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: 10602425
• 负责人: Oleh Taratula
• 金额: $ 43.74万
• 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/10602425
• 关键词: Activins; Address; Affect; Attenuated; Behavior; Behavioral; Binding; Cachexia; Cancer Model; Cancer Patient; Cause of Death; Cells; Cessation of life; Circulation; 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; 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; Play; Postoperative Complications; Production; Proliferating; 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; cancer cachexia; cancer therapy; chemotherapy; design; effective therapy; efficacious treatment; gene therapy; improved; intravenous administration; intravenous injection; lean body mass; morphogens; mouse model; multidisciplinary; muscle form; nanomedicine; nanoparticle; nanopolymer; nanotechnology platform; novel; novel therapeutics; overexpression; palliation; pancreatic ductal adenocarcinoma model; patient population; pharmacologic; preclinical study; preservation; prevent; receptor; skeletal muscle wasting; skeletal preservation; subcutaneous; systemic inflammatory response; translational potential; translational therapeutics; tumor; validation studies

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 恶氧化疾病是一种令人衰弱的综合征，发生在包括癌症在内的许多疾病中，其特征是 营养支持无法逆转骨骼肌质量（有或没有脂肪损失）的显着损失。 它最常见于胃（85％的患者），胰腺（83％）和肺（61％）癌症，最高30％ 这些患者人群中的死亡仅归因于病虫气。众多临床试验证实 浪费骨骼肌质量是卡希克西亚的标志，它是较短生存的原因 治疗结果，对化学疗法的毒性增加，术后并发症和身体障碍。 尽管做出了所有努力，目前尚无有效的疗法来防止缓存患者浪费肌肉。 一支具有互补专业知识，基因疗法和癌症专业知识的研究人员的多学科团队 恶病质将开发有效的治疗缓存相关的肌肉浪费。它将基于 专门设计的聚合物纳米颗粒是为了在肝细胞中输送Follistatin Messenger RNA（mRNA）之后 系统管理。递送的mRNA将指导肝细胞的细胞机械产生 Follistatin，一种分泌的糖蛋白，能够通过抑制肌抑制素来增加瘦肌肉质量 和激活素A.最后两个是生长分化因子，其血清浓度在 缓存状态，它们在负调节肌肉质量方面起着至关重要的作用。 研究小组已经开发了载有mRNA的纳米板，无毒并提高了血清 皮下注射后8小时内卵泡蛋白的水平。用野生型小鼠接受了 纳米植物的体重显着增加。为了进一步推进这项技术，目标 为：（i）增强已经开发的纳米颗粒向肝脏的递送，（ii）评估递送 纳米颗粒在具有人源肝的小鼠中的效率，（iii）验证治疗疗效 新型鼠胰腺腺癌（PDAC）和肺癌模型中的纳米颗粒显示出所有 人类病质的标志性特征。这些目标将以以下特定目的来解决：1 评估静脉内给药后mRNA负载的纳米颗粒的效率。 2。测试纳米板 在带有人源化肝脏的小鼠中。 3。确定纳米颗粒介导的卵泡蛋白mRNA是否递送 PDAC和肺癌的小鼠模型中的病原体减弱。 该项目完成后，研究小组将提供有力的证据，表明拟议的疗法将 保持肌肉质量并衰减胰腺和肺癌的小鼠病虫气的其他特征。这 该项目的长期影响是新颖治疗在医学实践中的成功应用 充分限制了包括肺和胰腺癌在内的各种癌症的死亡和苦难。