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Myocyte-specific nanoplatform-enabling photodynamic cardiac ablation

肌细胞特异性纳米平台实现光动力心脏消融

基本信息

批准号：
8511808
负责人：
Jerome Kalifa
金额：
$ 22.21万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511808
关键词：
Ablation Action Potentials Adipocytes Adult Affect American Animals Antibodies Area Arrhythmia Binding Caliber Cancerous Cardiac Cardiac ablation Cell Death Cells Chest Chest wall structure Coculture Techniques Coronary Development Dyes Energy Transfer Epicardium Event Excision Fibroblasts Fibrosis Fistula Frequencies Generations Heart Hemorrhage Histology Inflammation Inflammatory Inflammatory Infiltrate Injury Investigation Lasers Left Light Lighting Maps Methodology Modality Modeling Motion Muscle Cells Myocardial Myofibroblast Nature Necrosis Neurons Optics Oxygen Peptides Perforation Perfusion Pharmaceutical Preparations Photochemotherapy Photosensitizing Agents Preparation Pulmonary veins Radio Radiofrequency Interstitial Ablation Rattus Reaction Reactive Oxygen Species Refractory Regional Perfusion Safety Sampling Spasm Staining method Stains Stenosis Subgroup Surgical sutures Techniques Testing Tissues Toxic effect Ventricular base blebbistatin experience in vivo innovation research study voltage

项目摘要

DESCRIPTION (provided by applicant): Regional myocardial ablation enabled by radio-frequency or other energies is currently the main treatment modality for drug-refractory arrhythmias. However, the highly unspecific nature of current ablation methodologies is responsible for unnecessary damage to cardiac or peri-cardiac tissue, thus severely hampering ablation safety and efficacy. Photodynamic therapy (PDT) has been extensively studied for treating cancerous cells. In PDT, after activation by light, photosensitizer agents transfer energy to oxygen molecules and generate reactive oxygen species which induce cell death exquisitely confined to photosensitized cells, while adjacent non photosensitized cells are spared. In specific aim 1, we will use a recently developed cardiac targeting peptide (CTP) that binds to myocytes while it does not attach to other cardiac cells. In preliminary experiments, we have demonstrated that CTP-PDT-NPs delivered in co-cultures of adult rat ventricular myocytes and fibroblasts, led to myocytes-specific damage after laser illumination. Thus, we hypothesize that in isolated Langendorff-perfused rat hearts, CTP- conjugated-PDT-NPs (CTP-PDT-NPs) will enable obtaining myocyte-specific ablation while fibroblasts will be spared. With optical mapping techniques, we will determine how myocyte-specific ablation after illumination of a ventricular region with a 671 nm Laser, compares with non-specific ablation in terms of impulse propagation during pacing and during reentry. In specific aim 2, we will determine whether myocyte-specific ablation with PDT-NPs could be implemented in the whole animal. In this aim, CTP-PDT-NPs will be injected intravenously in an anesthetized rat open chest model. After 10-30 minutes, we will illuminate a small region of the ventricular epicardium and subsequently, the heart will be removed and an immunohistological investigation with myocyte and fibroblast cell-specific antibody staining will be conducted. This will enable to assess the degree of damage induced to myocytes, and the extent to which fibroblasts and other non-myocyte cells were spared. Also, in a subgroup of rats, the chest wall will be sutured after ablation and animals will be followed-up for one month. Then, after heart removal, histological testing will be conducted to detect inflammatory infiltrates and fibrosis and assess fibroblast proliferation. Results will be compared with those of rats that underwent radiofrequency ablation or were sham operated. In this aim, we hypothesize that myocyte-specific ablation in vivo will associate with a decreased inflammatory reaction and fibroblast differentiation into myofibroblasts, as well as a dampened fibroblast proliferation and fibrosis formation.

描述（由申请人提供）：射频或其他能量的局部心肌消融是目前治疗药物难治性心律失常的主要方式。然而，当前消融方法的高度非特异性导致了对心脏或心脏周围组织的不必要损伤，从而严重阻碍了消融的安全性和有效性。光动力疗法（PDT）已被广泛研究用于治疗癌细胞。在PDT中，被光激活后，光敏剂传递能量