Catheter-injectable system for local drug delivery after myocardial infarct

用于心肌梗死后局部给药的导管注射系统

基本信息

批准号：
10722614
负责人：
Renato Samuel Navarro
金额：
$ 15.67万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722614
关键词：
Address Affect Aldehydes Anterior Apoptosis Arteries Biological Assay Biomedical Engineering Biopolymers Blood capillaries Bolus Infusion Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Catheters Cessation of life Chemistry Cicatrix Clinical Clinical Research Clinical Trials Coculture Techniques Complex Contracts Development Diffusion Dose Drug Delivery Systems Echocardiography Elastin Emulsions Encapsulated Environment Female Fibroblasts Fibrosis Gel Geometry Goals Grant Heart Heart failure Histologic Hydrogels Hydrophobicity Impairment In Situ In Vitro Infarction Inflammation Injectable Injections Kinetics Left Ligation Light Liquid substance Measurement Mechanics Mentors Methods Modality Modeling Modification Molecular Molecular Weight Myocardial Myocardial Infarction Myocardial tissue Myocardium Myofibroblast Natural regeneration Oils Outcome Output Pain Performance Pharmaceutical Preparations Pharmacology Phase Polymers Pre-Clinical Model Pressure Transducers Prevention Proteins Rattus Reaction Rheology Saline Stress Subcutaneous Injections System Technology Therapeutic Therapeutic Effect Thinness Time Tissues Toxic effect Ventricular Water Wistar Rats Work anakinra clinical translation combinatorial crosslink cytotoxic cytotoxicity density design dosage drug candidate experimental group healing heart function hydrophilicity improved light scattering lipid nanoparticle local drug delivery male materials science mortality multidisciplinary nanoparticle novel therapeutics power analysis pre-clinical preservation pressure prevent targeted delivery therapeutic nanoparticles therapeutically effective

项目摘要

PROJECT SUMMARY Myocardial infarction (MI) is a leading cause of cardiovascular disease and death. After an MI, limited regeneration occurs, and instead, inflammation and scarring cause the affected myocardial tissue to turn fibrotic and thin. This tissue remodeling results in abnormal tissue mechanics and impaired cardiac function, often leading to heart failure and death. Therefore, a promising therapeutic approach is to reduce inflammation and the adverse tissue remodeling of the infarct zone. Unfortunately, many emerging drug candidates to achieve these goals require prolonged dosing over multiple weeks, greatly limiting their clinical translation. To overcome this challenge, I propose the development of a hydrogel that is catheter-injectable and enables the one-time injection of a drug payload into the myocardium for long-term release. This multidisciplinary project merges my expertise in drug delivery, polymeric materials, and cardiovascular bioengineering. Specifically, I propose a nanoparticle-based, therapy-eluting gel that will be retained within the contractile myocardium to locally deliver the chosen therapy at a controlled rate. This hydrogel will address two challenges in cardiovascular therapies 1) retention in the myocardium due to the mechanically active heart and 2) delivery of a sustained therapeutic dose that preserves the bioactivity in the harsh environment of the infarct zone. In this project, I propose to deliver two potential therapeutics investigated in clinical trials to address inflammation and adverse remodeling. Anakinra delivered daily through subcutaneous injection has emerged as a promising candidate to reduce inflammation and prevent cardiomyocyte apoptosis after MI. Fresolimumab has potential to mitigate heart failure after MI by preventing fibroblast activation into myofibroblasts and thereby limiting fibrosis. However, to elicit a therapeutic effect, these drugs must be present for an extended duration via multiple daily injections. Therefore, novel therapeutics like Anakinra and Fresolimumab are limited in efficacy and clinical use and would greatly benefit from materials science approaches that would reduce the need for painful daily injections by enabling them to be delivered locally within the myocardium in a reservoir that can protect their bioactivity, limit their off-target effects, and offer tunable release kinetics that can match the therapeutic window of the chosen drugs. In the K99 mentored phase of this grant, I will develop the catheter-injectable hydrogel and demonstrate retention within the myocardium (Aim 1), tailor the release kinetics of the nanoparticles to achieve both rapid and sustained payload delivery of Anakinra (Aims 2), and demonstrate the therapeutic effect in a preclinical rat model of MI (Aim 3). In the R00 phase, the modular hydrogel technology will be expanded to include a second type of nanoparticle to enable the combinatorial release of Anakinra and Fresolimumab (hydrophobic and hydrophilic drugs, respectively) (Aim 4) and improve heart function quantitatively after an MI by preventing adverse remodeling in a rat preclinical model (Aim 5).

项目概要心肌梗塞（MI）是心血管疾病和死亡的主要原因。心梗后，有限发生再生，相反，炎症和疤痕导致受影响的心肌组织纤维化又薄。这种组织重塑通常会导致组织力学异常和心脏功能受损导致心力衰竭和死亡。因此，一种有前途的治疗方法是减少炎症和梗塞区的不良组织重塑。不幸的是，许多新兴候选药物无法实现这些目标需要延长数周的给药时间，这极大地限制了它们的临床转化。克服针对这一挑战，我建议开发一种可通过导管注射的水凝胶，并且能够一次性将药物有效负载注射到心肌中以长期释放。这个多学科项目融合了我的药物输送、高分子材料和心血管生物工程方面的专业知识。具体来说，我提出一个基于纳米颗粒的治疗洗脱凝胶将保留在收缩心肌内以局部输送以受控速率选择的治疗方法。这种水凝胶将解决心血管治疗中的两个挑战 1) 由于心脏机械活动而滞留在心肌中，并且 2) 输送持续的治疗剂量在梗塞区的恶劣环境中保留生物活性。在这个项目中，我建议交付两个临床试验中研究了解决炎症和不良重塑的潜在疗法。阿纳金拉每天通过皮下注射给药已成为减少炎症的有希望的候选者并预防 MI 后心肌细胞凋亡。 Fresolimumab 有潜力通过以下方式减轻 MI 后的心力衰竭：防止成纤维细胞活化成肌成纤维细胞，从而限制纤维化。然而，为了引发治疗为了达到效果，这些药物必须通过每天多次注射来延长持续时间。因此，小说像 Anakinra 和 Fresolimumab 这样的疗法在功效和临床应用上受到限制，但将大大受益材料科学方法可以减少每天痛苦的注射的需要，使他们能够在心肌内局部输送到储库中，可以保护其生物活性，限制其脱靶效果，并提供可调节的释放动力学，可以匹配所选药物的治疗窗口。在K99中在这笔资助的指导阶段，我将开发导管注射水凝胶并证明其保留能力心肌（目标 1），调整纳米粒子的释放动力学，以实现快速和持续 Anakinra 的有效负载递送（目标 2），并在 MI 临床前大鼠模型中证明治疗效果（目标 3）。在R00阶段，模块化水凝胶技术将扩展到包括第二种类型纳米颗粒能够组合释放 Anakinra 和 Fresolimumab（疏水性和亲水性）药物）（目标 4）并通过预防不良反应来定量改善 MI 后的心脏功能大鼠临床前模型中的重塑（目标 5）。