：
2023-11
期刊：
影响因子：
10
作者：
Schiffmann, Nathan;Liang, Yifei;Nemcovsky, Carlos E;Almogy, Michal;Halperin;Gianneschi, Nathan C;Adler;Rosen, Eyal
通讯作者：
Rosen, Eyal