Tumor-Specific Nanocontrast Agents for Improved Detection of Pancreatic Cancer

用于改进胰腺癌检测的肿瘤特异性纳米造影剂

• 批准号: 10387907
• 负责人: William MacCuaig
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-19 至 2025-01-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387907
• 关键词: Animal Model; Antibodies; Antibody-drug conjugates; Benign; Binding; Biodistribution; Blood; Caliber; Cells; Characteristics; Chitosan; Clinical; Contrast Media; Detection; Development; Diagnosis; Disease; Distant Metastasis; Drug Kinetics; Dyes; Ensure; Excision; Exhibits; Fibrosis; Fluorescence; Future; Gatekeeping; Gold; Hemoglobin; High Pressure Liquid Chromatography; Image-Guided Surgery; In Vitro; Liposomes; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Modality; Molecular; Oncopig; Operative Surgical Procedures; Organ; Palpation; Pancreas; Pancreatic Adenocarcinoma; Patient-Focused Outcomes; Patients; Penetration; Peptides; Polymers; Polysaccharides; Positron-Emission Tomography; Reproducibility; Resolution; Signal Transduction; Silicon Dioxide; Solid; Specificity; Spectrum Analysis; Surface; Surgeon; Techniques; Testing; Time; Tissue Sample; Tissue imaging; Tissues; Toxic effect; Tumor Tissue; Visual; base; chemotherapy; clinical imaging; clinical translation; experience; imaging modality; improved; in vivo; mortality; nanoparticle; nanorod; neoplastic cell; optical imaging; optoacoustic tomography; pancreas development; pancreatic neoplasm; photoacoustic imaging; plectin; prototype; research clinical testing; small molecule; success; tumor; tumor microenvironment; tumor specificity; uptake

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.

项目总结/摘要 抽象的。胰腺癌（PDAC）是一种高度侵袭性的癌症，具有高死亡率和高并发症。 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， 纤维化和肿瘤组织是困难的。目前，这种区分是基于视觉检查和触诊， 手术医生这种分化差通常会导致肿瘤切除不完全，导致可能的恶性肿瘤。 胰腺癌复发或远处转移。多光谱光声层析成像（MSOT） 是一种新兴的模式，最近已进入临床测试，并表现出高分辨率，实时， 适合术中成像的深度穿透。MSOT具有识别多个分子的能力， 试剂，但目前缺乏用于识别癌症的肿瘤特异性造影剂，以提供这种 信息.用于MSOT的PDAC特异性造影剂的开发代表了改善 术中PDAC检测。虽然小分子染料和抗体-药物缀合物具有 已经评估过，由于非特异性或很少的造影剂分子到达肿瘤而导致低信号。到 为了克服这些局限性，我的目标是：1）开发靶向的、肿瘤特异性的纳米造影剂（P-MSN）， 和2）使用MSOT测试P-MSN用于体内胰腺癌的检测。根据我的经验， 构建介孔二氧化硅纳米粒子，我建议开发一种新的，肿瘤靶向 纳米造影剂，P-MSN，其表现出三个独特的特征，以改善PDAC肿瘤特异性：1）小 （直径<50 nm）; 2）具有pH敏感性（PVA-PAAm）看门人的肿瘤特异性货物释放;和3） Plectin-1活性靶向肽的引入。肿瘤特异性纳米造影剂的开发可以 与单独的血红蛋白相比，使用MSOT提高了PDAC鉴定的准确性。我假设 通过PDAC的双重靶向作用，即使用plectin-1靶向肽（PTP）来提供特异性， 肿瘤细胞，和MSN守门与P（VA-AAm），靶向和释放造影剂，特别是在酸性肿瘤 微环境中，开发的MSN将有助于改善检测PDAC的MSOT。为了验证这一 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） 评估肿瘤特异性纳米造影剂（P-MSN）通过MSOT在体内检测PDAC的有效性。的影响 这项研究开发了一种胰腺癌特异性纳米造影剂， 分子特征和使用MSOT改进胰腺癌的识别。如果成功，我们的研究将 提供“一流的”胰腺癌特异性造影剂，可在术中使用， 区分恶性和良性组织，以确保完全切除PDAC患者的肿瘤。