Nanocarrier-formulated NF-kB inhibitors for Inflammatory diseases

描述（由申请人提供）：尽管tnf抑制剂和其他新的生物药物在治疗自身免疫性疾病和其他慢性炎症性疾病方面取得了成功，但仍有许多患者反应不佳。抑制NF-kB诱导治疗原发性th1型细胞因子的慢性炎症性疾病（如类风湿关节炎、多发性硬化症、1型糖尿病等）是包括tnf抑制剂在内的大多数治疗的目标。细胞内作用的NF-kB激活抑制剂，如ikb激酶抑制剂和NF-kB核易位抑制剂，在培养细胞中非常有效。然而，由于这些药物在血液中的半衰期很短，在体内使用这些药物治疗慢性炎症性疾病受到严重限制。将这些抑制剂配制成纳米载体可以保护这些抑制剂免受血液中的酶降解和肾脏的快速排泄。在这个应用中，这两种抑制剂将被配制成纳米载体。纳米载体是一种受保护的接枝共聚物（PGC），其中聚合物主链接枝：1)聚乙二醇（PEG）侧链，2)肽抑制剂的可逆粘合剂。抑制剂将与PGC结合，peg侧链将保护这些抑制剂免受血液中的酶降解和肾脏的快速排泄。由于复合物的大小（15-30nm），复合物会在炎症部位积聚，并通过基于亲和力的驱动释放释放抑制剂，这是一种平衡或解离常数（Kd）驱动释放。由于抑制剂含有细胞穿透序列，它们可以很容易地进入炎症部位的细胞，抑制NF-kB的激活，从而抑制炎症性疾病。胶原诱导的关节炎，一个类风湿性关节炎的小鼠模型，将在这个特殊的应用中进行治疗，以证明概念。在这个拟议的项目中，还将评估配方的急性和慢性毒性。我们这个项目的目标是开发一种治疗慢性炎症性疾病的产品，这将导致FDA批准用于人类的治疗。

DESCRIPTION (provided by applicant): Despite the success of TNF-inhibitors and other new biological drugs for the treatment of autoimmune and other chronic inflammatory diseases, there are still many patients that respond poorly. Suppressing NF-kB induction as treatment of chronic inflammatory diseases with a primary Th1-type cytokine profile (like e.g. Rheumatoid Arthritis, Multiple sclerosis, Type 1 diabetes and others) is the goal of majority of treatments including TNF-inhibitors. Intracellularly-acting NF-kB activation-inhibitors, such as IkB-kinase inhibitor and NF-kB nuclear translocation inhibitor, are very effective in cultured cells. However, in vivo use of these agents against chronic inflammatory diseases is severely limited by their very short half-life in blood. Formulating these inhibitors into a nanocarrier can protect these inhibitors from enzyme degradation in the blood and rapid excretion by the kidney. In this application these two inhibitors will be formulated into nanocarriers. The nanocarriers are a Protected Graft Copolymer (PGC), in which a polymer backbone is grafted with: 1) polyethylene glycol (PEG) side chains, and 2) reversible binders of the peptide inhibitors. The inhibitors will bind to PGC and the PEG-side chains will protect these inhibitors from enzyme degradation in the blood and rapid excretion by the kidney. Because of size (15-30nm), the complex will accumulate at site of inflammation and will release the inhibitors by an affinity based driven release, which is an equilibrium or dissociation constant (Kd) driven release. Because the inhibitors contain cell penetrating sequences, they will readily enter cells at site of inflammation, inhibit NF-kB activation, and thus suppress inflammatory diseases. Collagen induced arthritis, a mouse model of rheumatoid arthritis, will be treated in this particular application to show proof of concept. The acute and chronic toxicity of the formulations will also be evaluated in this proposed project. Our goal for this project is to develop a product for the treatment for chronic inflammatory diseases that will lead to FDA approved treatment for humans.