BRIGE: Engineering Polysaccharide Nanoparticles for Drug Delivery to Inflammatory Tissue

[32506]为了提高疗效和减少副作用，药物传递领域的范式已经转向将有毒药物与分子载体结合，并随后深入研究改变的药代动力学和药效学特性。这种载体系统通常有足够的大小，允许在增强的渗透性区域，特别是肿瘤和炎症组织内被动积聚。通过添加仅在病变区域内发现的受体特异性的活性靶向片段或配体，可以进一步提高此类材料的特异性和治疗功效。因此，靶向药物递送使得设计药物负载载体系统来治疗特定疾病成为可能。主要研究者的长期目标是为类风湿关节炎的选择性治疗量身定制输送系统。多糖是一种天然的、可生物降解的、非免疫原性的聚合物，在药物输送领域越来越受到关注。聚唾液酸尤其引起了人们的注意，因为人体缺乏所有已知的受体；因此，与其他更常用的材料相比，基于聚唾液酸的载体系统有望增加循环稳定性并减少网状内皮系统的摄取。这一建议的知识价值在于使用基于聚唾液酸的纳米颗粒载体系统来治疗类风湿关节炎。此外，另一种多糖，透明质酸，将被用来促进CD44透明质酸受体的活性靶向，CD44透明质酸受体是炎症关节组织中滑膜细胞过度表达的。我们假设基于多糖的纳米颗粒载体将(1)促进位点特异性递送，(2)提高现有治疗方法的疗效并减少非特异性毒性。第一个目标将是设计、合成和表征以凝胶和胶束形式存在的多糖基纳米颗粒，分别用于甲氨蝶呤和环孢素A的包封。作为第二个目标，将通过共聚焦显微镜监测类风湿性关节炎滑膜成纤维细胞的摄取，并通过多重免疫分析法评估细胞因子谱的变化，对载药多糖纳米颗粒进行体外测试。第三个目标是将基于多糖的纳米颗粒施用于类风湿关节炎的小鼠模型，以检查生物分布和疗效。因此，主要研究者将成功地开发一种改进的系统治疗类风湿关节炎。该项目的一个关键方面是更广泛的参与计划，旨在增加雪城大学工程专业残疾学生的数量。类风湿性关节炎与身体残疾密切相关，60%的确诊患者在发病过程中长时间无法工作或上学。因此，所提出的研究课题独特地与更广泛的参与计划相结合。首席研究员将与位于锡拉丘兹大学的伯顿布拉特研究所（BBI）密切合作。在世界范围内，BBI是促进残疾人公民、经济和社会参与的首要组织。在当地，BBI致力于将残疾相关内容纳入现有课程，增加残疾学生的入学人数，并创建一个更加残疾人友好的校园。通过BBI， PI将越来越多地参与影响残疾人的问题的讨论和研究。PI将在锡拉丘兹大学由BBI举办的系列研讨会上发表演讲，并积极参与BBI组织的会议、研讨会和其他公共活动。除了这些旨在提高大学和当地社区成员对残疾，特别是与类风湿性关节炎有关的残疾的认识的活动外，PI还打算在BBI的协助和工程与计算机科学学院院长的支持下，招募两名残疾学生（一名本科生，一名研究生）到她的实验室工作。这些最初的招聘努力将使雪城大学工程专业的残疾学生人数增加。

1032506Bader In an effort to enhance efficacy and reduce side effects, paradigms in the realm of drug delivery have shifted toward combining toxic drugs with molecular vehicles with subsequent in-depth investigation of the altered pharmacokinetic and pharmaco-dynamic properties. Such carrier systems are usually of sufficient size to permit passive accumulation within regions of enhanced permeability, specifically tumor and inflamed tissue. The specificity and therapeutic efficacy of such materials can be further improved through the addition of an active targeting moiety or ligand that is specific for receptors found only within the diseased region. Thus, targeted drug delivery makes real the possibility of designing drug loaded carrier systems to treat specific diseases. The principle investigator's long term objective is to tailor delivery systems for the selective treatment of rheumatoid arthritis. Polysaccharides are natural, biodegrable, non-immunogenic polymers of increasing interest in the field of drug delivery. Poly(sialic acid) in particular has garnered attention because the body lacks all known receptors; therefore, carrier systems based upon poly(sialic acid) are anticipated to increase circulatory stability and reduce uptake by the reticuloendothelial system beyond other more commonly used materials. The intellectual merit of this proposal lies in the use of poly(sialic acid)-based nanoparticle carrier systems for the treatment of rheumatoid arthritis. Additionally, another polysaccharide, hyaluronic acid, will be used facilitate active targeting of the CD44 hyaluronic acid receptor that is over-expressed by synovial cells found within inflamed joint tissue. We hypothesize that polysaccharide-based nanoparticle carriers will (1) facilitate site specific delivery and (2) increase the efficacy and reduce the non-specific toxicity of existing therapeutics. The first objective will be the design, synthesis, and characterization of polysaccharide-based nanoparticles in the form of gels and micelles for the encapsulation of methotrexate and cyclosporine A respectively. As a second objective, the drug loaded polysaccharide-based nanoparticles will be tested in vitro with rheumatoid arthritis synovial fibroblasts by monitoring uptake with confocal microscopy and assessing changes in the cytokine profile by multiplex immunoassay. The third objective will be administration of the polysaccharide-based nanoparticles to a murine model of rheumatoid arthritis to examine biodistribution and efficacy. Thus, the principle investigator will successfully develop an improved system for the treatment of rheumatoid arthritis. A key aspect of this project is the broader participation plan which aims to increase the number of students with disabilities in engineering at Syracuse University. With 60% of diagnosed people unable to work or attend school for extended periods of time over the course of the disease, rheumatoid arthritis is closely associated with physical disability. The proposed research topic therefore uniquely integrates with the broader participation plan. The principle investigator will be working closely with the Burton Blatt Institute (BBI) located at Syracuse University. Worldwide, the BBI is the premiere organization for advancing the civic, economic, and social participation of persons with disabilities. Locally, the BBI is committed to integrating disability related content into existing curricula, increasing the number of enrolled students with disabilities, and creating a more disability friendly campus. Through the BBI, the PI will become increasingly involved in the discussion and research of issues that affect people with disabilities. The PI will be a speaker in an ongoing seminar series held by the BBI at Syracuse University and will be an active participant in meetings, workshops, and other public engagements organized by the BBI. In addition to these activities intended to increase awareness of members of both the University and the local community to disabilities, particularly those related to rheumatoid arthritis, the PI intends to recruit two students with disability to her laboratory (one undergraduate, one graduate) with the assistance of the BBI and the support of the Dean of the College of Engineering and Computer Science. These initial recruitment efforts will matriculate in an increase in the number of students with disabilities in the engineering program at Syracuse University.