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

• 批准号: 10616740
• 负责人: RALPH P. MASON
• 金额: $ 53.03万
• 依托单位: UNIVERSITY OF TEXAS ARLINGTON
• 依托单位国家: 美国
• 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/10616740
• 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; Collateral Circulation; 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; Induction of Apoptosis; Inflammation; Intervention; Intramuscular; Ischemia; Leg; Ligation; 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; Predisposition; 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; Vascular Diseases; Work; angiogenesis; animal model selection; antibody conjugate; artery occlusion; biomaterial compatibility; blood perfusion; blood vessel development; combat; common treatment; effective therapy; effectiveness evaluation; elastomeric; endothelial stem cell; fabrication; 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; revascularization surgery; side effect; stem cells; success; therapeutic angiogenesis; therapeutic effectiveness; therapeutically effective; tool

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 外周动脉疾病（PAD）是一种严重的动脉血管损伤，导致正常血管阻塞。 腿部血液流动，导致急性或慢性下肢缺血，从而导致高发病率和 死亡率。 PAD 的常见治疗方法包括药物治疗和手术血运重建术 限制。例如，用于降低胆固醇、降低高血压、控制血糖的药物， 预防血栓，缓解腿部疼痛等症状，可能会延迟发病。尽管如此，他们还是不能对待既定的 疾病直接导致副作用，包括出血、头痛和腹泻。与此同时，许多 老年 PAD 患者无法接受手术选择。因此，开发替代疗法至关重要 治疗 PAD。我们的长期目标是开发新型可降解双模态成像纳米颗粒（DINP） 精确递送治疗试剂，提供细胞保护并促进血管形成 novo 在缺血部位同时允许检测 NP 位置并监测其治疗效果 PAD 治疗的有效性。我们有三个具体目标：（1）综合、表征和优化我们的 可生物降解双模荧光/光声弹性体命名为可生物降解光致发光 聚合物-苯胺四聚体 (BPLPAT)，(2) 配制和分析由优化的 BPLPAT 制成的 DINP 和 装载有促进细胞保护和血管生成的治疗试剂，以及（3）评估 使用动物模型研究 DINP 在体内治疗 PAD 的有效性。这项研究的创新之处是 i) 使用我们的新型 BPLPAT 材料可实现荧光和深层组织光声成像 检测这些纳米粒子的体内分布并评估其降解评估； ii) 发展 DINP 基于纳米技术和组织工程的最新进展，提供了独特的策略 将新的治疗剂递送至缺血部位，以增强细胞保护并促进 在缺氧条件下（例如缺血组织）原位血管生成。先前研究的严谨性和 我们开发的 DINP 的科学可行性已得到充分证实，因为我们已经证明了 (1) 通过荧光和光声成像可检测到，(2) 载有治疗剂的 DINP 的保留 缺血区的药物，（3）以持续的方式释放治疗化合物，以及（4）它们的 提供细胞保护和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。