Novel nanoparticles to stimulate therapeutic angiogenesis in peripheral arterial disease

摘要 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， 腿部血流，导致急性或慢性下肢缺血，随后发病率高， 死亡率。PAD的常见治疗方法，如药物治疗和手术血运重建，有几个 局限性。例如，用于降低胆固醇，降低高血压，控制血糖， 防止血栓形成，缓解腿部疼痛等症状，可能会延迟发病。然而，他们不能把既定的 疾病直接，并经常引起副作用，包括出血，头痛和腹泻。与此同时，许多 老年PAD患者不能接受手术治疗。因此，开发一种替代疗法至关重要， 治疗PAD。我们的长期目标是开发新型可降解双模成像纳米颗粒（DINPs）， 精确地递送提供细胞保护和促进血管形成的治疗试剂， 同时允许检测NP的位置并监测其治疗效果。 有效治疗PAD。我们有三个具体目标：（1）合成，表征和优化我们的 一种可生物降解的双模态荧光/光声弹性体 聚合物-苯胺四聚体（BPLPAT），（2）配制和分析由优化的BPLPAT制成的DINPs， 装载有用于促进细胞保护和血管生成的治疗试剂，以及（3）为了评估 使用动物模型在体内治疗PAD的DINPs的有效性。本研究的创新之处在于：i） 使用我们的新型BPLPAT材料，允许荧光和深层组织光声成像机会 检测这些NP的体内分布并评价其降解评估; ii）开发 DINPs基于纳米技术和组织工程的最新进展，提供了一种独特的策略， 将新的治疗剂递送到缺血部位以增强细胞保护和促进 在缺氧条件下原位血管生成，例如缺血组织。先前研究的严谨性和 我们开发的DINPs的科学可行性已经确立，因为我们已经证明了（1） 通过荧光和光声成像的可检测性，（2）装载治疗药物的DINPs的保留 药物在缺血区的作用，（3）治疗化合物以持续的方式释放，和（4）它们的 提供细胞保护和促进血管生成以恢复缺血后的血液灌注的能力。的 本研究的成功将为PAD的有效治疗提供一种新的治疗方法。

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.