MRI contrast agents targeting carbohydrate biomarkers

描述(申请人提供)：恶性转化通常与细胞表面碳水化合物的改变有关。某些碳水化合物的表达或过度表达，如唾液酸化的Lewis X(SleX)、唾液酸化的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肿瘤细胞的细胞特异性鉴定和靶向。最近，我们开发了基于硼酸的小分子凝集素模拟物(称为硼内酯)，可以选择性地识别某些碳水化合物。相同或相似的方法可用于制备多种碳水化合物的凝集素模拟物。该项目的长期目标是开发作为生物标记物导向的肿瘤显像剂的硼内酯-核磁共振造影剂的结合物。具体地说，这种结合物可以用于基于细胞表面碳水化合物生物标记物的MRI造影剂的输送。在这项应用的R21阶段，我们计划通过以下方式研究这种方法的可行性：(1)使用已知的选择性结合唾液酸路易斯X的硼油凝集素合成硼油酸-MRI造影剂结合物，(2)研究它们与目标碳水化合物生物标记物结合细胞的能力，以及(3)检查它们在体外和体内模型中对移植瘤成像的能力。如果R21阶段成功，在R33阶段，我们计划扩大我们的生物学评估，将种植在不同位置的肿瘤包括在内，并寻找其他可以与其他重要的碳水化合物癌症生物标记物特异结合的凝集素模拟物。此外，我们还计划检测硼脂素-核磁共振造影剂结合物的细胞毒性。这些基于小分子的识别/递送系统可能比基于抗体的系统具有以下优点：(1)在储存和体内更稳定；(2)更低的引发不良免疫反应的倾向；(3)更容易的偶联化学；(4)更理想的药学特性。

DESCRIPTION (provided by applicant): 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. Recently, we have developed boronic acid-based small molecule lectin mimics (named boronolectins) that can recognize certain carbohydrates with selectivity. The same or similar methods can be used for the preparation of lectin mimics for a wide variety of carbohydrates. The long-term goal of this project is the development of conjugates of boronolectin-MRI contrast agents as biomarker-directed cancer imaging agents. Specifically, such conjugates can be used for the delivery of MRI contrast agents based on cell-surface carbohydrate biomarkers. In the R21 phase of this application, we plan to study the feasibility of this approach by (1) synthesizing boronolectin-MRI contrast agent conjugates using a boronolectin which is known selectively bind to sialyl Lewis X, (2) studying their ability to bind to cells with the target carbohydrate biomarkers, and (3) examining their ability to image implanted tumors in both an ex vivo and in vivo models. If the R21 phase is successful, in the R33 phase we plan to expand our biological evaluation to include tumors implanted at different positions, and to search for other lectin mimics that can bind specifically for other important carbohydrate-based cancer biomarkers. In addition, we also plan to examine the cytotoxicity of the boronolectin-MRI contrast agent conjugates. These small molecule-based recognition/delivery systems may have the following advantages over antibody-based systems: (1) greater stability during storage and in vivo; (2) lower propensity to elicit undesirable immune responses, (3) easier conjugation chemistry, and (4) more desirable pharmaceutical properties.