Nanocarrier-formulated NF-kB inhibitors for Inflammatory diseases

纳米载体配制的用于炎症疾病的 NF-kB 抑制剂

基本信息

批准号：
8300786
负责人：
Gerardo M. Castillo
金额：
$ 30万
依托单位：
PHARMAIN CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300786
关键词：
Acute Affinity Antibodies Autoimmune Diseases Autoimmune Process Binding Biological Blood Blood Circulation Body Weight decreased Cells Cessation of life Chemistry Chronic Clinic Clinical Research Collagen Arthritis Complex Cultured Cells Development Disease Dissociation Dose Drug Formulations Drug Kinetics Enzyme Inhibitor Drugs Enzyme Inhibitors Equilibrium Evaluation Excretory function FDA approved Goals Half-Life Human In Vitro Individual Inflammation Inflammatory Injectable Insulin-Dependent Diabetes Mellitus Interleukin 6 Receptor Interleukin-1 Kidney Kilogram Lead Marketing Measurement Multiple Sclerosis Mus NF-kappa B Nature Nuclear Translocation Patients Penetration Peptide Hydrolases Peptide Synthesis Peptides Pharmaceutical Preparations Phase Polyethylene Glycols Polymers Process Proteins Quality of life Relative (related person)Rheumatoid Arthritis Rodent Model Side Site Swelling TNF gene Technology Testing Therapeutic Therapeutic Uses Time Toxic effect Translations Treatment Efficacy Vertebral column Weight alternative treatment base copolymer cytokine design foot glomerular filtration improved in vivo inhibitor/antagonist kinase inhibitor mouse model nanocarrier novel therapeutics outcome forecast patient population prevent protein aminoacid sequence research study response scale up stoichiometry success tositumomab tumor necrosis factor-alpha inhibitor

项目摘要

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.

描述（申请人提供）：尽管TNF抑制剂和其他新型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 诱导作为治疗具有主要 Th1 型细胞因子谱的慢性炎症性疾病（例如类风湿性关节炎、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，例如 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，这些药物在体内用于对抗慢性炎症疾病因其在血液中的半衰期非常短而受到严重限制。将这些抑制剂配制到纳米载体中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。在此应用中，这两种抑制剂将被配制成纳米载体。纳米载体是受保护的接枝共聚物 (PGC)，其中聚合物主链接枝有：1) 聚乙二醇 (PEG) 侧链和 2) 肽抑制剂的可逆结合剂。这些抑制剂将与 PGC 结合，而 PEG 侧链将保护这些抑制剂免遭血液中的酶降解和肾脏的快速排泄。由于尺寸（15-30nm），复合物将在炎症部位积聚，并通过基于亲和力的驱动释放来释放抑制剂，这是平衡或解离常数（Kd）驱动的释放。由于抑制剂含有细胞穿透序列，因此很容易进入炎症部位的细胞，抑制NF-kB活化，从而抑制炎症性疾病。胶原诱导的关节炎（类风湿性关节炎的小鼠模型）将在该特定应用中进行治疗以显示概念证明。该拟议项目还将评估制剂的急性和慢性毒性。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，从而获得 FDA 批准的人类治疗方法。