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

• 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
• 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

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）：本申请涉及肝纤维化药物的开发。已确诊的肝硬化的 10 年死亡率为 34-66%，很大程度上取决于肝硬化的病因；酒精性肝硬化的预后比原发性胆汁性肝硬化和肝炎性肝硬化差。国家酒精滥用和酒精中毒研究所将对此应用程序感兴趣。肝硬化是由感染、酒精、过量脂肪、胆汁阻塞以及铁或铜超载引起的疤痕组织堆积（纤维化）造成的长期肝损伤。大约有 40 万美国人患有肝硬化。肝硬化影响着全世界数百万患者，对于临床医生来说仍然是一个尚未解决的挑战。考虑到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。加快已成功进行临床前研究的化合物的临床试验有可能提供急需的药物并减少肝移植的需求。肝硬化的疤痕形成过程是由转化生长因子 2 (TGF2) 介导的，TGF2 是最强大的纤维化因子。许多已知的 TGF2 阻断剂大多是肽和蛋白质，由于一旦到达血流就会快速降解和肾脏消除，因此不能轻易开发成药物。在此应用中，我们建议使用先进的基于亲和力的纳米载体技术配制三种已知的 TGF2 阻断肽。这将防止快速降解和消除，并使血液中活性抗纤维化肽的浓度保持相对恒定，从而促进这些肽药物从临床前到临床的过渡。我们将合成适合每种抗纤维化肽的纳米载体，并确定肽与这些纳米载体的亲和力（1/Kd，其中Kd是解离常数）。然后我们将用适当的纳米载体配制这些肽并评估大鼠体内的药代动力学。最后，我们将测试配制的肽在肝纤维化动物模型中的功效。 公共卫生相关性：肝硬化影响着全世界数百万患者，对于临床医生来说仍然是一个尚未解决的挑战。肝硬化是由转化生长因子 2 (TGF2) 介导的，许多已知的 TGF2 作用阻断剂是肽和蛋白质，它们一旦进入血流就会迅速降解并被肾脏消除，因此不容易开发成药物。在此应用中，我们建议使用先进的基于亲和力的纳米载体技术配制已知的 TGF2 肽阻断剂，以防止其快速降解和消除，并维持血液中抗纤维化肽的相对恒定浓度。这将促进这些可能的肽药物从临床前到临床的过渡。