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: 6200138
• 负责人: Binghe Wang
• 金额: $ 14.8万
• 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/6200138
• 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.

恶性转化通常与细胞表面碳水化合物的改变有关。 某些碳水化合物如唾液酸刘易斯X（sLex）、唾液酸刘易斯a（sLea）、刘易斯X（Lex）和刘易斯Y（Ley）的表达或过表达与某些癌症的发展相关。 这些细胞表面碳水化合物可用于癌细胞的细胞特异性鉴定和靶向。 本项目的长期目标是开发能够以高选择性和亲和力识别靶糖结构的小分子人工受体。 此类受体可用于开发用于细胞特异性鉴定、组织特异性成像（例如MRI）和治疗剂的靶向递送的荧光标签。 由于sLex的表达与结肠癌的进展和转移密切相关，因此本研究以sLex作为模型糖，以结肠癌作为模型生物系统。本申请的短期目标是开发能够以高亲和力和选择性识别sLex的组织特异性荧光标签（传感器）。 对于这种荧光传感器的建设，我们计划使用一个综合的方法结合模板导向合成，组合化学，和计算机分子模拟辅助设计。 sLex-specific人工受体具有用于细胞鉴定、检测和标记的潜力，用于结肠癌细胞的定位、分期、组织活检和荧光导向手术切除的目的。 此类组织特异性化合物还可以作为癌症化疗剂靶向递送的载体。 这些小分子传感器还可以具有优于基于抗体的检测/递送系统的以下优点：（1）在储存期间和体内更大的稳定性;（2）通过生物膜的增加的渗透性，因此增强了目标可接近性;（3）对具有显著荧光强度的结合的固有灵敏度增加，使得检测和可视化更容易并且更适合于高通量筛选，和（4）较低的引发不希望的免疫应答的倾向。 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。