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).

项目摘要心肌梗死（MI）是心血管疾病和死亡的主要原因。在MI之后，有限发生再生，而相反，炎症和疤痕会导致受影响的心肌组织转动纤维化稀薄。这种组织重塑会导致异常组织力学和心脏功能受损，通常导致心力衰竭和死亡。因此，一种有希望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，许多新兴的候选毒品以实现这些目标需要长时间给药多个星期，从而极大地限制了它们的临床翻译。克服这项挑战，我提出了注射导管的水凝胶的开发，并实现了一次向心肌注入药物有效载荷以进行长期释放。这个多学科项目将我的药物输送，聚合材料和心血管生物工程方面的专业知识。具体来说，我建议基于纳米粒子的，洗脱凝胶将保留在收缩的心肌内以局部提供以受控速度选择的治疗。该水凝胶将解决心血管疗法中的两个挑战1）由于具有机械活性的心脏和2）递送持续的治疗剂量，在心肌中保留。这可以保留在梗塞区域恶劣环境中的生物活性。在这个项目中，我建议交付两个在临床试验中研究了潜在的治疗剂，以解决炎症和不良重塑。 Anakinra 每天通过皮下注射提供的已成为减少炎症的有前途的候选人并预防MI后心肌细胞凋亡。 Fresolimobab有可能减轻MI后心力衰竭防止成纤维细胞激活成肌纤维细胞，从而限制纤维化。但是，要引起治疗效果，这些药物必须通过多次注射延长持续时间。因此，新颖诸如Anakinra和Fresolimob的治疗疗法的功效和临床用途受到限制，将极大地受益从材料科学的方法中，可以减少每天痛苦的注射的需求可以在可以保护其生物活性的储层中的心肌内本地交付效果，并提供可调的释放动力学，可以与所选药物的治疗窗口相匹配。在K99中这笔赠款的指导阶段，我将开发注射导管的水凝胶，并在内部证明保留率心肌（AIM 1），量身定制纳米颗粒的释放动力学，以达到快速和持续 Anakinra的有效载荷输送（AIMS 2），并在MI的临床前大鼠模型中演示了治疗效果（目标3）。在R00阶段，模块化水凝胶技术将扩展到第二种类型的纳米颗粒可以使anakinra和fresolimumab的联合释放（疏水和亲水性药物分别）（AIM 4）和通过防止不良反应来定量改善心脏功能在大鼠临床前模型中进行重塑（AIM 5）。