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。肝硬化的10年死亡率为34-66%，主要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肝硬化差。该应用程序将引起国家酒精滥用和酒精中毒研究所的兴趣。肝硬化是由感染、酒精、过量脂肪、胆汁阻塞和铁或铜过量引起的疤痕组织（纤维化）积聚引起的长期肝脏损伤。大约40万美国人患有肝硬化。肝硬化影响着全世界数以百万计的患者，对临床医生来说仍然是一个未解决的挑战。鉴于这种疾病的发病率/死亡率，迫切需要将新兴的抗纤维化分子转化为有效的治疗方法。加快已成功通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。肝硬化的瘢痕形成过程是由转化生长因子2 （TGF2）介导的，它是最强大的纤维化因子。许多已知的TGF2阻滞剂大多是多肽和蛋白质，由于它们一旦进入血液就会迅速降解和肾脏消除，因此不容易开发成药物。在这个应用中，我们建议使用先进的基于亲和的纳米载体技术来制备三种已知的TGF2阻断肽。这将防止快速降解和消除，并将保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到临床环境的过渡。我们将为每一种抗纤维化肽合成合适的纳米载体，并确定这些纳米载体对肽的亲和力（1/Kd，其中Kd是解离常数）。然后，我们将用合适的纳米载体制备这些肽，并在大鼠体内评估其药代动力学。最后，我们将在肝纤维化动物模型中测试所配制肽的功效。