Near-Infrared Nanopolymer Agents for Real-Time, In Vivo Imaging of Tumor Margins

用于肿瘤边缘实时体内成像的近红外纳米聚合物试剂

• 批准号: 7482651
• 负责人: Jianjun Wei
• 金额: $ 10万
• 依托单位: CFD RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-18 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7482651
• 关键词: Acids; Address; Affinity; Animal Model; Animals; Arginine; Asparagine; Aspartate; Back; Binding; Biocompatible; Biodistribution; Biological Models; Blood Vessels; Breast Carcinoma; Breast-Conserving Surgery; Buffers; Cancer Patient; Carboxylic Acids; Carcinoma; Cell Communication; Cell Nucleolus; Cell Nucleus; Cell surface; Cells; Characteristics; Chemicals; Condition; Depth; Detection; Development; Devices; Diagnosis; Drug Delivery Systems; Employee Strikes; Endothelial Cells; Fluorescence; GFE-1 peptide; Glutamine; Glycine; Health system; High Mobility Group Proteins; Human; Image; Imagery; Imaging Techniques; In Vitro; Incubated; Integrin Binding; Integrins; Invasive; Ligands; Light; Link; Lung; Lymphatic; Lymphatic vessel; Lys-Asp; Maleimides; Malignant - descriptor; Mammary Neoplasms; Marketing; Membrane; Methods; Military Personnel; Neoplasms in Vascular Tissue; Normal tissue morphology; Optics; Penetration; Peptide Fragments; Peptide Phage Display Library; Peptides; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Polyethylene Glycols; Polymers; Population; Production; Property; Protocols documentation; RGD (sequence); Range; Reporting; Reproducibility; Research; Route; Screening procedure; Series; Side; Signal Transduction; Solubility; Solutions; Specificity; Stimulus; Surface; System; Techniques; Testing; Time; Tissue Sample; Tissues; Title; Toxic effect; Tumor Specific Peptide; United States; United States Food and Drug Administration; Universities; Vertebral column; absorption; alanine aminopeptidase; alanylproline; arginylarginine; aspartylglutamate; base; beryllium trifluoride; biomaterial compatibility; breast cancer diagnosis; breast lumpectomy; cancer cell; cancer diagnosis; cancer recurrence; cellular imaging; chromophore; clinical application; commercialization; concept; cost; crosslink; density; design; experience; fluorophore; functional group; human tissue; image processing; improved; in vivo; leucylarginine; lysyllysine; lysylproline; malignant breast neoplasm; membrane dipeptidase; monomer; neoplastic cell; noninvasive diagnosis; novel; optical imaging; polymerization; prolyl-proline; prolylglutamic acid; receptor; receptor binding; research clinical testing; response; success; tool; tumor

DESCRIPTION (provided by applicant): Optical imaging as a noninvasive diagnosis technique is a highly promising tool for real-time, in-vivo detection of tumor margins during breast-conserving surgery. This can decrease false-negative diagnoses and local recurrences of the cancer that occur after conventional diagnoses and lumpectomy. Its clinical application has been held back by lack of suitable imaging agents. There is a clear need to develop imaging agents for extending applications of optical imaging method for real-time breast cancer diagnosis. The challenge of a real- time agent requires deep tissue penetration and visualization, good biocompatibility and stability, as well as capability to distinguish malignant cancer cells from surrounding healthy cells. To address the challenge, we propose to develop novel near-infrared (NIR) nanopolymer agents to real-time identify tumor margins through recognition of molecules that are specifically expressed in tumor cells. A series of tumor-homing peptides for specific binding integrins on cancer cells will be introduced to the polymer agent and tested for optimizing tumor-binding specificity. Our concept is based on an intrinsic NIR-fluorescent conjugated polymer backbone which features: a) high intensity and photostability, b) deep tissue penetration, c) specific sensitivity to tumor cells, d) biocompatibility and e) low cost production. An already established conjugated polymer synthetic route, incorporating chemical and optical characterization, NIR fluorescent imaging will be the starting point for the synergistic effort. Building on our significant preliminary results, the Phase I research will first synthesize the designed agent by incorporating multi-NIR fluorophores and high-density biocompatible side-chains to the conjugated polymer backbone, while the binding peptide will be covalently linked to the side chain. Secondly, we will demonstrate the feasibility of imaging-detection of tumor cells and small clusters of tumor cells (1 mm) within a larger population of cells as proof-of-concept. Phase II efforts will focus on further development of the nanopolymer agent, and deliver mature protocols for synthesis of the NIR imaging agent. We will validate the real-time imaging of breast tumor margin of our nanopolymer agents in animal model imaging using a non-invasive optical imaging system (IVIS 50 fro Xenogen). The success of Phase II will provide a list of optical imaging agents suitable for real-time identification of breast cancer margins. The agents will be primarily marketed to pharmaceutical companies for FDA approval and clinical testing.

