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

• 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
• 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

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（由申请人提供）：尽管TNF抑制剂和其他新的生物药物成功用于治疗自身免疫性疾病和其他慢性炎症性疾病，但仍有许多患者反应不佳。抑制NF-kB诱导作为具有原发性Th 1型细胞因子谱的慢性炎性疾病（例如风湿性关节炎、多发性硬化、1型糖尿病等）的治疗是包括TNF抑制剂在内的大多数治疗的目标。细胞内作用的NF-κ B激活抑制剂，如IkB激酶抑制剂和NF-κ B核转位抑制剂，在培养的细胞中是非常有效的。然而，这些药物在体内用于治疗慢性炎性疾病受到其在血液中非常短的半衰期的严重限制。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。在本申请中，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。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。由于尺寸（15- 30 nm），复合物将在炎症部位积聚，并将通过基于亲和力的驱动释放释放抑制剂，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，它们将容易地进入炎症部位的细胞，抑制NF-κ B活化，从而抑制炎性疾病。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。本拟议项目还将评价制剂的急性和慢性毒性。我们这个项目的目标是开发一种用于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。