PLGA Nanoparticles as a Localized Therapy for Experimental Autoimmune Neuritis?

PLGA 纳米颗粒作为实验性自身免疫性神经炎的局部疗法？

• 批准号: 9396954
• 负责人: Kelly A Langert
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396954
• 关键词: Acute; Address; Adhesions; Adjuvant; Advanced Development; Adverse effects; Affect; Animals; Attenuated; Autoimmune Diseases; Autoimmune Process; Biocompatible Materials; Biodistribution; Biological Assay; Biological Availability; Blood-Nerve Barrier; CCL2 gene; CD8B1 gene; CXCL10 gene; Cell membrane; Cholesterol; Clinical; Data; Demyelinating Polyneuropathy; Development; Dialysis procedure; Disease; Dose; Drug Delivery Systems; Drug Targeting; Economic Burden; Encapsulated; Endothelial Cells; Environment; Etiology; Exhibits; Experimental Autoimmune Neuritis; Glycolates; Goals; Guanosine Triphosphate Phosphohydrolases; Guillain-Barré Syndrome; Harvest; Hydrophobicity; Immune; Immune system; Immunization; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Intercellular adhesion molecule 1; Label; Laboratory Animals; Leukocytes; Local Therapy; Lovastatin; Mediating; Microspheres; Modeling; Myelin; Neuropathy; P2 peptide; Pathogenicity; Pathologic; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Polyradiculopathy; Prevalence; Proteins; RANTES; Rattus; Rehabilitation therapy; Research; Role; Signal Transduction; Site; Small Interfering RNA; Splenocyte; Surface; TNF gene; Testing; Therapeutic; Training; Variant; Veterans; autoreactivity; base; chemokine; clinical translation; controlled release; health administration; in vivo; inhibitor/antagonist; macrophage; migration; monolayer; nanoparticle; nervous system disorder; novel; palliative; particle; patient population; pleiotropism; programs; sciatic nerve; social; socioeconomics; systemic toxicity; targeted treatment; trafficking

Inflammatory peripheral neuropathies constitute one of the largest and least understood spectrums of neurologic disorders. Among these disorders is acute inflammatory demyelinating polyneuropathy (AIDP), a disabling inflammatory autoimmune disease of the peripheral nervous system. Inflammatory peripheral neuropathies collectively represent a major socioeconomic strain to our Veteran patient population and to the Veterans Health Administration. Despite overwhelming prevalence and socioeconomic impact, the treatment options available for Veterans suffering from inflammatory peripheral neuropathies, including AIDP, remain palliative, nonspecific, and ineffective. Immunization of susceptible strains of laboratory animals with peripheral nerve myelin P2 peptide and adjuvant induces experimental autoimmune neuritis (EAN), which closely models the pathogenicity of AIDP. Statins, a group of established cholesterol lowering agents, therapeutically attenuate EAN by inhibiting the transendothelial migration of autoreactive leukocytes into peripheral nerves. The effect of statins on the immune system is now known to be pleiotropic. Our lab has demonstrated that statins specifically attenuate TNF-α mediated release of the chemokine CCL2 from the peripheral nerve microvascular endoneurial endothelial cells (PNMECs) that form the blood-nerve barrier (BNB). Poor bioavailability necessitates high systemic doses to achieve the pleiotropic effects of statins, and rare but serious side effects preclude clinical translation. Biomaterials-based drug delivery represents a novel means by which to administer drugs that exhibit low bioavailability and high systemic toxicity. Poly(lactic-co- glycolic)acid (PLGA) can be used to form biodegradable nanoparticles that encapsulate hydrophobic compounds, including statins, for controlled release. In addition, PLGA can be modified to express moieties that direct circulating particles to sites of inflammation, allowing for targeted systemic administration. In this CDA-2 application, our objective is to determine the therapeutic potential of a novel, targeted drug delivery system to modulate endothelial GTPase signaling at the inflamed peripheral nerve. To accomplish this, we will utilize PLGA nanoparticles that encapsulate lovastatin and are surface-functionalized with purified macrophage plasma membranes. We hypothesize that targeted disruption of endothelial GTPase signaling with functionalized, lovastatin-encapsulating nanoparticles will therapeutically limit CCL2-dependent trafficking of autoreactive leukocytes in EAN. This will be tested using in vitro and in vivo approaches. First, we will assess the ability of surface-functionalized, PLGA nanoparticles to adhere to, migrate across, and deliver a payload within the activated BNB in vitro. Second, we will determine the therapeutic potential of targeting the inflamed BNB with systemically-administered, surface-functionalized, lovastatin-encapsulating nanoparticles in EAN. Third, we will elucidate the roles of Cdc42 and RalA GTPases in activation of the BNB in vitro under flow conditions. The immediate goals of this VA RR&D CDA-2 program are evaluating the therapeutic potential of targeted disruption of GTPase signaling in EAN while continuing to elucidate the mechanisms governing chemokine expression and pathological transendothelial migration at the blood-nerve barrier. Thus, this program will significantly advance the development of novel, selective immune-modulating strategies for the management and rehabilitation of Veterans with debilitating inflammatory peripheral neuropathies.