描述（由申请人提供）：光学成像作为一种非侵入性诊断技术，是一种非常有前途的工具，用于在保乳手术期间实时、体内检测肿瘤边缘。这可以减少常规诊断和肿瘤切除术后发生的假阴性诊断和局部复发。由于缺乏合适的显像剂，其临床应用受到阻碍。有一个明确的需要，以开发成像剂的光学成像方法的实时乳腺癌诊断的扩展应用。真实的时间代理的挑战需要深入的组织渗透和可视化，良好的生物相容性和稳定性，以及区分恶性癌细胞与周围健康细胞的能力。为了应对这一挑战，我们建议开发新型近红外（NIR）纳米聚合物试剂，通过识别肿瘤细胞中特异性表达的分子来实时识别肿瘤边缘。一系列特异性结合癌细胞上整联蛋白的肿瘤归巢肽将被引入聚合物试剂中，并测试优化肿瘤结合特异性。我们的概念是基于固有的NIR-荧光共轭聚合物主链，其特征在于：a）高强度和光稳定性，B）深组织渗透，c）对肿瘤细胞的特异性敏感性，d）生物相容性和e）低成本生产。一个已经建立的共轭聚合物合成路线，结合化学和光学表征，近红外荧光成像将是协同努力的起点。在我们重要的初步结果的基础上，第一阶段研究将首先通过将多NIR荧光团和高密度生物相容性侧链结合到共轭聚合物主链上来合成所设计的试剂，而结合肽将共价连接到侧链上。其次，我们将证明在更大的细胞群体中成像检测肿瘤细胞和小肿瘤细胞簇（1 mm）的可行性，作为概念验证。第二阶段的工作将集中在进一步开发的纳米聚合物剂，并提供成熟的协议合成的近红外成像剂。我们将使用非侵入性光学成像系统（IVIS 50，来自Xenogen）在动物模型成像中验证我们的纳米聚合物药剂的乳腺肿瘤边缘的实时成像。第二阶段的成功将提供一个适用于实时识别乳腺癌边缘的光学成像剂清单。这些药物将主要销售给制药公司，以获得FDA的批准和临床试验。

项目成果

Highly water-soluble, near-infrared emissive BODIPY polymeric dye bearing RGD peptide residues for cancer imaging.

• DOI: 10.1016/j.aca.2012.10.026
• 发表时间: 2013-01-03
• 期刊: Analytica chimica acta
• 影响因子: 6.2
• 作者: Zhu S;Zhang J;Janjanam J;Bi J;Vegesna G;Tiwari A;Luo FT;Wei J;Liu H
• 通讯作者: Liu H

Highly water-soluble neutral BODIPY dyes with controllable fluorescence quantum yields.

• DOI: 10.1021/ol102758z
• 发表时间: 2011-02-04
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Zhu, Shilei;Zhang, Jingtuo;Vegesna, Giri;Luo, Fen-Tair;Green, Sarah A.;Liu, Haiying
• 通讯作者: Liu, Haiying