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：
8196005
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8196005
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

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

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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. PUBLIC HEALTH RELEVANCE: 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, although effective, is severely limited by their very short half-life in blood. In this project, these inhibitors will be formulated into nanocarriers that: 1) accumulates at sites of inflammation; 2) can protect these inhibitors from enzyme degradation in the blood; and 3) prevent rapid excretion by the kidney. The project will allow use of these agents in many human 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成功地治疗自身免疫性和其他慢性炎症性疾病，但仍有许多患者反应良好。抑制NF-KB诱导作为用原发性Th1型细胞因子谱（例如类风湿关节炎，多发性硬化症，1型糖尿病等）治疗的慢性炎症性疾病的治疗是大多数治疗方法的目标。细胞内作用的NF-KB活化抑制剂，例如IKB-激酶抑制剂和NF-KB核转运抑制剂，在培养的细胞中非常有效。然而，在体内使用这些药物针对慢性炎症性疾病的使用受到了非常短的半衰期的血液的严重限制。将这些抑制剂制成纳米载体可以保护这些抑制剂免受血液中的酶降解，并通过肾脏快速排泄。在此应用中，这两种抑制剂将被配制为纳米载体。纳米载体是一种受保护的移植共聚物（PGC），其中聚合物骨架与：1）聚乙烯乙二醇（PEG）侧链和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，并通过肾脏快速排泄。由于大小（15-30nm），该复合物将在炎症部位积聚，并通过基于亲和力的驱动释放释放抑制剂，该释放是平衡或分离常数（KD）驱动释放。由于抑制剂包含细胞穿透序列，因此它们将很容易在炎症部位进入细胞，抑制NF-KB激活，从而抑制炎症性疾病。胶原蛋白诱导的关节炎是类风湿关节炎的小鼠模型，将在此特定应用中进行治疗，以显示概念证明。该提议的项目还将评估配方的急性和慢性毒性。该项目的目标是开发用于治疗慢性炎症性疾病的产品，这将导致FDA批准的人类治疗。公共卫生相关性：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，在体内使用这些药物针对慢性炎症性疾病的使用，尽管有效，但由于血液中的半衰期很短，因此受到严重限制。在该项目中，这些抑制剂将被配制为纳米载体：1）在炎症部位积聚； 2）可以保护这些抑制剂免受血液中的酶降解； 3）防止肾脏快速排泄。该项目将允许在许多人类炎症性疾病中使用这些药物。