Image Guided Delivery of Bioresponsive Hydrogels

摘要 心肌梗死(MI)导致局部功能障碍，使心脏的偏远区域 机械缺陷导致长期不良的左心室(LV)重构和并发症 充血性心力衰竭(CHF)，在西方世界，充血性心力衰竭仍然是导致发病和死亡的主要原因。 目前的项目将集中于评估和调节基质金属蛋白酶的关键平衡。 基质金属蛋白酶(MMPs)和组织抑制物(TIMP)，已知在其中起重要作用 在心肌梗塞后的重塑过程中。已经提出了一些药物和外科治疗方法来限制 心肌梗塞后的重塑，包括：生物材料的心肌内给药。这些聚合物疗法 在缩小梗死面积、增加血管生成、改善局部区域方面取得了喜忧参半的成功 功能，并限制心肌梗塞后的重构，在临床前研究，最近已被翻译到患者。 我们已经建立了新的无创性SPECT/CT混合方法来评估区域的变化 心肌灌注、血管生成、基质金属蛋白酶激活以及超声心动图成像方法 定量评价局部心肌应变和心室重构。当前的多PI方案 将重点放在：1)开发一种新的可成像的用于心肌梗死后治疗的基质金属蛋白酶反应性水凝胶 以及水凝胶保留量的跟踪传递和系列评估；2)多模式无创应用 应用解剖学、生理学和分子成像方法指导和评价经皮穿刺术 基质金属蛋白酶反应性水凝胶的心肌内递送，以及3)其机制的评价 这些可注射的基质金属蛋白酶反应性水凝胶释放局部TIMP，改变心肌力学并限制术后 心肌梗死重塑。我们假设，心肌内传递的基质金属蛋白酶反应水凝胶局部 心肌梗死后早期释放TIMP-3将导致：1)局部MMP-TIMP平衡的调节和炎性反应 心肌梗死内的反应，2)局部和整体心肌力学的改变，3)改善 血管生成和心肌灌注，以及4)减少不利的心肌梗死后全球重构。我们也 假设我们的多模式成像方法将有助于治疗嗅觉水凝胶的最佳输送， 并允许跟踪关键的解剖学、生理学和分子事件以及治疗效果。 因此，我们提出了以下具体的建议：1)开发一种可成像的基质金属蛋白酶反应性水凝胶 对于心肌梗死后的治疗，2)应用多模式成像来指导和评估经皮图像引导 使用临床相关的心肌梗死后重构的猪模型，在心肌内注射这些水凝胶，以及3) 评价其治疗效果的机制。诊断和治疗方法是在 提议的项目将直接转化为心肌梗塞后患者的管理。

Summary Myocardial infarction (MI) causes regional dysfunction placing remote areas of the heart at a mechanical disadvantage resulting in long term adverse left ventricular (LV) remodeling and complicating congestive heart failure (CHF), which remains a leading cause of morbidity and death in the Western world. The current project will focus on evaluating and modulating the critical balance of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) which is known to play an important role during remodeling post-MI. A number of pharmacological and surgical therapies have been proposed to limit post-MI remodeling, including; the intramyocardial administration of biomaterials. These polymeric therapies have demonstrated mixed success in reducing infarct size, increasing angiogenesis, improving regional function, and limiting post-MI remodeling in pre-clinical studies, and have been recently translated to patients. We have established novel noninvasive hybrid SPECT/CT approaches for evaluation of changes in regional myocardial perfusion, angiogenesis, MMP activation, along with echocardiographic imaging approaches for quantitative evaluation of regional myocardial strain and ventricular remodeling. The current multi-PI proposal will focus on; 1) development of a novel imageable MMP-responsive theranostic hydrogel for post-MI therapy and tracking delivery and serial evaluation of hydrogel retention, 2) application of multimodality non-invasive anatomical, physiological and molecular imaging approaches for directing and evaluating the percutaneous intramyocardial delivery of MMP-responsive hydrogels, and 3) the evaluation of the mechanisms by which these injectable MMP-responsive hydrogels that release local TIMP alter myocardial mechanics and limit post- MI remodeling. We hypothesize that the intramyocardial delivery of MMP-responsive hydrogels that locally release TIMP-3 early post-MI will result in; 1) modulation of the local MMP-TIMP balance and the inflammatory response within the MI, 2) alteration of regional and global myocardial mechanics, 3) improvement in angiogenesis and myocardial perfusion, and 4) a reduction of adverse global post-MI remodeling. We also hypothesize that our multimodality imaging approach will facilitate optimal delivery of a theranostic hydrogel, and allow tracking of critical anatomical, physiological and molecular events, along with therapeutic efficacy. Accordingly, we propose to specifically: 1) development an imageable MMP-responsive theranostic hydrogels for post-MI therapy, 2) apply multimodality imaging to direct and evaluate percutaneous image-guided intramyocardial delivery these hydrogels using clinically relevant porcine models of post-MI remodeling, and 3) evaluate the mechanisms of therapeutic efficacy. The diagnostic and therapeutic approaches developed in the proposed project will be directly translatable to the management of patients following MI.