Enzyme responsive nanoparticle delivery of a small molecule MMP inhibitor following acute myocardial infarction

急性心肌梗死后小分子 MMP 抑制剂的酶响应纳米颗粒递送

基本信息

批准号：
10477063
负责人：
Holly Sullivan
金额：
$ 3.96万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477063
关键词：
Acute Acute myocardial infarction Apoptosis Attenuated Behavior Biocompatible Materials Biodistribution Biological Blood Circulation Cardiac Cardiac Myocytes Cardiovascular Diseases Catheters Cause of Death Cells Congestive Heart Failure Control Groups Development Diagnosis Disease Dose Dose-Limiting Drug Delivery Systems Drug Prescriptions Drug Targeting Enzymes Evaluation Event Exposure to Extracellular Matrix Face Fibrosis Future Heart Heart failure Homing Hydrophobicity Image Analysis Immune Incidence Incubated Infarction Inhibition of Matrix Metalloproteinases Pathway Injectable Injections Intravenous Kinetics Lead Left Ventricular Remodeling Left ventricular structure Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Methods Modeling Myocardial Infarction Myocardium Needles Operative Surgical Procedures Patients Peptide Hydrolases Peptides Persons Pharmaceutical Preparations Phase Polymers Population Premature Mortality Process Rattus Recurrence Research Risk Safety Solubility Surface System Therapeutic Thermolysin Time Tissue Sample Tissues Treatment Efficacy United States Vertebral column base clinical translation clinically translatable cost dosage drug clearance drug efficacy enzyme activity experimental study heart function improved in vivo interest light scattering minimally invasive nanomedicine nanoparticle nanoparticle delivery nanoparticle drug preclinical study preservation prevent protein aminoacid sequence reduce symptoms side effect small molecule small molecule therapeutics standard of care targeted treatment therapy design therapy outcome

项目摘要

Project Summary Myocardial infarction (MI) is a main contributor to cardiovascular disease with an annual incidence of 605,000 new attacks and 200,000 recurrent attacks annually. Many of these patients will go on to develop heart failure and ultimately face premature mortality within five years of diagnosis. Current standard of care includes surgical intervention and prescribed medications that attenuate future damage to the heart and mitigate the likelihood of another adverse cardiac event, but they do not treat the damage that has already been done. Though there have been many pre-clinical studies of various cell and biomaterial therapies designed to treat patients post-MI, in most cases they are administered via intramyocardial injections, a method that is not clinically relevant because the heart is too fragile following MI. Thus, there exists a need to develop a therapeutic that can be administered immediately after MI to prevent the extent of damage to the heart. Targeted drug delivery via nanoparticle carriers has renewed promise for many small molecule drugs that have been previously hampered by high dosages and/or poor solubility. Previously, we have demonstrated the aggregation and localization of peptide-polymer amphiphile nanoparticles in the heart following myocardial infarction (MI). Following IV injection, these nanoparticles extravasated from the leaky vasculature into the infarct where endogenous matrix metalloproteinases (MMPs), proteolytic enzymes that degrade the extracellular matrix, cleaved the MMP-responsive peptide to expose the hydrophobic core and form micron-scale aggregates. Building upon this robust nanoparticle system, here we move from a proof of concept platform to an actual therapeutic by conjugating a small molecule drug to the polymer backbone. In doing this, we will investigate the preserved ability of drug- loaded nanoparticles to localize to the infarcted region of the heart and release a biologically active small molecule MMP-inhibitor. In addition, we are interested in improving the targeting capability of our nanoparticles by incorporating a cardiac homing peptide (CHP) sequence that has demonstrated specific localization to the ischemic region of the myocardium. By increasing localization, we will be able to lower the necessary effective dose and decrease any off-target effects. There is not currently a targeted therapeutic that can be administered during the acute phase of MI to prevent damage. While MMP inhibition with small molecule drugs has been shown to decrease left ventricle dilation and expansion following MI, there remains a need for localized, non-invasive delivery to the infarct to make these drugs clinically translatable. Thus, we hypothesize that our targeting NPs will improve drug delivery to the infarcted region of the heart, resulting in decreased MMP activity in the acute MI-stage and improved cardiac function over time.

项目摘要心肌梗死（MI）是导致心血管疾病的主要因素，年发病率为每年有605,000次新攻击和200,000次反复攻击。这些患者中有许多会继续发展心力衰竭，最终在诊断后的五年内面临过早死亡。当前标准的护理包括手术干预和处方药，可减轻未来对心脏的损害并减轻另一场不良心脏事件的可能性，但它们没有治疗具有的损害已经完成了。尽管有许多有关各种细胞和生物材料的临床前研究旨在治疗MI后治疗患者的疗法，在大多数情况下，它们是通过心膜内给药的注射剂，这种方法在临床上无关紧要，因为MI之后的心脏太脆弱了。因此，那里存在需要开发可以在MI之后立即进行治疗的治疗方法，以防止程度对心脏的伤害。通过纳米颗粒载体的有针对性的药物递送已更新了许多人的承诺以前已被高剂量和/或溶解度差的小分子药物。以前，我们已经证明了肽聚合物两亲的聚集和定位心肌梗塞（MI）后心脏中的纳米颗粒。注射静脉注射后，这些纳米颗粒从漏水的脉管系统中渗入内源性基质金属蛋白酶的梗塞（MMP），降解细胞外基质的蛋白水解酶，裂解了MMP反应性肽暴露疏水核心并形成微米级聚集体。基于这种强大的纳米颗粒系统，在这里，我们从概念平台的证明转变为实际的治疗方法，通过结合一个小的分子药物到聚合物主链。为此，我们将研究药物的保留能力加载纳米颗粒以定位于心脏的梗塞区域，并释放一个生物活性的小分子MMP抑制剂。此外，我们有兴趣提高我们的目标能力纳米颗粒通过掺入心脏归巢肽（CHP）序列，该序列已证明了特异性位于心肌缺血区域。通过增加本地化，我们将能够降低必要的有效剂量并降低任何脱靶效应。目前没有目标可以在MI的急性阶段进行治疗，以防止损害。而MMP 用小分子药物抑制可以减少左心室扩张和膨胀在MI之后，仍然需要局部，非侵入性递送到梗塞以制造这些药物临床翻译。因此，我们假设我们的靶向NP将改善药物的递送心脏梗塞区域，导致急性MI阶段的MMP活性降低，并且随着时间的推移，心脏功能改善。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inflammation-Responsive Micellar Nanoparticles from Degradable Polyphosphoramidates for Targeted Delivery to Myocardial Infarction.

来自可降解聚磷酸酰胺的炎症响应性胶束纳米颗粒用于靶向递送至心肌梗塞。

DOI：
10.1021/jacs.3c01054
发表时间：
2023
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Liang,Yifei;Sullivan,HollyL;Carrow,Kendal;Mesfin,JoshuaM;Korpanty,Joanna;Worthington,Kendra;Luo,Colin;Christman,KarenL;Gianneschi,NathanC
通讯作者：
Gianneschi,NathanC

Enzyme-Responsive Nanoparticles for the Targeted Delivery of an MMP Inhibitor to Acute Myocardial Infarction.

DOI：
10.1021/acs.biomac.3c00421
发表时间：
2023-11-13
期刊：
BIOMACROMOLECULES
影响因子：
6.2
作者：
Sullivan, Holly L.;Liang, Yifei;Worthington, Kendra;Luo, Colin;Gianneschi, Nathan C.;Christman, Karen L.
通讯作者：
Christman, Karen L.

Targeted nanoscale therapeutics for myocardial infarction.