X-ray Targeted Therapeutic Genes within Nanoparticles

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。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。我们已经完成了肿瘤特异性噬菌体的并列比较，发现噬菌体展示的HGDPNHVGGSSV多肽在低剂量辐射治疗后，在肿瘤微血管内持续结合(9天)。肿瘤切片显示，该肽与肿瘤血管内皮细胞结合。在建议的AIMS中，我们将表征HGDPNHVGGSSV在照射的微血管内结合的机制。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。我们将向肿瘤运送一个基因表达系统，并研究该基因产物的靶向性和生物学效应。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。在目标1中，我们将确定HGDPNHVGGSSV与照射的肿瘤微血管结合的机制。亲和纯化将用于鉴定与该多肽结合的蛋白质。我们已经发现，HGDPNHVGGSSV多肽沉淀一种内皮蛋白。我们将验证这种蛋白受体在辐射肿瘤中肽结合过程中的作用。在目标2中，我们将利用靶向肿瘤血管内辐射诱导受体的多肽-纳米颗粒偶联给药系统来确定辐射增敏药物的生物利用度。我们将多肽与纳米颗粒偶联，并确定是否实现了肿瘤特异性结合。在AIM3中，我们将确定纳米粒子偶联HGDPNHVGGSSV是否有助于肿瘤特异性药物的传递和疗效。我们将确定HGDPNHVGGSSV多肽-纳米颗粒结合物是否实现肿瘤特异性结合并保持其生物活性。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。

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. 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 completed side-by-side comparisons of tumor-specific phage and found that the phage-displayed HGDPNHVGGSSV peptide has sustained binding (9 days) within the tumor microvasculature following treatment with low dose irradiation. Tumor sections show that the peptide binds to the tumor vascular endothelium. 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. We will deliver a gene expression system to the tumor and study targeting and biological effects of the gene product. The proposed Aims will test the hypothesis that HGDPNHVGGSSV peptide-conjugated nanoparticles provide tumor specific targeting of drug delivery to irradiated tumors. In Aim 1, we will determine the mechanisms by which HGDPNHVGGSSV binds to irradiated tumor microvasculature. Affinity purification will be used to identify proteins that bind to this peptide. We have found that the HGDPNHVGGSSV peptide precipitates an endothelial protein. We will verify the role of this protein receptor during peptide binding within irradiated tumors. In Aim 2, we will determine the bioavailability of radiation sensitizing drugs by use of peptide-nanoparticle conjugated drug delivery systems targeted to radiation- inducible receptors within tumor vessels. We will conjugate peptides to nanoparticles and determine whether tumor-specific binding is achieved. In Aim3, we will determine whether tumor specific drug delivery and efficacy is facilitated by nanoparticle conjugation to HGDPNHVGGSSV irradiated prostate tumors. We will determine whether HGDPNHVGGSSV peptide-nanoparticle conjugates achieve tumor specific binding and maintains its biological activity. We envision that radiation sensitizing drugs can be targeted specifically to tumor micro-vasculature by use of peptide conjugated drug delivery systems during radiotherapy.