炎症性周围神经病构成了最大，最少理解的频谱之一 神经系统疾病。这些疾病包括急性炎症性脱髓鞘性多神经病（AIDP），A 残疾外周神经系统的炎症自身免疫性疾病。炎症周围 神经病共同代表了我们的退伍军人群体的主要社会经济压力 退伍军人卫生管理局。尽管严重的患病率和社会经济影响，但治疗 患有炎症性周围神经病（包括AIDP）的退伍军人可获得的选择仍然 姑息性，非特异性和无效。 用周围神经髓鞘P2胡椒和 辅助诱导实验性自身免疫神经（EAN），它与AIDP的致病性密切建模。 他汀类药物是一群已建立的降低胆固醇剂，历史上通过抑制EAN来减轻EAN 自身反应性白细胞跨内皮迁移到周围神经。他汀类药物对 现在已知免疫系统是多效性的。我们的实验室证明了他汀类药物特别减弱 TNF-α介导的趋化因子CCL2从周围神经微血管内核释放 内皮细胞（PNMEC）形成血液障碍物（BNB）。 不良的生物利用度需要高的全身性剂量才能达到他汀类药物的多效作用，并且很少见 但是严重的副作用排除了临床翻译。基于生物材料的药物递送代表一种新颖 通过使用低暴露生物利用度和高系统性毒性的药物的方法。聚（乳酸 - 糖酸）酸（PLGA）可用于形成可生物降解的纳米颗粒，以封装疏水性 包括他汀类药物在内的化合物用于受控释放。此外，可以修改PLGA以表达部分 将颗粒直接循环到炎症部位，从而允许靶向全身性给药。 在此CDA-2应用中，我们的目标是确定针对性的小说的治疗潜力 药物输送系统以调节发炎的周围神经处的内皮GTPase信号传导。到 这样做，我们将利用封装lovastatin并表面官能化的PLGA纳米颗粒 带有纯化的巨噬细胞质膜。我们假设有针对性的内皮破坏 GTPase信号传导，具有功能化的，洛伐他汀的封装纳米颗粒将热 限制EAN自动反应性白细胞的CCL2依赖性运输。这将使用体外和 体内方法。首先，我们将评估表面官能化的PLGA纳米颗粒粘附的能力 在体外激活的BNB内迁移，迁移并提供有效载荷。第二，我们将确定 用全身管理，表面官能化的，靶向发炎的BNB的治疗潜力 lovastatin在EAN中封装纳米颗粒。第三，我们将阐明Cdc42和Rala的作用 在流动条件下，BNB在体外激活的GTPases。 该VA RR＆D CDA-2计划的直接目标正在评估目标的治疗潜力 EAN中GTPase信号的破坏，同时继续阐明趋化因子的机制 血液障碍物的表达和病理跨内皮迁移。那，这个程序将 显着提高新颖，选择性免疫调节策略的管理 以及对炎症性周围神经病的老兵的康复。