FLUORESCENT TAGS TARGETED ON CELL SURFACE CARBOHYDRATES

针对细胞表面碳水化合物的荧光标签

• 批准号: 6573328
• 负责人: Binghe Wang
• 金额: $ 26.69万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573328
• 关键词: carbohydrates; chemical models; colon neoplasms; combinatorial chemistry; computer simulation; drug design /synthesis /production; fluorescent dye /probe; surface antigens; tissue /cell culture

Malignant transformation is often associated with alteration of cell surface carbohydrates. The expression or over-expression of certain carbohydrates, such as sialyl Lewis X (sLex), sialyl Lewis a (sLea), Lewis X (Lex) and Lewis Y (Ley), has been correlated with the development of certain cancers. These cell surface carbohydrates can be used for cell-specific identification and targeting of carcinoma cells. The long-term goal of this project is the development of small molecule artificial receptors which can recognize target carbohydrate structures with high selectivity and affinity. Such receptors could be used for the development of fluorescent tags for cell- specific identification, tissue-specific imaging (such as MRI), and targeted delivery of therapeutic agents. In this study, we will use sLex as the model carbohydrate and use colon cancer as the model biological system because the expression of sLex is often associated with progression and metastasis of colon cancer. The short-term objective of this application is to develop tissue-specific fluorescent tags (sensors) which can recognize sLex with high affinity and selectivity. For the construction of such fluorescent sensors, we plan to use an integrated approach combining template-directed synthesis, combinatorial chemistry, and computer molecular modeling aided design. The sLex-specific artificial receptors have the potential to be used for cell identification, detection and tagging for the purpose of localization, staging, tissue biopsy, and fluorescence-directed surgical removal of colon cancer cells. Such tissue-specific compounds could also serve as vehicles for targeted delivery of cancer chemotherapeutic agents. These small molecule sensors may also have the following advantages over antibody-based detection/delivery systems: (1) greater stability during storage and in vivo; (2) increased permeability through biological membranes and, therefore, enhanced target accessibility; (3) intrinsic sensitivity to binding with significant fluorescence intensity increases, making detection and visualization easier and more suitable for high throughout screening, and (4) lower propensity to elicit undesirable immune responses. Similar methods, once developed, could also be used for the construction of fluorescent tags for other cell surface carbohydrates implicated in human malignancies.

恶性转化常与细胞表面碳水化合物的改变有关。某些碳水化合物的表达或过表达，如sialyl Lewis X （sLex）、sialyl Lewis a （sLea）、Lewis X （Lex）和Lewis Y (Ley)，与某些癌症的发生有关。这些细胞表面碳水化合物可用于细胞特异性鉴定和靶向癌细胞。该项目的长期目标是开发具有高选择性和亲和力的靶向碳水化合物结构的小分子人工受体。这些受体可用于开发用于细胞特异性鉴定、组织特异性成像（如MRI）和靶向递送治疗剂的荧光标签。在本研究中，我们将使用sLex作为模型碳水化合物，并使用结肠癌作为模型生物系统，因为sLex的表达往往与结肠癌的进展和转移有关。该应用程序的短期目标是开发组织特异性荧光标签（传感器），可以识别高亲和力和选择性的sLex。为了构建这样的荧光传感器，我们计划采用结合模板定向合成、组合化学和计算机分子建模辅助设计的综合方法。slex特异性人工受体有潜力用于细胞鉴定、检测和标记，用于定位、分期、组织活检和荧光定向手术切除结肠癌细胞。这种组织特异性化合物也可以作为癌症化疗药物靶向递送的载体。与基于抗体的检测/递送系统相比，这些小分子传感器也可能具有以下优点：(1)在储存和体内具有更高的稳定性；(2)增加了生物膜的渗透性，从而增强了靶标的可及性；(3)对结合的固有灵敏度显著增加，使检测和可视化更容易，更适合于高通量筛选；(4)引起不良免疫反应的倾向降低。类似的方法一旦开发出来，也可以用于构建与人类恶性肿瘤有关的其他细胞表面碳水化合物的荧光标记。