Novel nanoparticles to stimulate therapeutic angiogenesis in peripheral arterial disease

刺激外周动脉疾病治疗性血管生成的新型纳米颗粒

基本信息

批准号：
10462909
负责人：
RALPH P. MASON
金额：
$ 53.67万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-02 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10462909
关键词：
Acute Affect Aftercare Alternative Therapies Aniline Animal Model Apoptosis Arteries Binding Biocompatible Materials Biodistribution Blood Glucose Blood Vessels Blood coagulation Blood flow CD34 gene Cell Survival Cells Cholesterol Chronic Complementary DNA Cytoprotection Data Detection Development Diarrhea Disease Elastomers Elderly Erythropoietin Receptor Evaluation Goals Growth Factor Headache Hematopoietic Stem Cell Mobilization Hemorrhage Hypertension Hypoxia Impairment In Situ In Vitro Individual Intervention Intramuscular Ischemia Leg Location Lower Extremity Mediating Modality Monitor Morbidity - disease rate Multimodal Imaging Names Nanotechnology Obstruction Operative Surgical Procedures Pain in lower limb Patients Peripheral Peripheral arterial disease Persons Pharmaceutical Preparations Pharmacotherapy Polymers Property Quality of life Reagent Research Research Project Grants Research Support Role Site Stress Structure Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Intervention Tissue Engineering Tissues Treatment Efficacy United States Work angiogenesis antibody conjugate artery occlusion base biomaterial compatibility blood perfusion blood pressure control blood vessel development combat common treatment effective therapy effectiveness evaluation endothelial stem cell femoral artery fluorescence imaging gene therapy imaging modality imaging properties improved in vivo in vivo evaluation innovation limb ischemia limb loss mortality mouse model nanoparticle non-invasive imaging novel novel therapeutics photoacoustic imaging prevent recruit reduce symptoms side effect stem cells success therapeutic angiogenesis therapeutic effectiveness therapeutically effective tool

项目摘要

ABSTRACT Peripheral arterial disease (PAD) is a severe impairment of arterial vessels resulting in obstruction of normal blood flow in the legs, leading to acute or chronic lower limb ischemia and subsequently high morbidity and mortality rates. Common treatments for PAD, such as medications and surgical revascularization, have several limitations. For instance, medications used to lower cholesterol, reduce high blood pressure, control blood sugar, prevent blood clots, and relieve symptoms like leg pains may delay onset. Still, they cannot treat the established disease directly and often cause side effects, including bleeding, headache, and diarrhea. Meanwhile, many elderly PAD patients cannot undergo surgical options. Therefore, it is vital to develop an alternative therapy to treat PAD. Our long-term goal is to develop novel degradable dual-modal imaging nanoparticles (DINPs) to precisely deliver therapeutic reagents that provide cell protection and facilitate the formation of blood vessels de novo at ischemic sites while allowing detection of the NP location and monitoring of their therapeutic effectiveness for PAD treatment. We have three specific aims: (1) To synthesize, characterize and optimize our biodegradable dual-modal fluorescent/photoacoustic elastomers named biodegradable photoluminescent polymers-aniline tetramers (BPLPAT), (2) To formulate and analyze DINPs made of optimized BPLPATs and loaded with therapeutic reagents for facilitating cell protection and angiogenesis, and (3) To evaluate the effectiveness of DINPs to treat PAD in vivo using animal models. Innovative aspects of this research are i) the use of our novel BPLPAT material allowing both fluorescent and deep-tissue photoacoustic imaging opportunities to detect the in vivo distribution of these NPs and evaluate their degradation assessment; ii) development of DINPs based on recent advances in nanotechnology and tissue engineering providing a unique strategy to deliver new therapeutic agents to the ischemic site in order to enhance cellular protection and promote angiogenesis in situ under hypoxic conditions such as ischemic tissues. The rigor of prior research and scientific feasibility of our developed DINPs are well-established as we have already demonstrated (1) their detectability via both fluorescence and photoacoustic imaging, (2) the retention of DINPs loaded with therapeutic agents at the ischemic zones, (3) the release of therapeutic compounds in a sustained manner, and (4) their capacity to provide cell protection and promote angiogenesis to recover blood perfusion after ischemia. The success of our research will provide a novel therapy for the effective treatment of PAD.

抽象的周围动脉疾病（PAD）是动脉血管的严重损害，导致正常障碍腿部的血液流动，导致急性或慢性下肢缺血，随后发病率高，并且死亡率。 PAD的常见治疗方法，例如药物和手术血运重建，有几种限制。例如，用于降低胆固醇，降低高血压，对照血糖的药物，防止血液凝块，并缓解诸如腿部疼痛之类的症状可能会延迟发作。尽管如此，他们仍无法对待已建立的疾病直接并经常引起副作用，包括出血，头痛和腹泻。同时，许多人老年垫患者无法接受手术选择。因此，开发一种替代疗法至关重要治疗垫。我们的长期目标是开发新型可降解的双模式成像纳米颗粒（DINP）精确提供治疗试剂，可提供细胞保护并促进血管形成DE Novo在缺血部位，同时允许检测NP位置并监测其治疗性 PAD治疗的有效性。我们有三个特定的目标：（1）合成，表征和优化我们的可生物降解的双模式荧光/光声弹性体，称为可生物降解的光致发光聚合物 - 苯胺四聚体（BPLPAT），（2），以优化的BPLPAT和装有治疗试剂，可促进细胞保护和血管生成，（3）评估 DINP使用动物模型在体内处理垫的有效性。这项研究的创新方面是我）使用我们的新型BPLPAT材料，允许荧光和深度组织光声成像机会检测这些NP的体内分布并评估其降解评估； ii）开发 DINPS基于纳米技术和组织工程的最新进展，提供了独特的策略向缺血部位提供新的治疗剂，以增强细胞保护并促进在缺氧条件下（等缺血组织）的原位血管生成。先前研究和我们已经证明的，我们发达的dinps的科学可行性已经建立了良好的（1）通过荧光和光声成像的可检测性，（2）装有治疗性的DINP的保留性缺血区域的特工，（3）以持续的方式释放治疗化合物，（4）提供细胞保护并促进血管生成以恢复缺血后血液灌注的能力。这我们研究的成功将为有效治疗PAD提供新的疗法。