Catheter-injectable system for local drug delivery after myocardial infarct

项目摘要 心肌梗死（MI）是心血管疾病和死亡的主要原因。MI后，有限 再生发生，相反，炎症和瘢痕形成导致受影响的心肌组织变成纤维化 或坏的事情这种组织重塑导致异常的组织力学和受损的心脏功能，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， 梗死区的不良组织重塑。不幸的是，许多新兴的候选药物，以实现 这些目标需要在多周内延长给药，极大地限制了它们的临床转化。克服 为了应对这一挑战，我建议开发一种水凝胶，这种水凝胶可以通过导管注射， 将药物有效载荷注射到心肌中用于长期释放。这个多学科项目融合了我的 在药物输送、聚合物材料和心血管生物工程方面的专业知识。具体来说，我建议 基于纳米颗粒的治疗洗脱凝胶，其将保留在收缩心肌内以局部递送 以受控的速率进行选择的治疗。这种水凝胶将解决心血管治疗中的两个挑战1） 由于机械活性心脏而滞留在心肌中，以及2）输送持续的治疗剂量 其在梗塞区的恶劣环境中保持生物活性。在这个项目中，我建议提供两个 在临床试验中研究了潜在的治疗方法，以解决炎症和不良重塑。Anakinra 每天通过皮下注射给药， 预防MI后心肌细胞凋亡。Fresolimumab有可能通过以下方式减轻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，为了引出一种治疗方法， 这些药物必须通过每日多次注射延长持续时间。因此，小说 像阿那白滞素和Fresolimumab这样的治疗剂在疗效和临床应用方面是有限的， 从材料科学的方法，将减少痛苦的日常注射的需要，使他们能够 可以在心肌内局部递送到储库中，该储库可以保护其生物活性，限制其脱靶 效果，并提供可调的释放动力学，可以匹配所选药物的治疗窗口。在K99 指导阶段，这项赠款，我将开发导管注射水凝胶，并证明保留在 心肌（目标1），调整纳米颗粒的释放动力学，以实现快速和持续 阿那白滞素的有效载荷递送（目的2），并证明在MI的临床前大鼠模型中的治疗效果 (Aim 3）。在R00阶段，模块化水凝胶技术将扩展到包括第二种类型的 纳米颗粒以使得阿那白滞素和Fresolimumab（疏水和亲水的）的组合释放成为可能 药物）（目的4），并通过预防不良反应来定量改善MI后的心脏功能 在大鼠临床前模型中的重构（目的5）。

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).