BRIGE: Engineering Polysaccharide Nanoparticles for Drug Delivery to Inflammatory Tissue

为了提高疗效和减少副作用，药物递送领域的范例已经转向将毒性药物与分子载体结合，随后深入研究改变的药代动力学和药效学特性。这种载体系统通常具有足够的大小以允许在渗透性增强的区域（特别是肿瘤和发炎组织）内被动积累。这种材料的特异性和治疗功效可以通过添加对仅在患病区域内发现的受体具有特异性的活性靶向部分或配体来进一步改善。因此，靶向药物递送使得设计载药载体系统以治疗特定疾病的可能性成为真实的。主要研究者的长期目标是为类风湿性关节炎的选择性治疗定制输送系统。 多糖是天然的、可生物降解的、非免疫原性的聚合物，在药物递送领域中越来越受到关注。聚（唾液酸）特别受到关注，因为身体缺乏所有已知的受体;因此，基于聚（唾液酸）的载体系统预计将增加循环稳定性并减少网状内皮系统的摄取，超过其他更常用的材料。 该建议的智力价值在于使用基于聚（唾液酸）的纳米颗粒载体系统治疗类风湿性关节炎。此外，另一种多糖，透明质酸，将用于促进CD44透明质酸受体的主动靶向，该受体由炎症关节组织内发现的滑膜细胞过度表达。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和（2）增加现有治疗剂的功效并降低非特异性毒性。第一个目标将是分别用于甲氨蝶呤和环孢菌素A的胶囊化的凝胶和胶束形式的基于多糖的纳米颗粒的设计、合成和表征。作为第二个目的，将在体外用类风湿性关节炎滑膜成纤维细胞通过用共聚焦显微镜监测摄取和通过多重免疫测定评估细胞因子谱的变化来测试载药的基于多糖的纳米颗粒。第三个目标是将基于多糖的纳米颗粒给予类风湿性关节炎的小鼠模型，以检查生物分布和功效。因此，主要研究者将成功地开发出一种用于治疗类风湿性关节炎的改进系统。 该项目的一个关键方面是更广泛的参与计划，旨在增加锡拉丘兹大学工程专业的残疾学生人数。60%的确诊患者在疾病过程中长时间无法工作或上学，类风湿性关节炎与身体残疾密切相关。因此，拟议的研究课题独特地与更广泛的参与计划相结合。主要研究者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是促进残疾人参与公民、经济和社会的首要组织。在当地，BBI致力于将残疾相关内容融入现有课程，增加残疾学生的入学人数，并创建一个更加残疾友好的校园。通过BBI，PI将越来越多地参与对影响残疾人的问题的讨论和研究。PI将在BBI在锡拉丘兹大学举办的一系列研讨会上发表演讲，并将积极参与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打算在BBI的协助下和工程与计算机科学学院院长的支持下，招募两名残疾学生到她的实验室（一名本科生，一名研究生）。这些最初的招聘工作将使锡拉丘兹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.