Matrix regenerative nanotherapeutics for small abdominal aortic aneurysm repair

用于修复小腹主动脉瘤的基质再生纳米疗法

基本信息

批准号：
10281418
负责人：
ANAND RAMAMURTHI
金额：
$ 36.23万
依托单位：
LEHIGH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10281418
关键词：
Abdominal Aortic Aneurysm Active Sites Adult Anabolism Animal Model Aorta Aortic Diseases Apoptosis Attenuated Biodistribution Biomimetics Caliber Catheters Cations Cell Culture Techniques Cells Charge Chronic Clinical Trials Collagen Fiber Complement Factor B Data Diagnosis Dose Doxycycline Elastic Fiber Elastin Elderly Enzymes Etiology Event Extracellular Matrix Extracellular Structure Fiber Formulation Future Glycolates Growth Homeostasis Hydrophobicity Image Infusion procedures Link Literature MAPK8 gene MMP2 gene Magnetism Mediating Messenger RNA Metalloproteases Modeling Mus Operative Surgical Procedures Oral Outcome Patients Pharmaceutical Preparations Pharmacotherapy Polymers Property Protein Isoforms Rattus Rupture SP600125 Safety Severities Signal Transduction Smoker Smooth Muscle Myocytes Specificity Stimulus Stretching Structure Surface System Testing Time Tissues Transforming Growth Factor beta Transforming Growth Factors Treatment Efficacy Vascular Diseases Vascular Smooth Muscle abdominal aorta acyl group biodegradable polymer crosslink density design flexibility high risk inhibitor/antagonist injured iron oxide nanoparticle male minimally invasive nanoparticle nanoparticle delivery nanosized nanotherapeutic nanotherapy older patient overexpression particle pre-clinical prevent prospective regenerative regenerative repair repaired restoration side effect stress activated protein kinase synergism uptake

项目摘要

Abstract Our objective is to investigate a new, minimally-invasive regenerative nanotherapy to arrest or regress growth of small (<5.5 cm diameter) abdominal aortic aneurysms (AAAs). AAAs are localized expansions of the abdominal aorta that ultimately rupture. Early surgery on small AAAs provides no treatment benefit and no other proven therapies exist. While reinstating homeostasis of the structural extracellular matrix (ECM; collagen and elastic fibers) in the AAA wall is critical to stop or reverse AAA growth, this is impeded by a) their chronic breakdown in the aorta wall by upregulated matrix metalloprotease (MMPs) enzymes and b) lack of approaches to overcome intrinsically deficient and defective elastic fiber regenerative repair by adult vascular smooth muscle cells (SMCs). Oral dosing of doxycycline (DOX) has been shown to inhibit MMPs in the AAA wall to slow AAA growth, but has systemic side effects and inhibits elastin biosynthesis at the high doses. To avoid this, we have formulated biodegradable polylactic-co- glycolic acid (PLGA) nanoparticles (NPs) for steady, sustained release of doxycycline (DOX), an MMP inhibitor within the AAA wall following one-time, catheter-wise infusion to a transiently flow-occluded AAA segment. At the much lower release levels (<10 μg/ml), DOX was found to maintain its MMP inhibitory effects, but also to beneficially stimulate elastic matrix neoassembly (elastogenesis). We also uniquely surface-functionalized our NPs with cationic amphiphiles that have pro-elastogenic & anti-proteolytic separate from the effects of the released DOX. Building on this promising preliminary data, we now propose to confirm the signaling mechanisms underlying the unique pro- matrix regenerative and anti-MMP effects of DOX at sub-oral doses, identify DOX-NP formulations that provide a significant stimulus to biomimetic and stable elastic fiber assembly, design and test a magnetic guidance system for efficient NP delivery to the AAA wall, and demonstrate efficacy of the DOX-NPs in regressing already formed small AAAs in a preclinical (rat) model. Our aims will test hypotheses that 1) pro-elastogenic effects of DOX are mediated by JNK decreases which trigger increases in TGF-β1, 2) quantity and quality of elastic fiber assembly can be regulated by modulating severity of JNK inhibition by DOX, 3) DOX is more effective than SP600125 (at their IC50 doses for JNK) in stimulating elastin since it also directly inactivates MMPs, and 4) regenerative stimuli due to DOX-NPs will restore matrix homeostasis in the AAA wall to arrest its growth. Aim 1 will correlate severity of DOX inhibition of JNK to downstream elastogenesis and anti-MMP outcomes in rat AAA SMC cultures. Aim 2 will generate DOX-NP formulations with superior pro-elastogenic & matrix reparative properties. Aim 3 will develop a magnetic system to target DOX-NPs to the AAA wall in a rat model. Aim 4 will assess therapeutic efficacy of magnetically-responsive DOX-NPs in rat AAAs. If successful, our approach will be validated in larger animal models to rationalize future clinical trials. Our approach can prospectively reduce or delay need for future surgery in high risk elderly AAA patients.

