Nanocarrier-formulated anti-fibrotic peptides for cirrhosis - Fast Track SBIR

纳米载体配制的抗纤维化肽治疗肝硬化 - Fast Track SBIR

基本信息

批准号：
8102077
负责人：
Elijah M. Bolotin
金额：
$ 43.23万
依托单位：
PHARMAIN CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8102077
关键词：
Affect Affinity Alcohol abuse Alcoholic Liver Cirrhosis Alcoholism Alcohols American Animal Model Animals Antibodies Atrial Natriuretic Factor Binding Biological Blood Blood flow Carbon Tetrachloride Cause of Death Cholestasis Cicatrix Cirrhosis Clinical Clinical Trials Complex Copper Detection Development Dimethylnitrosamine Disease Dissociation Dose Drug Carriers Drug Delivery Systems Drug Formulations Drug Kinetics Enzymes Fatty acid glycerol esters Fibrosis Figs - dietary Frequencies Half-Life Heavy Drinking Hemochromatosis Hepatitis Hepatolenticular Degeneration Hour Imaging technology In Vitro Infection Injection of therapeutic agent Institutes Intravenous infusion procedures Iron Iron Overload Kidney Licensing Liver Liver Cirrhosis Liver Fibrosis Liver diseases Maximum Tolerated Dose Measures Mediating Morbidity - disease rate National Institute on Alcohol Abuse and Alcoholism Organ Patients Peptide Fragments Peptides Pharmaceutical Preparations Phase Polyethylene Glycols Polymers Primary biliary cirrhosis Process Production Proteins Rattus Regimen Reticuloendothelial System Self Administration Serum Site Small Business Innovation Research Grant Stream Syringes Technology Testing Tissues Transforming Growth Factors Translations Vascular Permeabilities Virus Diseases Weight analytical method base copolymer design effective therapy efficacy testing experience in vivo inhibitor/antagonist interest intravenous injection liver transplantation molecular mass mortality nanocarrier non-alcoholic fatty liver outcome forecast pre-clinical preclinical study prevent public health relevance receptor subcutaneous success

项目摘要

DESCRIPTION (provided by applicant): This application pertains to the development of Medication for Hepatic Fibrosis. Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis. This application will be of interest to National institute of Alcohol Abuse and Alcoholism. Cirrhosis is long-term liver damage from the buildup of scar tissue (fibrosis) caused by infections, alcohol, excess fat, bile obstruction, and iron or cupper overload. Approximately 400,000 Americans suffer from liver cirrhosis. Cirrhosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Given the morbidity/mortality associated with this disease, there is an urgent need for translation of emerging anti-fibrotic molecules into effective therapies. Expediting clinical trials for compounds that have successfully undergone preclinical studies has the potential to make much needed medications available and reduce the need for liver transplantations. The scarring process in liver cirrhosis is mediated by Transforming Growth Factor 2 (TGF2) which is the most powerful fibrotic agent. Many known blockers of TGF2 are mostly peptides and proteins which cannot be easily developed onto drugs due to rapid degradation and kidney elimination once it reaches the blood stream. In this application, we propose to formulate three known TGF2 blocker peptides using advanced affinity-based nanocarrier technology. This will prevent rapid degradation and elimination and will maintain relatively constant concentration of active anti-fibrotic peptides in the blood, thus facilitating the transition of these peptide drugs from pre-clinical to clinical setting. We will synthesize nanocarriers appropriate for each of the anti-fibrotic peptides and we will determine affinity (1/Kd, where Kd is the dissociation constant) of the peptide for these nanocarriers. We will then formulate these peptides with appropriate nanocarriers and evaluate the in vivo pharmacokinetics in rats. Finally we will test the efficacy of formulated peptides in animal models of liver fibrosis. PUBLIC HEALTH RELEVANCE: Cirrhosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Cirrhosis is mediated by Transforming Growth Factor 2 (TGF2) and many known blockers of TGF2 action are peptides and proteins which cannot be easily developed onto drugs due to their rapid degradation and kidney elimination once they reach the blood stream. In this application, we propose to formulate known peptide blockers of TGF2 using advanced affinity-based nanocarrier technology that will prevent their rapid degradation and elimination and will maintain relatively constant concentration of anti-fibrotic peptides in the blood. This will facilitate the transition of these possible peptide drugs from pre-clinical to clinical settings.

描述（由申请人提供）：此申请与肝纤维化药物的开发有关。已建立的肝硬化的死亡率为34-66％，在很大程度上取决于肝硬化的原因。酒精性肝硬化的预后比原发性胆道肝硬化和肝炎引起的肝硬化。国家酒精滥用和酒精中毒研究所将感兴趣。肝硬化是由于感染，酒精，多余的脂肪，胆汁阻塞以及铁或饲料超负荷引起的疤痕组织（纤维化）的长期肝脏损害。大约40万美国人患有肝硬化。肝硬化会影响全世界数百万的患者，对于临床医生来说仍然是尚未解决的挑战。鉴于与这种疾病相关的发病率/死亡率，迫切需要将新兴的抗纤维化分子转化为有效的疗法。加快经过临床前研究的化合物的临床试验有可能使急需的药物可用并减少对肝移植的需求。肝硬化中的疤痕过程是通过转化生长因子2（TGF2）的介导的，该因子2（TGF2）是最强大的纤维化剂。许多已知的TGF2阻滞剂主要是肽和蛋白质，由于快速降解和肾脏消除，它们一旦到达血液，因此无法轻易地开发到药物上。在此应用程序中，我们建议使用基于高级亲和力的纳米载体技术制定三种已知的TGF2阻滞剂肽。这将防止快速降解和消除，并将维持血液中活性抗纤维化肽的相对恒定浓度，从而促进这些肽药物从临床前临床到临床环境的过渡。我们将合成适用于每种抗纤维化肽的纳米载体，并确定肽对这些纳米载体的亲和力（1/kd，Kd为解离常数）。然后，我们将使用适当的纳米载体制定这些肽，并评估大鼠体内药代动力学。最后，我们将测试配方肽在肝纤维化动物模型中的功效。公共卫生相关性：肝硬化会影响全球数百万的患者，对于临床医生来说仍然是尚未解决的挑战。肝硬化是通过转化生长因子2（TGF2）介导的，许多已知的TGF2作用阻滞剂是肽和蛋白质，由于药物的快速降解和肾脏消除，它们一旦到达血液，它们就无法轻易开发到药物上。在此应用中，我们建议使用基于高级亲和力的纳米载体技术制定已知的TGF2肽阻滞剂，以防止其快速降解和消除，并将保持相对恒定的抗纤维化肽浓度。这将促进这些可能的肽药物从临床前转变为临床环境。