X-ray Targeted Therapeutic Genes within Nanoparticles

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。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结合。在拟议的目的中，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。我们将把基因表达系统传递到肿瘤中，研究基因产物的靶向性和生物学效应。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。在Aim 1中，我们将确定HGDPNHVGGSSV与辐照肿瘤微血管结合的机制。亲和纯化将用于鉴定与该肽结合的蛋白质。我们发现HGDPNHVGGSSV肽沉淀内皮蛋白。我们将验证该蛋白受体在辐照肿瘤内肽结合过程中的作用。在目标2中，我们将通过使用针对肿瘤血管内辐射诱导受体的肽-纳米颗粒偶联药物递送系统来确定辐射致敏药物的生物利用度。我们将把多肽结合到纳米颗粒上，并确定是否实现了肿瘤特异性结合。在Aim3中，我们将确定纳米颗粒结合HGDPNHVGGSSV照射的前列腺肿瘤是否有助于肿瘤特异性药物递送和疗效。我们将确定HGDPNHVGGSSV肽-纳米颗粒缀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。

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.