MRI contrast agents targeting carbohydrate biomarkers

描述（由申请人提供）：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。最近，我们开发了基于硼酸的小分子凝集素模拟物（命名为boronolectins），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硼凝集素-MRI造影剂的缀合物作为生物标志物导向的癌症成像剂。具体地，此类缀合物可用于递送基于细胞表面碳水化合物生物标志物的MRI造影剂。在本申请的R21阶段，我们计划通过以下方式研究该方法的可行性：（1）使用已知选择性结合唾液酸刘易斯X的硼连接素合成硼连接素-MRI造影剂偶联物，（2）研究其结合具有靶碳水化合物生物标志物的细胞的能力，以及（3）检查其在离体和体内模型中对植入肿瘤成像的能力。如果R21阶段是成功的，在R33阶段，我们计划扩大我们的生物学评估，包括在不同位置植入的肿瘤，并寻找其他凝集素模拟物，可以特异性结合其他重要的碳水化合物为基础的癌症生物标志物。此外，我们还计划检查硼凝集素-MRI造影剂偶联物的细胞毒性。这些基于小分子的识别/递送系统相对于基于抗体的系统可具有以下优点：（1）在储存期间和体内更大的稳定性;（2）引发不期望的免疫应答的倾向更低，（3）更容易的缀合化学，和（4）更期望的药物性质。

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.