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：
7982954
负责人：
Russell J Mumper
金额：
$ 33.26万
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：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7982954
关键词：
A549 Animals Apoptosis Biodistribution CCNE1 gene 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 Printing Prodrugs Quality of life Rapid Access to Intervention Development Resistance Safety Schedule Screening procedure 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 efficacy immunogenicity improved in vivo killings luminescence meetings mouse model nanoparticle nanosystems neoplastic cell novel outcome forecast pre-clinical receptor mediated endocytosis 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, directiy 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 fiexible 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 ofthe drug NP product for eariy 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：用于改善小分子非小分子细胞肺癌（NSCLC）改善肺癌治疗的转化纳米系统杀死的患者更多的患者比下三种最高癌症的总和。直到预后不良的IV期转移性疾病，大约70％的患者才被诊断出。铂药和紫杉醇的护理标准仅由于许多因素，包括制剂限制，耐药性，转移治疗不良以及与药物相关的毒性，因此延长了生命。 Project 3采用了转化管道方法，使用了出色的转移性NSCLC的原始小鼠模型，这是第一次进行指导比较三种不同的纳米颗粒（NP）方法，以提供有效的小分子化学疗法。三个NP的独特化学，组成，药物释放特性，配方和表面将优化，然后在敏感和抗性的NSCLC细胞中进行测试。开发的含有顺铂或Paditaxel的药物NP，符合定义的性能和安全标准，将在已建立的原位NSCLC模型中进行筛选，该模型是转移性且敏感或抗性的。同时，使用独特的表皮生长因子受体（EGFR）识别配体在靶向配体核心中开发的独特的表皮生长因子受体（EGFR）识别配体将靶向肿瘤细胞。将与PK/PD核心合作进行复杂的药代动力学和Vivo药物输送的直接测量。在与动物研究核心和小动物成像核心合作，将药物NP的体内疗效在原位模型中对含有肺癌细胞的荧光素酶进行发光检测。 CT/PET扫描将确认积极的结果。该项目的优势是其项目管理方法以及在我们当前CCNE中开发和测试的三个核心纳米技术平台的比较； 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 fiexible 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发布功能。在原位模型中，将使用UNC-Chapel Hill，NCI NCL/RAID和/或初创公司的支持，开发了原位模型中的成功结果。大学癌症研究基金（UCRF）已承诺100万美元，以加速选定的药物NP产品测试