Tumor-Specific Nanocontrast Agents for Improved Detection of Pancreatic Cancer

项目摘要/摘要 抽象的。胰腺癌(PDAC)是一种高度侵袭性的癌症，具有高死亡率和 晚期诊断。接受化疗和随后的肿瘤切除手术是唯一的 PDAC患者的潜在治疗选择。然而，良性疾病之间的区别，例如， 纤维化，肿瘤组织难以形成。目前，这种区分是基于对 手术医生。这种分化不良往往会导致肿瘤切除不完全，导致很可能 胰腺癌复发或远处转移。多光谱光声成像(MSOT) 是一种最近进入临床测试的新兴模式，具有高分辨率、实时和 适合于术中成像的深度穿透。MSOT具有识别多个分子的能力 药物同步，但目前缺乏肿瘤特异性造影剂来识别癌症提供这种 信息。PDAC特异性MSOT造影剂的开发代表着改进的潜力 术中环境下PDAC的检测。而小分子染料和抗体-药物结合物 经评估，低信号是由于非特异性或较少的对比剂分子到达肿瘤所致。至 克服这些限制，我的目标是：1)开发靶向、肿瘤特异性纳米造影剂(P-MSN)， 2)用MSOT检测P-MSN对胰腺癌的活体检测。根据我的经验， 构建介孔二氧化硅纳米颗粒，我提出了一种新的，肿瘤靶向的开发 纳米造影剂P-MSN，它表现出三个独特的特征，可以改善PDAC的肿瘤特异性：1)小 (&lt；50 nm直径)；2)用pH敏感的(PVA-PAAM)门卫释放肿瘤特异性货物；和3) Plectin-1活性靶向多肽简介。一种肿瘤特异性纳米造影剂的开发可能 与单独使用血红蛋白相比，使用MSOT提高了PDAC识别的准确性。我假设 通过PDAC的双重靶向，即使用plectin-1靶向多肽(PTP)来提供特异性 肿瘤细胞和MSN与P(VA-AAm)的守门作用，以靶向并在酸性肿瘤中特异地释放对比剂 在微环境下，开发的MSN将有助于改进MSOT对PDAC的检测。为了测试这一点 假设，我提出了以下目标：1)开发肿瘤特异性纳米造影剂(P-MSN)；2) 评价肿瘤特异性纳米对比剂(P-MSN)在MSOT体内检测PDAC的有效性。网络的影响 这项研究是一种胰腺癌特异性纳米造影剂的开发，它具有识别 胰腺癌的分子特征及MSOT鉴别诊断的改进。如果成功，我们的研究将 提供一流的胰腺癌特异性造影剂，可用于术中明确 鉴别良恶性组织以确保PDAC患者肿瘤的完全切除。

PROJECT SUMMARY/ABSTRACT Abstract. Pancreatic adenocarcinoma (PDAC) is a highly aggressive form of cancer that has high mortality and late stage diagnosis. Undergoing chemotherapy and subsequent surgery for tumor resection is the only potentially curative options for patients with PDAC. However, differentiation between benign disease, e.g., fibrosis, and tumor tissue is difficult. Currently, this differentiation is based on visual inspection and palpation of the operating surgeon. This poor differentiation can often result in incomplete resection of tumor, leading to likely reoccurrence of cancer in the pancreas or as distant metastases. Multispectral optoacoustic tomography (MSOT) is an emerging modality which has recently entered clinical testing and exhibits high resolution, real-time, and depth penetration suitable for intraoperative imaging. MSOT has the capability of identifying multiple molecular agents simultaneously, but current lacks tumor-specific contrast agents for identifying cancer to provide such information. Development of PDAC-specific contrast agents for MSOT represents the potential for improved detection of PDAC in an intraoperative setting. While small molecule dyes and antibody-drug conjugates have been evaluated, low signal has resulted due to non-specificity or few contrast molecules reaching the tumor. To overcome these limitations, my objective is to: 1) develop targeted, tumor-specific nanocontrast agent (P-MSN), and 2) test P-MSN for detection of pancreatic cancer in vivo using MSOT. Building upon my experience with constructing mesoporous silica nanoparticles, I am proposing the development of a new, tumor-targeted nanocontrast agent, P-MSN, which exhibits three unique features for improved PDAC tumor-specificity: 1) small (<50 nm diameter); 2) tumor-specific cargo release with pH-sensitive (PVA-PAAm) gatekeeper; and 3) introduction of Plectin-1 active targeting peptide. The development of a tumor-specific nanocontrast agent could increase the accuracy of PDAC identification using MSOT compared to hemoglobin alone. I hypothesize that through the dual-targeting of PDAC, i.e. the use of plectin-1-targeting peptide (PTP) to provide specificity to tumor cells, and MSN gatekeeping with P(VA-AAm), to target and release contrast specifically in the acidic tumor microenvironment, the developed MSNs will facilitate improved detection of PDAC by MSOT. To test this hypothesis, I propose the following aims: 1) Develop a tumor-specific nanocontrast agent (P-MSN), and 2) Assess efficacy of tumor-specific nanocontrast (P-MSN) for detection of PDAC in vivo by MSOT. The impact of this study is the development of a pancreatic cancer specific nanocontrast agent that has potential to identify molecular features and improve identification of pancreatic cancer using MSOT. If successful, our studies will provide “first-in-class” pancreatic cancer specific contrast agent which could be used intraoperatively to clearly differentiate between malignant and benign tissue to ensure complete resection of tumor in PDAC patients.