Nanoparticles Targeting Pancreatic Cancer

描述(申请人提供)：这项研究的目标是通过使用与癌症内可辐射诱导的受体结合的配体来实现肿瘤特异性的放射增敏药物的输送。提要。在所有肿瘤模型中，肿瘤血管内皮细胞对电离辐射的反应方式相似。因此，我们利用噬菌体展示文库来选择结合在几类肿瘤模型的微血管内的多肽配体。我们已经筛选了12个不同的多肽文库，这些文库包括展示在噬菌体上的不同长度的线状和环状多肽。我们已经完成了肿瘤特异性噬菌体的并列比较，发现展示的噬菌体HGDPNHVGGSSV多肽配体在低剂量辐射治疗后，在肿瘤微血管内持续结合(9天)。这种多肽配体在48小时内从循环中清除，并在肿瘤内特异性结合9天。肿瘤切片显示，该肽与肿瘤血管内皮细胞结合。我们的初步结果表明，Biotinylated-HGDPNHVGGSSV可沉淀一种内皮蛋白，该蛋白将在AIM 1中被鉴定。PHS 398(Rev.04/06)首席研究员：Hallahan，Dennis E.项目描述：在拟议的AIMS中，我们将表征HGDPNHVGGSSV在辐射微血管系统中结合的机制。我们还将研究这种多肽通过纳米颗粒递送载体在照射肿瘤的微血管内实现肿瘤特异性药物递送的有效性。最后，我们将把一个基因表达系统(放射增敏蛋白)输送到内皮部位，并研究该基因产物的靶向性和生物学效应。我们设想放射增敏药物可以在放射治疗过程中通过使用多肽偶联给药系统来针对肿瘤微血管。建议的目标将检验这样一种假设，即HGDPNHVGGSSV多肽偶联纳米颗粒为受辐射的肿瘤提供肿瘤特异性靶向药物输送。我们还将测试HGDPNHVGGSSV多肽与肿瘤微血管内皮细胞上辐射诱导蛋白结合的假设。

DESCRIPTION (provided by applicant): The goal of this research is to achieve tumor specific delivery of radiosensitizing drugs by use of ligands that bind to radiation-inducible receptors within cancer. Synopsis. The tumor vascular endothelium responds to ionizing radiation in a similar manner in all tumor models. We, therefore, utilized phage displayed libraries to select peptide ligands that bind within the microvasculature of several classes of tumor models. We have screened 12 different peptide libraries that consist of varying lengths of both linear and cyclic peptides displayed upon phage. We have completed side-by-side comparisons of tumor-specific phage and found that the phage-displayed HGDPNHVGGSSV peptide ligand has sustained binding (9 days) within the tumor microvasculature following treatment with low dose irradiation. This peptide ligand clears from the circulation within 48 hours and binds specifically within tumors for nine days. Tumor sections show that the peptide binds to the tumor vascular endothelium. Our Preliminary Results show that biotinylated-HGDPNHVGGSSV precipitates an endothelial protein that will be identified in Aim 1. PHS 398 (Rev. 04/06) Principal Investigator: Hallahan, Dennis E. PROJECT NARRATIVE: In the proposed Aims, we will characterize the mechanism of HGDPNHVGGSSV binding within irradiated microvasculature. We will also study the effectiveness of this peptide at achieving tumor specific drug delivery within the microvasculature of irradiated tumors by means of a nanoparticulate delivery vehicle. Finally, we will deliver a gene expression system (radiosensitizing protein) to the endothelium site and study targeting and biological effects of the gene product. We envision that radiation sensitizing drugs can be targeted specifically to tumor micro-vasculature by use of peptide conjugated drug delivery systems during radiotherapy. The proposed Aims will test the hypothesis that HGDPNHVGGSSV peptide-conjugated nanoparticles provide tumor specific targeting of drug delivery to irradiated tumors. We will also test the hypothesis that the HGDPNHVGGSSV peptide binds to radiation-inducible proteins on the tumor microvascular endothelium.