Molecular Probes for Biomembrane Recognition

描述(申请人提供)：有机分子探针被设计成选择性地与特定类型的生物膜结合。该探针由两个结构成分组成：膜靶向配体和光活性报告基团。主要的膜靶标是人类癌细胞、濒临死亡的癌细胞和细菌的表面，其应用范围从体内肿瘤的光学成像到细菌的光学成像再到抗生素光动力疗法。本论文的主要目标是：1.开发方酸轮烷类新型荧光近红外有机染料，具有前所未有的亮度和稳定性。这些染料将被转化为探针，用于各种类型的光学成像应用，包括对小鼠异种移植模型中生长或死亡的肿瘤进行成像。最终目标是检测活体动物中的肿瘤或监测抗癌治疗的有效性。2.合成的二吡啶甲胺锌(ZN-DPA)亲和配体将被固定在各种荧光支架上，以制备新型的细菌光学成像探针。初步结果显示，植入的小鼠细菌感染可以用发射近红外荧光的探针进行成像；这是第一个对活体动物中的细菌进行靶向光学成像的例子。这种新的成像方法的范围将被确定，包括对各种细菌菌株的选择性和敏感性。其他研究将开发高灵敏度的荧光方法来检测混合介质中的细菌污染，特别是生物医学样品和食品。3.将锌-DPA亲和配体连接到光敏剂上的双功能探针将被评估在抗生素光动力疗法中的应用。由于锌-DPA亲和配体针对细菌细胞膜中普遍存在的极性脂类，这些双功能探针将对大多数形式的耐药细菌有效，长期使用这些探针不太可能诱导高水平的细菌耐药性。与公共健康相关：这项研究生产的荧光探针分子将用于成像活动物中的癌症、肿瘤和细菌感染。成像技术将帮助研究人员发现新的治疗方法，最终将帮助医生为特定患者选择最合适的治疗方法。后一种应用是光学成像将如何促进个性化医学概念演变的一个例子。

DESCRIPTION (provided by applicant): Organic molecular probes are designed to selectively associate with specific types of biomembranes. The probes are comprised of two structural components: a membrane targeting ligand and a photoactive reporter group. The primary membrane targets are the surfaces of human cancer cells, dying cancer cells, and bacteria, with applications ranging from in vivo optical imaging of tumors to optical imaging of bacteria to antibiotic photodynamic therapy. The major aims are: 1. Develop squaraine-rotaxanes as a new family of fluorescent near-IR organic dyes with unprecedented brightness and high stability. The dyes will be converted into probes for various types of optical imaging applications including imaging of growing or dying tumors in murine xenograft models. The eventual objective is to detect tumors in living animals or monitor the effectiveness of anticancer therapy. 2. Synthetic zinc dipicolylamine (Zn-DPA) affinity ligands will be attached to various fluorescent scaffolds to produce new optical imaging probes for bacteria. Preliminary results show that implanted murine bacterial infections can be imaged with probes that emit near-IR fluorescence; the first example of targeted optical imaging of bacteria in a living animal. The scope of this novel imaging method will be determined, including the selectivity and sensitivity for various strains of bacteria. Additional studies will develop highly sensitive fluorescent methods for detecting bacterial contamination in mixed media, especially biomedical samples and food products. 3. Bifunctional probes with Zn-DPA affinity ligands attached to a photosensitizer will be evaluated for utility in antibiotic photodynamic therapy. Since the Zn-DPA affinity ligands target ubiquitous polar lipids in the bacterial cell membrane, these bifunctional probes will be effective against most forms of drug resistant bacteria and prolonged treatment with these probes is unlikely to induce high levels of bacterial resistance. Relevance to Public Health: The fluorescent probe molecules produced by this research will be used to image cancer tumors and bacterial infection in living animals. The imaging technology will help researchers discover new therapies and eventually it will help physicians choose the most appropriate therapy for a specific patient. This latter application is an example of how optical imaging will contribute to the evolving concept of personalized medicine.