Nanoparticles Targeting Pancreatic Cancer

描述（由申请人提供）：本研究的目标是通过使用与癌症内辐射诱导受体结合的配体来实现放射致敏药物的肿瘤特异性递送。剧情简介。肿瘤血管内皮对电离辐射的反应在所有肿瘤模型中都是相似的。因此，我们利用噬菌体展示文库来选择结合在几种肿瘤模型微血管内的肽配体。我们筛选了12种不同的肽库，包括不同长度的线性和环状肽显示在噬菌体上。我们完成了肿瘤特异性噬菌体的并排比较，发现在低剂量照射治疗后，噬菌体显示的HGDPNHVGGSSV肽配体在肿瘤微血管内持续结合（9天）。这种肽配体在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结合。我们的初步结果表明，生物素化的hgdpnhvggssv沉淀了一种内皮蛋白，该蛋白将在Aim 1中鉴定。项目描述：在拟议的目标中，我们将表征HGDPNHVGGSSV在辐照微血管内结合的机制。我们还将研究这种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）传递到内皮细胞部位，并研究该基因产物的靶向性和生物学效应。我们设想放射致敏药物可以通过在放射治疗期间使用肽偶联药物递送系统特异性靶向肿瘤微血管。提出的目的将验证HGDPNHVGGSSV肽缀合纳米颗粒为照射肿瘤提供肿瘤特异性靶向药物递送的假设。我们还将验证HGDPNHVGGSSV肽与肿瘤微血管内皮上的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.