Translational Nanosystems for Improved Lung Cancer Treatment with Small Molecules

利用小分子改善肺癌治疗的转化纳米系统

基本信息

批准号：
8540377
负责人：
Russell J Mumper
金额：
$ 30.16万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8540377
关键词：
A549 Animals Apoptosis Biodistribution CCNE1 gene Cancer Center Cancer Model Cancer Patient Cancer cell line Caring Cause of Death Cells Characteristics Chemistry Cisplatin Collaborations Commit Detection Developed Countries Development Diagnosis Disease Dose Drug Delivery Systems Drug Formulations Drug Kinetics Drug Stability Engineering Epidermal Growth Factor Receptor Funding Human Hybrids Image Inflammation Instruction Laboratories Life Ligands Longevity Luciferases Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Maximum Tolerated Dose Measurement Mitochondria Modeling Multi-Drug Resistance Mus Nanotechnology Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oils Organ PET/CT scan Paclitaxel Patients Performance Pharmaceutical Preparations Phase Platinum Platinum Compounds Positron-Emission Tomography Prodrugs Quality of life Rapid Access to Intervention Development Resistance Safety Schedule Shapes Staging Surface System Techniques Technology Testing Time Toxic effect Universities Xenograft Model analytical method anticancer research cancer cell cancer therapy chemotherapy cytotoxicity density drug development drug efficacy flexibility immunogenicity improved in vivo killings luminescence meetings mouse model nanocapsule nanoparticle nanosystems neoplastic cell novel outcome forecast pre-clinical receptor mediated endocytosis screening small molecule standard of care uptake

项目摘要

Project 3: Translational Nanosystems for Improved Lung Cancer Treatment with Small Molecules Non-small cell lung cancer (NSCLC) kills more patients than the next three highest cancers combined. Approximately 70% of the patients are not diagnosed until stage IV metastatic disease where the prognosis is very poor. The standard-of-care with a platinum drug and Taxol only extends life minimally due to many factors including formulation limitations, resistance, poor treatment of metastases, and drug related toxicities. Project 3 takes a translational pipeline approach, using an excellent orthotopic mouse model of metastatic NSCLC to, for the first time, directly compare three distinct nanoparticle (NP) approaches to deliver otherwise effective small molecule chemotherapies. The unique chemistry, composition, drug release characteristics, formulation and surfaces of the three NPs will optimized and then tested in sensitive and resistant NSCLC cells. Developed drug NPs containing either cisplatin or paditaxel, meeting defined performance and safety criteria, will be screened in an established orthotopic NSCLC model that is metastatic and either sensitive or resistant. In parallel, NPs will be targeted to tumor cells using unique epidermal growth factor receptor (EGFR) recognition ligands developed in the Targeting Ligand Core. Sophisticated pharmacokinetics and direct measurement of in-vivo drug delivery will be performed In collaboration with the PK/PD Core. In-vivo efficacy of drug NPs will be followed with luminescence detection of the luciferase containing lung cancer cells in the orthotopic model in partnership with the Animal Studies Core and the Small Animal Imaging Core. Positive results will be confirmed by CT/PET scanning. The strength of the project is its project management approach and the comparison of three core nanotechnology platforms developed and tested In our current CCNE; 1) BTM - a highly scalable oil-core nanocapsule approach with unique activity in multidrug resistant expressing cells and mouse models, 2) PRINT - a 'top-down' fabrication technique to engineer a shape and size specific delivery system with high packaging efficiency and flexible surface chemistry, and 3) PSQ - a unique inorganic/organic hybrid technology that packages platinum agents in nanoparticles that are targetable and have very favorable drug release capabilities. Successful results in the orthotopic models will be followed by development of the drug NP product for early phase human trials using UNC-Chapel Hill, NCI NCL/RAID and/or start-up company support. The University Cancer Research Fund (UCRF) has committed $1 million to accelerate selected drug NP product testing in IND enabling studies

项目 3：利用小分子改善肺癌治疗的转化纳米系统非小细胞肺癌 (NSCLC) 导致的死亡人数比排名第二的三种癌症的总和还多。大约70%的患者直到IV期转移性疾病才被诊断出来，此时预后非常差。由于许多因素，包括配方限制、耐药性、转移治疗效果不佳以及药物相关毒性等，铂类药物和紫杉醇的护理标准仅能有限地延长生命。项目 3 采用转化管道方法，使用优秀的转移性非小细胞肺癌原位小鼠模型，首次直接比较三种不同的纳米颗粒 (NP) 方法，以提供其他有效的小分子化疗。三种纳米颗粒独特的化学、成分、药物释放特性、配方和表面将被优化，然后在敏感和耐药的 NSCLC 细胞中进行测试。已开发的含有顺铂或帕紫杉醇的药物纳米颗粒，满足既定的性能和安全标准，将在已建立的转移性、敏感或耐药的原位非小细胞肺癌模型中进行筛选。与此同时，纳米颗粒将使用靶向配体核心中开发的独特表皮生长因子受体（EGFR）识别配体靶向肿瘤细胞。将与 PK/PD 核心合作进行复杂的药代动力学和体内药物递送的直接测量。将与动物研究核心和小动物成像核心合作，通过在原位模型中对含有荧光素酶的肺癌细胞进行发光检测来跟踪药物纳米颗粒的体内功效。阳性结果将通过 CT/PET 扫描确认。该项目的优势在于其项目管理方法以及在我们当前的 CCNE 中开发和测试的三个核心纳米技术平台的比较； 1) BTM - 一种高度可扩展的油核纳米胶囊方法，在多药耐药表达细胞和小鼠模型中具有独特的活性，2) PRINT - 一种“自上而下”的制造技术，用于设计具有高包装效率和形状和尺寸的特定递送系统灵活的表面化学，以及 3) PSQ - 一种独特的无机/有机混合技术，将铂制剂包装在可靶向且具有非常有利的药物释放能力的纳米颗粒中。原位模型取得成功后，将利用北卡罗来纳大学教堂山分校、NCI NCL/RAID 和/或初创公司的支持开发用于早期人体试验的药物 NP 产品。大学癌症研究基金 (UCRF) 已承诺投入 100 万美元，以加速 IND 中选定的药物 NP 产品测试，从而实现研究