Preclinical Development and Testing of Multifunctional Tumor-Targeted Hybrid Nano

描述(申请人提供)：肺癌是美国最主要的死亡原因。2008年将诊断出约213,380例新的肺癌病例，每年死亡人数超过160,390人。尽管最近在治疗策略上取得了进展，但总体5年存活率不到16%。因此，迫切需要新的治疗方法。在了解癌症“分子驱动因素”方面的进展导致了针对肺癌的小分子抑制剂和生物制品的测试，如西妥昔单抗、吉非替尼和厄洛替尼，所有这些药物都针对表皮生长因子受体(EGFR)。尽管FDA批准的EGFR抑制剂正在进行广泛的测试，但一个主要的临床问题是无法证明这些抑制剂针对肿瘤。此外，这些抑制剂在治疗过程中和治疗后产生的治疗效果不能迅速确定。因此，患者可能会对无效的治疗持续较长时间。为了克服目前癌症治疗的局限性，改善健康，发展和加快纳米技术和纳米材料等生物医学技术的应用是必要的。这些技术的发展将为肺癌的治疗提供一个新的范式。关于纳米粒子对分子成像、药物输送或癌症治疗有用的报道已经存在。然而，开发和测试多功能纳米粒子，使其能够进行分子成像和肺部肿瘤的治疗，目前还没有报道，这是有必要的。在目前的应用中，我们建议进行初步的可行性研究，以肺癌为模型测试一种新型的肿瘤靶向多功能纳米颗粒。我们的纳米颗粒由包覆金的超顺磁性铁(SPIO)核组成，创建了一种用于磁共振成像(MRI)和光学成像的铁-氧化物/金杂化材料。临床批准的抗EGFR抗体(西妥昔单抗)被装饰在金纳米颗粒的表面，作为靶向部分和治疗剂。我们假设我们的肿瘤靶向多功能纳米颗粒将选择性地靶向表达EGFR的肿瘤细胞，并产生可通过非侵入性成像监测的治疗效果。为了验证我们的假设，我们确定了两个特定的目标：特定的目标1：针对不同水平表达EGFR的人肺癌细胞的EGFR靶向多功能纳米粒子的分子表征，并在体外与正常细胞进行比较。特定目的2：检测EGFR靶向多功能纳米粒对EGFR阳性和阴性肺癌移植瘤的体内疗效。本申请中提出的特定目标的目标将通过利用分子、细胞和动物模型来实现。拟议的可行性研究的结果将导致深入的临床前研究，并最终转化为用于肺癌治疗的肿瘤靶向多功能纳米颗粒的临床测试。 与公共健康相关：这项新颖和创新的研究建议开发和测试肿瘤靶向的金铁杂化纳米颗粒，这种纳米颗粒具有多功能特性，可用于肺癌的分子成像和治疗。我们的研究将导致先进的临床前研究，并最终在临床上测试这些多功能纳米颗粒。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of death in the United States. About 213,380 new cases of lung cancer will be diagnosed in 2008 accounting for over 160,390 deaths annually. Despite recent advances in treatment strategies, the overall 5-year survival rate of less than 16%. Therefore, novel therapies are urgently needed. Progress in understanding the "molecular drivers" of cancer has resulted in the testing of small molecule inhibitors and biologics for lung cancer, such as cetuximab, gefitinib, and erlotinib, all targeting the epidermal growth factor receptor (EGFR). Although the FDA approved EGFR inhibitors are being widely tested, a major clinical problem is the inability to demonstrate that the inhibitors targeted the tumors. Furthermore, the therapeutic effect produced by these inhibitors during and after treatment cannot be determined rapidly. Therefore, patients may continue for extended periods of time on an ineffective treatment. To overcome the current limitations of cancer treatment and improve the health, development and acceleration of the application of biomedical technologies such as nanotechnology and nanomaterials are warranted. Development of such technologies will provide a new paradigm for lung cancer treatment. Reports on nanoparticles that are useful either for molecular imaging, drug delivery, or therapy of cancer exist. However, development and testing of multifunctional nanoparticles that enables both molecular imaging and therapy of lung tumors have not been reported and is warranted. In the present application we propose to conduct pilot feasibility studies to test a novel tumor-targeted multifunctional nanoparticle using lung cancer as a model. Our nanoparticles are composed of a superparamagnetic iron (SPIO) core coated with gold creating an iron-oxide/gold hybrid useful for Magnetic Resonance Imaging (MRI) and optical imaging. The clinically approved anti-EGFR antibody (cetuximab) is decorated on the surface of gold nanoparticles that serves both as a targeting moiety and therapeutic agent. We hypothesize that our tumor-targeted multifunctional nanoparticles will selectively target EGFR-expressing tumor cells and produce a therapeutic effect that can be monitored by non-invasive imaging. To test our hypothesis we have identified two specific aims: Specific Aim 1: Molecular characterization of EGFR-targeted multifunctional nanoparticles against human lung cancer cells expressing EGFR at different levels and comparison with normal cells in vitro. Specific Aim 2: Test the in vivo efficacy of EGFR-targeted multifunctional nanoparticles against EGFR-positive and -negative lung tumor xenografts. The goals of the specific aims proposed in this application will be achieved by utilizing molecular, cellular and animal models. Results from the proposed feasibility studies will lead to advanced preclinical studies and finally translate to clinical testing of the tumor-targeted multifunctional nanoparticles for lung cancer treatment. Public Health Relevance: This novel and innovative study proposes to develop and test tumor-targeted gold-iron hybrid nanoparticles that have multifunctional properties useful for molecular imaging of and therapy of lung cancer. Our studies will lead to advanced preclinical studies and ultimately testing of these multifunctional nanoparticles in the clinic.