Nanotechnology Platforms for Targeting Ovarian Cancer Vasculature

项目总结(见说明)： 项目2标题：靶向卵巢癌血管的纳米技术平台 项目简介：卵巢癌仍然是最致命的恶性肿瘤。Targefing血管生成是一种特别吸引人的策略，因为假定内皮细胞具有遗传稳定性。最近在实体瘤患者中成功的抗血管生成治疗(如贝伐单抗)就是最好的例证。 然而，尽管有不良反应，大多数患者最终会发展为肿瘤进展，导致他们死亡。因此，需要新的ANFI-血管生成治疗策略。该项目的总体目标是开发基于纳米颗粒的新策略，以特定的肿瘤血管为靶点。我们建议利用两种生物相容的治疗纳米颗粒(壳聚糖和金纳米壳纳米颗粒)来传递治疗有效载荷(例如，siRNA)或近红外(NIR)激光介导的热烧蚀。 这些平台得到了集成方法的支持，这些方法使用经过放射设计的多阶段载体或从基于选择素结合的筛选文库中选择的表面配体(硫代核酸)选择性地传递到肿瘤血管系统。利用基因组学方法，我们已经在卵巢癌血管系统中确定了新的候选靶基因，这些基因将使用RNAi方法(目标1)进行靶向，因为许多基因很难用小分子或单抗抑制。在我们的初步发现中，基于使用新鲜分离的人卵巢癌或正常卵巢内皮细胞的反向选择策略，我们已经确定了硫代磷酸寡核苷酸适配子(硫代适配子)，它选择性地与肿瘤结合，但不与正常内皮细胞结合。在目标1中，我们将开发硫代核酸靶向纳米颗粒，用于选择性地传递治疗性siRNA。在我们关于纳米粒子的大小和形状在血管定位中的关键作用的初步发现的基础上，我们将在目标2中寻求合理的纳米粒子设计来靶向肿瘤血管。基于金基的纳米壳为使用近红外光进行热消融提供了独特的机会。在目标3中，我们将开发和表征使用靶向金纳米壳热消融卵巢癌血管的新方法。所有这三个目标都是相辅相成的，这项研究的发现应该可以为卵巢癌女性设计和移植新的治疗方法。

PROJECT SUMMARY (See instructions): PROJECT 2 TITLE: Nanotechnology Platforms for Targeting Ovarian Cancer Vasculature PROJECT SUMMARY: Ovarian cancer remains the most deadly malignancy. Targefing angiogenesis is a particulariy attracfive strategy because of the presumed genetic stability of endothelial cells. This is best illustrated by recent successes of anti-angiogenic therapy (e.g., bevacizumab) in patients with solid tumors. However, despite inifial responses, most patients eventually develop tumor progression resulting in their demise. Therefore, new anfi-angiogenesis therapeufic strategies are needed. The overall goal of this project is to develop novel nanoparticle-based strategies to target the tumor vasculature specifically. We propose to ufilize two types of biocompatible therapeufic nanoparticles (chitosan and gold nanoshell nanoparticles) for the delivery of therapeutic payloads (e.g., siRNA) or near-infrared (NIR) laser mediated thermal ablafion. These platforms are supported by Integrated approaches for selective delivery into the tumor vasculature using either rafionally designed mulfi-stage carriers or surface ligands (thioaptamers) selected from screening libraries based on selecfive binding. Using genomic approaches, we have identified novel candidate target genes in ovarian cancer vasculature that will be targeted using RNAi approaches (Aim 1) because many are difficult to inhibit with small molecules or monoclonal anfibodies. In our preliminary findings, we have identified thiophosphate oligonucleotide aptamers (thio-aptamers) that selecfively bind to tumor, but not to normal endothelial cells based on counter selection strategies using freshly isolated endothelial cells from human ovarian cancer or normal ovaries. In Aim 1, we will develop thioaptamertargeted nanoparticles for selecfive delivery of therapeufic siRNA. On the basis of our preliminary findings regarding the critical role of size and shape in vascular localization of nanoparticles, we will pursue rational design of nanoparticles for targeting the tumor vasculature in Aim 2. Gold-based nanoshells offer unique opportunities for thermal ablation using NIR light. In Aim 3, we will develop and characterize novel approaches for thermal ablation of ovarian cancer vasculature using targeted gold nanoshells. All three aims are complementary to each other and findings of this study should allow the design and translafion of new therapeufic approaches for women with ovarian cancer.