Preclinical Development and Testing of Multifunctional Tumor-Targeted Hybrid Nano

描述（由申请人提供）：肺癌是美国死亡的主要原因。在2008年，将会有大约213,380个新肺癌病例被诊断出来，每年有超过160,390人死亡。尽管最近在治疗策略方面取得了进展，但总体5年生存率仍低于16%。因此，迫切需要新的治疗方法。在了解癌症的“分子驱动因素”方面取得的进展导致了肺癌小分子抑制剂和生物制剂的测试，如西妥昔单抗、吉非替尼和厄洛替尼，它们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，这些抑制剂在治疗期间和治疗后产生的治疗效果不能快速确定。因此，患者可能会在一种无效的治疗上持续很长一段时间。为了克服目前癌症治疗的局限性，改善健康，有必要开发和加速生物医学技术的应用，如纳米技术和纳米材料。这些技术的发展将为肺癌治疗提供一个新的范例。关于纳米颗粒在分子成像、药物传递或癌症治疗中有用的报道已经存在。然而，开发和测试多功能纳米颗粒，使分子成像和治疗肺肿瘤尚未报道，是有必要的。在目前的应用中，我们建议进行试点可行性研究，以肺癌为模型，测试一种新的肿瘤靶向多功能纳米颗粒。我们的纳米颗粒由包裹有金的超顺磁性铁（SPIO）核心组成，形成一种氧化铁/金混合物，可用于磁共振成像（MRI）和光学成像。临床批准的抗egfr抗体（西妥昔单抗）修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：特定目标1：靶向EGFR的多功能纳米颗粒的分子特征，针对不同水平表达EGFR的人肺癌细胞，并在体外与正常细胞进行比较。特异性目的2：测试egfr靶向多功能纳米颗粒对egfr阳性和阴性肺肿瘤异种移植物的体内疗效。在本应用程序中提出的具体目标将通过利用分子，细胞和动物模型来实现。可行性研究的结果将引导临床前研究，并最终转化为肿瘤靶向多功能纳米颗粒用于肺癌治疗的临床试验。

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.