Translational Nanosystems for Improved Lung Cancer Treatment with Small Molecules

项目3：用于改善小分子非小细胞肺癌(NSCLC)肺癌治疗的翻译纳米系统(NSCLC)导致的患者死亡人数超过排在其后的三种癌症的总和。 大约70%的患者直到IV期转移性疾病才被诊断出来，而这些转移性疾病的预后非常差。铂类药物和紫杉醇的标准护理只能最小限度地延长生命，这是由于许多因素，包括配方限制、耐药性、转移治疗不善以及药物相关毒性。项目3采用了翻译管道方法，使用了一个优秀的转移性非小细胞肺癌原位小鼠模型，首次直接比较了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药物。这三种纳米粒独特的化学成分、药物释放特性、配方和表面将进行优化，然后在敏感和耐药的NSCLC细胞中进行测试。含有顺铂或紫杉醇的已开发药物NPs符合规定的性能和安全标准，将在建立的转移性、敏感或耐药的原位NSCLC模型中进行筛选。同时，利用靶向配基核心中开发的独特的表皮生长因子受体(EGFR)识别配体，NPs将被靶向肿瘤细胞。将与PK/PD Core合作进行复杂的药代动力学和体内药物传递的直接测量。药物NPs的体内疗效之后，将与动物研究核心和小动物成像核心合作，在原位模型中对含有荧光素酶的肺癌细胞进行发光检测。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目前的CCNE中开发和测试的三种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，可以设计出具有高包装效率和灵活的表面化学特性的形状和尺寸特定给药系统；以及3)PSQ-一种独特的无机/有机混合技术，将铂制剂包装在具有非常良好的药物释放能力的纳米颗粒中。在原位模型中取得成功结果之后，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)承诺提供100万美元，以加快IND支持研究中选定的药物NP产品的测试

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