抽象的我们的目的是调查一种新的，微创的再生纳米疗法以逮捕或退化腹主动脉瘤（AAAS）的小（直径<5.5 cm）的生长。 AAA是局部扩展腹主动脉最终破裂。小型AAA的早期手术没有治疗益处，也没有还有其他经过验证的疗法。同时恢复结构性细胞外基质（ECM; AAA壁中的胶原蛋白和弹性纤维）对于停止或逆转AAA的生长至关重要，这受到A）的阻碍通过上调的基质金属蛋白酶（MMP）酶在主动脉壁中的慢性分解和b）缺乏通过成年血管克服本质上确定和有缺陷的弹性纤维再生修复的方法平滑肌细胞（SMC）。表明强力霉素（DOX）的口服剂量抑制AAA中的MMP 壁以减慢AAA的生长，但具有全身性副作用并抑制高剂量的弹性蛋白生物合成。到避免这种情况，我们已经制定了可生物降解的聚乳酸 - 乙醇酸（PLGA）纳米颗粒（NPS）一次稳定，持续释放多西环素（DOX），一次是AAA墙内的MMP抑制剂将导管的瞬时流动aAA段输注。在低得多的发行级别（<10 发现μg/ml），发现DOX可以维持其MMP抑制作用，但也有益地刺激弹性矩阵新组装（弹性发生）。我们还用阳离子两亲的NP唯一地将其表面函数化具有促载体和抗蛋白质水解与释放的DOX的作用分开。基于此有希望的初步数据，我们现在建议确认唯一pro的信号传导机制 DOX在次剂量下的基质再生和抗MMP效应，识别提供的DOX-NP公式仿生和稳定弹性纤维组件的显着刺激，设计和测试磁引导有效的NP向AAA墙传递的系统，并证明了DOX-NP的效率已经在临床前（大鼠）模型中形成了小的AAA。我们的目标将检验假设1）促载体 DOX的效果是由JNK介导的，在TGF-β1中触发的增加，2）数量和质量弹性纤维组件可以通过调节DOX的JNK抑制严重程度来调节，3）DOX更多在刺激弹性蛋白中，比SP600125（以JNK的IC50剂量为JNK）有效，因为它也直接失活 MMP和4）由于DOX-NP引起的再生刺激将恢复AAA墙中的基质稳态以逮捕其生长。 AIM 1将将JNK的DOX抑制严重程度与下游弹性发生和抗MMP相关大鼠AAA SMC文化的结果。 AIM 2将产生具有优质启发性＆的DOX-NP公式矩阵修复属性。 AIM 3将开发磁系统将DOX-NP靶向大鼠的AAA壁模型。 AIM 4将评估大鼠AAA中磁响应的DOX-NP的治疗效率。如果成功，我们的方法将在较大的动物模型中得到验证，以合理化未来的临床试验。我们的方法可以前瞻性地减少或延迟需要在AAA患者的高风险中对未来手术的需求。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adult Mesenchymal Stem Cells and Derivatives in Improved Elastin Homeostasis in a Rat Model of Abdominal Aortic Aneurysms.

DOI：
10.1093/stcltm/szac043
发表时间：
2022-08-23
期刊：
STEM CELLS TRANSLATIONAL MEDICINE
影响因子：
6
作者：
Dahal, Shataakshi;Dayal, Simran;Androjna, Charlie;Peterson, John;Ramamurthi, Anand
通讯作者：
Ramamurthi, Anand

Sodium Nitroprusside Stimulation of Elastic Matrix Regeneration by Aneurysmal Smooth Muscle Cells