Micellar Nanotherapeutics for Targeted Lung Cancer Therapy

描述（由申请人提供）：肺癌是美国男性和女性癌症死亡的主要原因。目前用于肺癌的细胞毒性化疗缺乏特异性和有效性，这为开发靶向治疗以实现更大的疗效和更少的副作用提供了动力。该应用的长期目标是开发聚合物胶束作为使能纳米医学平台，以实现肺癌的靶向治疗。疏水性药物将被装载在胶束核心内以克服低水溶性和差的药代动力学的限制。最近，我们证明了编码表面官能化的环状Arg-Gly-Asp（cRGD）肽的胶束在α（v）β（3）整联蛋白过表达的肿瘤内皮细胞中显著增加（>30倍）摄取，随后导致体内有效靶向实体瘤。在本申请中，我们将应用胶束技术将从噬菌体筛选中鉴定的一类新型肺癌靶向肽用于靶向肺癌细胞的特异性药物。分离的肽已显示出显著的结合亲和力（<nM）和细胞特异性（20-1000倍）以区分不同的细胞类型。我们的中心假设是，肺癌肽（LCP）编码的胶束将提供一个安全有效的治疗系统，肺癌的靶向治疗。为了验证这一假设，我们将进行以下三个具体的目的：（1）开发LCP编码的胶束，并在体外评估其对不同肺癌细胞的亲和力和特异性。(2)评价体内LCP编码胶束的药代动力学和肿瘤内分布。(3)验证LCP编码的胶束在体内携带原位人肺异种移植物的小鼠中的治疗功效。如果成功建立，这些胶束将提供一个强大的纳米医学平台，将影响肺癌临床治疗中新分子靶点的翻译。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer mortality for both men and women in the US. Current cytotoxic chemotherapy for lung cancer lacks specificity and efficacy, which provides an impetus to develop targeted therapies to achieve greater efficacy with fewer side effects. The long-term goal of this application is to develop polymeric micelles as an enabling nanomedicine platform to achieve targeted therapy for lung cancer. Hydrophobic drugs will be loaded inside the micelle cores to overcome limitations of low water solubility and poor pharmacokinetics. Recently, we demonstrated that micelles encoding surface functionalized cyclic Arg-Gly-Asp (cRGD) peptide have dramatically increased (>30 fold) uptake in alpha(v)beta(3) integrin-overexpressing tumor endothelial cells and subsequently resulted in efficient targeting to solid tumors in vivo. In this application, we will apply the micelle technology to incorporate a novel class of lung cancer targeting peptides identified from phage screening for specific drug targeting to lung cancer cells. The isolated peptides have demonstrated remarkable binding affinities (<nM) and cell specificities (20-1000 fold) to discriminate between different cell types. Our central hypothesis is that lung cancer peptide (LCP)-encoded micelles will provide a safe and efficacious therapeutic system for targeted therapy of lung cancer. To test this hypothesis, we will carry out the following three Specific Aims: (1) Develop LCP-encoded micelles and evaluate their affinity and specificity to different lung cancer cells in vitro. (2) Evaluate the pharmacokinetics and intratumoral distribution of LCP-encoded micelles in vivo. (3) Validate the therapeutic efficacy of LCP-encoded micelles in mice bearing orthotopic human lung xenografts in vivo. If successfully established, these micelles will provide a powerful nanomedicine platform that will impact the translation of novel molecular targets of lung cancer in clinical therapy.