Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma.
Targeted nanoparticles for imaging incipient pancreatic ductal adenocarcinoma.
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DOI：
10.1371/journal.pmed.0050085
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发表时间：
2008-04-15
期刊：
影响因子：
15.8
通讯作者：
Weissleder, Ralph
中科院分区：
文献类型：
--
作者：
Kelly, Kimberly A.;Bardeesy, Nabeel;Anbazhagan, Rajesh;Gurumurthy, Sushma;Berger, Justin;Alencar, Herlen;DePinho, Ronald A.;Mahmood, Umar;Weissleder, Ralph
胰腺导管腺癌（PDAC）的预后极差，通常在诊断时就出现转移，并对现有疗法表现出严重的耐药性。针对早期 PDAC 的分子标记和成像探针的开发将使早期检测成为可能，并指导干预疗法的开发。在这里，我们试图鉴定新型分子标记并测试它们作为靶向显像剂的潜力。在此，在 PDAC 小鼠模型中使用噬菌体展示方法来筛选与 PDAC 细胞上的细胞表面抗原特异性结合的肽。这些筛选产生了一个在体外将 PDAC 细胞与正常胰管细胞区分开来的基序，经过蛋白质组学分析，将 plectin-1 鉴定为 PDAC 的新型生物标志物。为了评估其在体内成像的效用，将 plectin-1 靶向肽 (PTP) 与磁荧光纳米粒子缀合。与活体共聚焦显微镜和 MRI 相结合，这些纳米颗粒能够检测工程小鼠模型中的小 PDAC 和前体病变。我们的方法利用了明确定义的 PDAC 模型，能够快速识别和验证 PTP。开发的特异性成像探针，以及 plectin-1 作为新型生物标志物的发现，可能在人类 PDAC 的诊断和治疗中具有临床实用性。 Kimberly Kelly 及其同事描述了 plectin-1 作为胰腺导管腺癌新型生物标志物的发现，以及随后使用该标志物开发的特定成像探针。胰腺癌是美国癌症相关死亡的主要原因。与所有癌症一样，当细胞由于基因变化（突变）而开始不受控制地生长并在体内移动（转移）时，就会发生癌症。如果早期发现胰腺癌，手术切除肿瘤有时可以治愈。不幸的是，这种癌症在早期阶段很少引起任何症状，而它最终引起的症状——黄疸、腹部和背部疼痛以及体重减轻——也出现在其他疾病中。此外，尽管磁共振成像 (MRI) 或其他非侵入性成像技术可用于观察胰腺，但当肿瘤大到足以在 MRI 扫描中显示出来时，它们通常已经扩散。因此，在大多数患者中，诊断时胰腺癌已处于晚期，因此手术不再有用。这些患者接受放疗和化疗，但这些治疗很少能治愈，大多数患者在诊断后一年内死亡。如果能够在转移之前发现更多的胰腺癌，那么应该可以延长患有此类癌症的患者的预期寿命。早期检测方法对于监测胰腺癌高风险人群特别有用。其中包括患有某些遗传性癌症综合征、胰腺炎（胰腺炎症）和糖尿病的人。由于癌细胞有许多突变，它们在细胞表面表达与正常细胞不同的蛋白质。如果能够识别这些蛋白质，就有可能开发出一种“成像探针”——一种与仅在癌细胞上发现的蛋白质结合的分子，并且可以通过 MRI 等方法进行检测——用于早期检测胰腺癌。在这项研究中，研究人员使用一种称为“噬菌体展示”的技术来识别几种在胰腺癌细胞发育早期特异性结合的肽（氨基酸的短序列，蛋白质的组成部分）。然后他们研究了从这些肽之一开发成像探针的可能性。研究人员从人类胰腺导管腺癌（PDAC；最常见的胰腺癌类型）小鼠模型中分离出早期胰腺癌细胞。然后，通过将这些细胞和正常小鼠胰腺细胞与噬菌体克隆文库（噬菌体是感染细菌的病毒；克隆是一组基因相同的生物体）混合在一起，每个噬菌体克隆文库在实验室中进行改造以表达随机的七个氨基酸肽，他们鉴定出一个克隆，即克隆27，它与小鼠肿瘤细胞结合，但不与正常细胞结合。克隆 27 还出现在小鼠胰腺上皮内瘤变（PanIN；胰腺癌前体）、小鼠 PDAC 和人类 PDAC 样本的癌细胞中。研究人员报告说，克隆 27 中的肽与 plectin-1 结合，plectin-1 是一种蛋白质，存在于人类和小鼠 PDAC 细胞的内部和膜上，但仅存在于正常胰腺细胞的内部。最后，研究人员将这种 plectin-1 靶向肽 (PTP) 附着到磁性和荧光纳米颗粒 (PTP-NP) 上，并使用特殊显微镜（检测这种非常小的颗粒的荧光部分）和 MRI（检测其磁性部分）来表明，在人类 PDAC 小鼠模型的 PDAC 区域（但不在正常胰腺组织中）发现了这种潜在的成像探针。这些发现将 PTP 确定为一种可以区分正常胰腺细胞和胰腺癌细胞的肽。 plectin-1（一种细胞骨架成分）在 PDAC 细胞表面异常表达的发现提供了有关胰腺癌发展的新信息，最终可能导致治疗这种疾病的新方法。这些发现还表明，PTP 可用于生成基于纳米颗粒的成像剂，可检测正常胰腺内的 PDAC。这些结果需要在人类身上得到证实——在小鼠模型中获得的结果并不总是反映在人类身上发生的情况。尽管如此，他们认为 PTP-NP 可能允许对胰腺癌高危人群的早期肿瘤进行无创检测，这一进步可以通过更早地识别肿瘤（当肿瘤可以通过手术切除时）来延长他们的生命。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0050085。 • 胰腺癌行动网络和Lustgarten 胰腺癌研究基金会为患者、家庭和医疗保健专业人员提供信息、支持和宣传。 • MedlinePlus 百科全书有一个关于胰腺癌的页面（英语和西班牙语）。 MedlinePlus 提供更多信息的链接 • 美国国家癌症研究所为患者和健康专业人员提供有关胰腺癌的信息（英语和西班牙语） • 英国慈善机构 Cancerbackup 也为患者提供有关胰腺癌的信息
Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents. Here, a phage display approach was used in a mouse model of PDAC to screen for peptides that specifically bind to cell surface antigens on PDAC cells. These screens yielded a motif that distinguishes PDAC cells from normal pancreatic duct cells in vitro, which, upon proteomics analysis, identified plectin-1 as a novel biomarker of PDAC. To assess their utility for in vivo imaging, the plectin-1 targeted peptides (PTP) were conjugated to magnetofluorescent nanoparticles. In conjunction with intravital confocal microscopy and MRI, these nanoparticles enabled detection of small PDAC and precursor lesions in engineered mouse models. Our approach exploited a well-defined model of PDAC, enabling rapid identification and validation of PTP. The developed specific imaging probe, along with the discovery of plectin-1 as a novel biomarker, may have clinical utility in the diagnosis and management of PDAC in humans. Kimberly Kelly and colleagues describe the discovery of plectin-1 as a novel biomarker for pancreatic ductal adenocarcinoma and the subsequent development of a specific imaging probe using this marker. Pancreatic cancer is a leading cause of cancer-related death in the US. Like all cancers, it occurs when cells begin to grow uncontrollably and to move around the body (metastasize) because of changes (mutations) in their genes. If pancreatic cancer is found early, surgical removal of the tumor can sometimes provide a cure. Unfortunately, this cancer rarely causes any symptoms in its early stages and the symptoms it does eventually cause—jaundice, abdominal and back pain, and weight loss—are also seen in other illnesses. In addition, even though magnetic resonance imaging (MRI) or other noninvasive imaging