Translational Nanosystems for Improved Lung Cancer Treatment with Small Molecules

项目三：非小细胞肺癌（NSCLC）是一种常见的恶性肿瘤，其死亡人数超过其他三种癌症的总和。 大约70%的患者直到预后非常差的IV期转移性疾病才被诊断出来。由于多种因素，包括配方限制、耐药性、转移瘤治疗效果不佳和药物相关毒性，铂类药物和紫杉醇的标准治疗只能最低限度地延长生命。项目3采用转化管道方法，使用转移性NSCLC的优良原位小鼠模型，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。这三种纳米粒的独特化学、组成、药物释放特性、配方和表面将进行优化，然后在敏感和耐药NSCLC细胞中进行测试。将在已建立的转移性原位NSCLC模型（敏感或耐药）中筛选符合规定的性能和安全性标准的含顺铂或紫杉醇的已开发药物NP。同时，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，将NP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，在原位模型中对含荧光素酶的肺癌细胞进行发光检测，以跟踪药物NP的体内疗效。阳性结果将通过CT/PET扫描确认。该项目的优势是其项目管理方法和比较三个核心纳米技术平台的开发和测试在我们目前的CCNE; 1）BTM -一种高度可扩展的油芯纳米胶囊方法，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柔性表面化学的形状和尺寸特定的递送系统，和3）PSQ -一种独特的无机/有机混合技术，其将铂剂包装在可靶向的纳米颗粒中并具有非常有利的药物释放能力。原位模型取得成功结果后，将利用UNC-Chapel Hill、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100万美元，以加速IND使能研究中选定的药物NP产品测试

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