Activated nano-sized MR contrast agents for imaging of tumor proteolytic activity

用于肿瘤蛋白水解活性成像的活化纳米级磁共振造影剂

基本信息

批准号：
7739994
负责人：
Dmitri Artemov
金额：
$ 18.04万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7739994
关键词：
Acidosis Affinity Area Binding Biodistribution Biological Models Biological Process Blood Vessels Blood capillaries Breast Cancer Cell Breast Cancer Model Cell model Chemicals Clinic Clinical Complex Contrast Media Coupled Development Diffuse Diffusion Digestion Disease Dissociation Drug Kinetics Electron Microscopy Elements Environment Environmental Risk Factor Enzymes Epitopes Event Fresh Tissue Functional Imaging Gadolinium Gel Human Hypoxia Image Imaging technology In Vitro Label Left MCF7 cell Magnetic Resonance Imaging Malignant Neoplasms Mass Spectrum Analysis Matrilysin Matrix Metalloproteinases Measures Methods Molecular Molecular Weight Monitor Nanotechnology Pattern Peptide Hydrolases Peptides Phagocytes Plasma Pre-Clinical Model Property Relaxation Research Resolution Route Scanning Screening for cancer Serum Albumin Signal Transduction Site Slice System Techniques Technology Testing Tissues Translations Vascular Permeabilities Weight Xenograft procedure base blood perfusion capillary density design imaging modality improved in vivo interest iron oxide light scattering malignant breast neoplasm molecular imaging nanoparticle nanoscale nanosized novel optical imaging particle polymerization pre-clinical prognostic public health relevance response soft tissue tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Contrast agents activated by biological processes can be extremely useful for functional imaging of various diseases including cancer, which is typically characterized by unique microenvironment with increased concentration of proteolytic enzymes, hypoxia, and acidosis. This concept has been successfully applied for NIR optical imaging, however it remains an elusive technology for MRI, although several methods had recently been explored including activated chelating compounds for Gd and clustering of SPIO nanoparticles to increase T2 relaxivity. In this application, we will develop a novel class of activated contrast agent for MR imaging using combination of superparamegnetic iron-oxide nanoparticles (SPIO) and multiple Gd groups. When both components are localized in close proximity the resulting complex will produce strong negative T2 contrast in T1/T2-weighted MRI due to high T2 relaxivity of SPIO particles. Upon dissociation of the complex, small Gd groups will diffuse away from the SPIO core and generate positive T1 MR contrast in areas within the diffusion range of Gd but outside the diffusion range of the relatively immobile SPIO nanoparticle. Activated MR imaging agent will be synthesized using an SPIO core, matrix metalloproteinase (MMP-7) and broad-spectrum (FS-1) MMP- specific cleavable peptide linkers, and gadolinium chelates. The constructs will be characterized with DLS, EM, and element analysis by ICP-MS techniques. Proof-of-principle studies of the probe activation will be performed in a model, cell free gel system and in cultured breast cancer cells in vitro. Activation of the MR contrast agents will also be studied in preclinical models of human breast cancer. For biodistribution studies agents will be additionally labeled with multicolor fluorescent tags for SPIO and the leaving Gd group respectively. Biodistribution of the intact agent and its components will be measured using optical imaging of fluorescently labeled CA in fresh tissue sections and histological slices. A novel class of activated MR contrast agents that dramatically changes signal enhancement pattern from negative contrast enhancement (signal loss) to positive (increased signal) upon activation by proteolytic breast cancer associated MMP enzymes can provide noninvasive assessment of proteolytic activity in breast cancers. This is an important prognostic parameter as tumor aggressiveness and metastatic potential strongly correlate with the expression of proteinases. The agent consists of components that are currently approved for clinical use and therefore there are good chances for rapid translation of this imaging nanotechnology to clinic. PUBLIC HEALTH RELEVANCE: MR imaging provides an outstanding spatial resolution and soft tissue contrast, however, its ability to probe subtle features of chemical environment of a tumor is currently limited due to the lack of sensitive imaging contrast agents. In this application, we will use advances in nanotechnology to develop a novel class of MR contrast agents which will be specifically activated within the tumor microenvironment by tumor associated proteolytic enzymes and will provide significant enhancement of the tumor in MR images. These nanoscale activated MR contrast agents can improve existing imaging technology for early cancer detection and/or for noninvasive monitoring of tumor response to therapy.

描述（由申请人提供）：由生物过程激活的造影剂对于包括癌症在内的各种疾病的功能成像非常有用，癌症的典型特征是具有蛋白水解酶浓度增加、缺氧和酸中毒的独特微环境。这一概念已成功应用于近红外光学成像，但对于 MRI 来说，它仍然是一项难以捉摸的技术，尽管最近已经探索了几种方法，包括激活 Gd 螯合化合物和聚集 SPIO 纳米粒子以增加 T2 弛豫率。在此应用中，我们将使用超顺磁性氧化铁纳米颗粒 (SPIO) 和多个 Gd 基团的组合，开发一种用于 MR 成像的新型活化造影剂。当两种成分非常接近时，由于 SPIO 颗粒的高 T2 弛豫率，所得复合物将在 T1/T2 加权 MRI 中产生强烈的负 T2 对比度。复合物解离后，小 Gd 基团将从 SPIO 核心扩散开，并在 Gd 扩散范围内但在相对固定的 SPIO 纳米颗粒扩散范围之外的区域产生正 T1 MR 对比度。活化的 MR 成像剂将使用 SPIO 核心、基质金属蛋白酶 (MMP-7) 和广谱 (FS-1) MMP 特异性可裂解肽接头以及钆螯合物合成。该结构将通过 DLS、EM 和 ICP-MS 技术进行元素分析来表征。探针激活的原理验证研究将在模型、无细胞凝胶系统和体外培养的乳腺癌细胞中进行。 MR 造影剂的激活也将在人类乳腺癌的临床前模型中进行研究。对于生物分布研究，试剂将另外分别标记 SPIO 和离去 Gd 基团的多色荧光标签。将使用新鲜组织切片和组织学切片中荧光标记的 CA 的光学成像来测量完整药剂及其成分的生物分布。一类新型的活化 MR 造影剂在被蛋白水解乳腺癌相关 MMP 酶激活后，可显着改变信号增强模式，从负对比度增强（信号丢失）变为正性（信号增强），可以对乳腺癌中的蛋白水解活性提供无创评估。这是一个重要的预后参数，因为肿瘤侵袭性和转移潜力与蛋白酶的表达密切相关。该试剂由目前批准用于临床的成分组成，因此这种成像纳米技术有很好的机会快速转化为临床。公共健康相关性：磁共振成像提供了出色的空间分辨率和软组织对比度，然而，由于缺乏敏感的成像造影剂，其探测肿瘤化学环境微妙特征的能力目前受到限制。在此应用中，我们将利用纳米技术的进步来开发一类新型 MR 造影剂，该造影剂将在肿瘤微环境中被肿瘤相关蛋白水解酶特异性激活，并在 MR 图像中显着增强肿瘤的效果。这些纳米级活化磁共振造影剂可以改进现有的成像技术，用于早期癌症检测和/或无创监测肿瘤对治疗的反应。