techniques can be used to look at the pancreas, by the time tumors are large enough to show up on MRI scans, they have often already spread. Consequently, in most patients, pancreatic cancer is advanced by the time a diagnosis is made, hence surgery is no longer useful. These patients are given radiotherapy and chemotherapy but these treatments are rarely curative and most patients die within a year of diagnosis. If more pancreatic cancers could be found before they had metastasized, it should extend the life expectancy of patients with this type of cancer. An early detection method would be particularly useful for monitoring people at high risk of developing pancreatic cancer. These include people with certain inherited cancer syndromes, pancreatitis (inflammation of the pancreas), and diabetes. Because cancer cells have many mutations, they express different proteins on their cell surface from normal cells. If these proteins could be identified, it might be possible to develop an “imaging probe”—a molecule that binds to a protein found only on cancer cells and that can be detected with MRI, for example—for early detection of pancreatic cancer. In this study, the researchers use a technique called “phage display” to identify several peptides (short sequences of amino acids, the constituent parts of proteins) that specifically bind to pancreatic cancer cells early in their development. They then investigate the possibility of developing an imaging probe from one of these peptides. The researchers isolated early pancreatic cancer cells from a mouse model of human pancreatic ductal adenocarcinoma (PDAC; the commonest type of pancreatic cancer). Then, by mixing together these cells and normal mouse pancreatic cells with a library of phage clones (phages are viruses that infect bacteria; a clone is a group of genetically identical organisms), each engineered in the laboratory to express a random seven amino-acid peptide, they identified one clone, clone 27, that bound to the mouse tumor cells but not to normal cells. Clone 27 also showed up in the cancer cells in samples of mouse pancreatic intraepithelial neoplasias (PanINs; precursors to pancreatic cancer), mouse PDACs, and human PDACs. The peptide in clone 27, the researchers report, binds to plectin-1, a protein present both inside and on the membrane of human and mouse PDAC cells but only on the inside of normal pancreatic cells. Finally, the researchers attached this plectin-1–targeted peptide (PTP) to a nanoparticles that was both magnetic and fluorescent (PTP-NP) and used special microscopy (which detects the fluorescent part of this very small particle) and MRI (which detects its magnetic portion) to show that this potential imaging probe was found in areas of PDAC (but not in normal pancreatic tissue) in the mouse model of human PDAC. These findings identify PTP as a peptide that can distinguish normal pancreatic cells from pancreatic cancer cells. The discovery that plectin-1 (a cytoskeletal component) is abnormally expressed on the cell surface of PDACs provides new information about the development of pancreatic cancer that could eventually lead to new ways to treat this disease. These findings also show that PTP can be used to generate a nanoparticle-based imaging agent that can detect PDAC within a normal pancreas. These results need to be confirmed in people—results obtained in mouse models do not always reflect what happens in people. Nevertheless, they suggest that PTP-NPs might allow the noninvasive detection of early tumors in people at high risk of developing pancreatic cancer, an advance that could extend their lives by identifying tumors earlier, when they can be removed surgically. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050085. • The Panreatic Cancer Action Network and the Lustgarten Foundation for Pancreatic Cancer Research provide information, support, and advocacy for patients, families, and healthcare professionals • The MedlinePlus Encyclopedia has a page on pancreatic cancer (in English and Spanish). Links to further information are provided by MedlinePlus • The US National Cancer Institute has information about pancreatic cancer for patients and health professionals (in English and Spanish) • The UK charity Cancerbackup also provides information for patients about pancreatic cancer
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