Novel Nanomedicine-Based Therapeutic Approach For Treatment of Cancer Cachexia

治疗癌症恶病质的新型纳米医学治疗方法

• 批准号: 10400155
• 负责人: Oleh Taratula
• 金额: $ 44.64万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400155
• 关键词: Activins; Address; Affect; Attenuated; Behavior; Behavioral; Binding; Blood Circulation; Cachexia; Cancer Model; Cancer Patient; Cause of Death; Cells; Cessation of life; Clinical Trials; Data; Differentiation and Growth; Disease; Drug Delivery Systems; Exhibits; Fatty acid glycerol esters; Follistatin; GDF8 gene; Gene Delivery; Glycoproteins; Goals; Health; Hepatocyte; Hormone secretion; Hormones; Human; Impairment; Inflammation; Injections; Intravenous; Kupffer Cells; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Medical; Messenger RNA; Metabolic; Modeling; Mus; Muscular Atrophy; Myoblasts; Nutritional Support; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Persons; Pharmacology; Play; Polymers; Postoperative Complications; Production; Proteins; Quality of life; Research; Research Personnel; Role; Route; Serum; Skeletal Muscle; Stomach; Subcutaneous Injections; Syndrome; System; Technology; Testing; Therapeutic; Thinness; Toxic effect; Treatment Efficacy; Treatment outcome; Wild Type Mouse; activin A; antagonist; attributable mortality; base; cancer cachexia; cancer therapy; chemotherapy; design; effective therapy; efficacious treatment; gene therapy; improved; intravenous administration; lean body mass; morphogens; mouse model; multidisciplinary; muscle form; nanomedicine; nanoparticle; nanotechnology platform; novel; novel therapeutics; overexpression; palliation; pancreatic ductal adenocarcinoma model; patient population; preclinical study; preservation; prevent; receptor; skeletal muscle wasting; skeletal preservation; subcutaneous; systemic inflammatory response; translational potential; translational therapeutics; tumor

Project Summary Cachexia is a debilitating syndrome that occurs in numerous diseases including cancer and is characterized by a significant loss of skeletal muscle mass (with or without fat loss) that cannot be reversed by nutritional support. It most commonly occurs in gastric (85% of patients), pancreatic (83%) and lung (61%) cancers and up to 30% of deaths in these patient populations are attributable to cachexia alone. The numerous clinical trials confirmed that wasting of skeletal muscle mass is the hallmark of cachexia and it is responsible for shorter survival, poor treatment outcomes, increased toxicity to chemotherapy, post-operative complications, and physical impairment. Despite all efforts, there are currently no effective therapies to prevent muscle wasting in cachectic patients. A multidisciplinary team of investigators with complementary expertise in drug delivery, gene therapy, and cancer cachexia will develop an effective treatment for cachexia-associated muscle wasting. It will be based on polymeric nanoparticles specifically designed to deliver follistatin messenger RNA (mRNA) to the liver cells after systemic administration. The delivered mRNA will direct the cellular machinery of the liver cells to produce follistatin, a secreted glycoprotein that is capable of increasing lean muscle mass through inhibition of myostatin and Activin A. The last two are growth differentiation factors whose serum concentrations are increased in cachectic states, and they play a critical role in negatively regulating muscle mass. The research team has already developed mRNA-loaded nanoplatform that is non-toxic and elevates serum levels of follistatin protein within 8 h after subcutaneous injection. Wild-type mice that were treated with the nanoplatform exhibited significant increases in lean body mass. To further advance this technology, the goals are: (i) to enhance the delivery of the already developed nanoparticles to the liver, (ii) to evaluate delivery efficiency of the nanoparticles in mice with the humanized liver, and (iii) to validate therapeutic efficacy of the nanoparticles in novel murine pancreatic ductal adenocarcinoma (PDAC) and lung cancer models that exhibit all the hallmark features of human cachexia. These goals will be addressed with the following Specific Aims: 1 Evaluate the efficiency of mRNA-loaded nanoparticles following intravenous administration. 2. Test nanoplatform in mice with the humanized liver. 3. Determine whether nanoparticle-mediated delivery of follistatin mRNA attenuates cachexia in mouse models of PDAC and lung cancer. At the completion of this project, the research team will produce strong evidence that the proposed therapy will preserve muscle mass and attenuate other features of cachexia in mice with pancreatic and lung cancers. The long-term impact of this project is the successful application of the novel treatment in medical practice to sufficiently limit death and suffering from various cancers including lung and pancreatic cancers.

项目摘要 恶病质是一种衰弱综合征，发生在包括癌症在内的许多疾病中，其特征在于： 骨骼肌质量的显著损失（有或没有脂肪损失），不能通过营养支持逆转。 最常见于胃癌（85%的患者）、胰腺癌（83%）和肺癌（61%）， 这些患者人群的死亡仅归因于恶病质。大量的临床试验证实 骨骼肌质量的消耗是恶病质的标志， 治疗结果、化疗毒性增加、术后并发症和身体损伤。 尽管所有的努力，目前没有有效的治疗方法来防止恶病质患者的肌肉萎缩。 一个多学科的研究团队，在药物输送、基因治疗和癌症方面具有互补的专业知识。 恶病质将开发出恶病质相关的肌肉消耗的有效治疗。它将基于 聚合物纳米颗粒，其被专门设计用于在施用后将卵泡抑素信使RNA（mRNA）递送至肝细胞， 系统管理。递送的mRNA将指导肝细胞的细胞机器产生 卵泡抑素，一种分泌的糖蛋白，能够通过抑制肌肉生长抑制素增加瘦肌肉质量 激活素A。最后两种是生长分化因子，其血清浓度在哺乳动物中增加。 恶病质状态，它们在负调节肌肉质量中起着关键作用。 该研究小组已经开发出了无毒并提高血清的mRNA负载纳米平台 皮下注射后8 h内卵泡抑素蛋白水平。野生型小鼠， 纳米平台表现出瘦体重的显著增加。为了进一步推进这项技术，目标 （i）增强已经开发的纳米颗粒向肝脏的递送，（ii）评估递送 （iii）验证纳米颗粒在具有人源化肝脏的小鼠中的治疗功效， 在新型鼠胰腺导管腺癌（PDAC）和肺癌模型中， 人类恶病质的标志性特征这些目标将通过以下具体目标来实现：1 评价静脉内给药后装载mRNA的纳米颗粒的有效性。2.测试纳米平台 人类化肝脏的小鼠。3.确定纳米颗粒介导的卵泡抑素mRNA的递送 减轻PDAC和肺癌小鼠模型中的恶病质。 在这个项目完成后，研究小组将提出强有力的证据，证明所提出的治疗将 在胰腺癌和肺癌小鼠中保留肌肉质量并减轻恶病质的其他特征。的 该项目的长期影响是在医疗实践中成功应用新疗法， 足以限制死亡和罹患各种癌症，包括肺癌和胰腺癌。