Molecular probes for biomembrane recognition

用于生物膜识别的分子探针

• 批准号: 8234439
• 负责人: BRADLEY D. SMITH
• 金额: $ 34.96万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234439
• 关键词: Affinity; Animal Model; Animals; Antibodies; Area; Autoimmune Diseases; Binding; Biomedical Research; Biomimetics; Blood; Blood Vessels; Body Temperature; Cardiology; Cell Culture Techniques; Cell Death; Cell membrane; Cell model; Cells; Cessation of life; Chemicals; Clinical; Colon Carcinoma; Colorectal Cancer; Complex; Development; Diagnosis; Diffusion; Disease; Dissociation; Drug Delivery Systems; Drug Kinetics; Dyes; Exhibits; Extravasation; Family; Fluorescence Microscopy; Fluorescent Dyes; Fluorescent Probes; Folate; Goals; Histology; Human; Image; Imaging technology; Individual; Investigation; Ions; Lead; Libraries; Ligands; Malignant neoplasm of prostate; Measures; Mediating; Medical; Membrane; Methods; Modality; Modeling; Molecular; Molecular Probes; Molecular Target; Mus; Neurology; Ophthalmology; Organ; Organ Transplantation; Patients; Peptides; Performance; Phosphatidylserines; Property; Prostatic Neoplasms; Proteins; Protocols documentation; Rattus; Reporter; Research; Rodent; Screening procedure; Site; Specimen; Stimulus; Surface; System; Testing; Therapeutic; Time; Tissues; Translations; Treatment Efficacy; Tumor Tissue; Work; Zinc; cancer therapy; cellular imaging; clinical application; cold temperature; design; disease diagnosis; fluorescence imaging; folate-binding protein; imaging probe; immunogenicity; improved; nanoparticle; next generation; novel; oncology; optical imaging; overexpression; pre-clinical; research study; response; small molecule; tumor; uptake

DESCRIPTION (provided by applicant): The objective is to produce new imaging probes and associated protocols for preclinical biomedical research and for clinical use in humans. The first specific aim is to discover small synthetic molecules that selectively target anionic cell membrane surfaces with exposed phosphatidylserine and distinguish them from the near-neutral membrane surfaces of healthy cells. One application is cell death imaging, as a method to detect disease and measure treatment efficacy. Preliminary work has shown that a family of fluorescent zinc coordination complexes can act as optical imaging probes for dead and dying tissue in various cell and animal models. The selectivity over healthy tissue is very high, even though binding affinities for exposed phosphatidylserine are moderate (low micromolar dissociation constants). To improve cell targeting performance for clinical applications, a systematic cycle of synthesis and screening will be employed to find next-generation compounds that have 500-fold higher binding affinity for phosphatidylserine. This will enable microdosing, which is the key to successful translation. The imaging ability of lead compounds will be evaluated in cell culture and animal models of cell death with a focus on producing the first set of practically useful, optical imaging probes for non-invasive assessment of the efficacy of anticancer therapies. The second specific aim is to create a new paradigm for planar optical imaging of tumors using near-infrared chemiluminescent and fluorescent (CLF) nanoparticles. The chemiluminescence is thermally-activated (that is, no chemical or electrical stimulus is needed) which means that the nanoparticles can be stored at low temperature and they only become chemiluminescent when warmed to body temperature. Preliminary results in mice show that chemiluminescence imaging permits identification of target sites that are more than two centimeters below the animal surface, which is about five times deeper than currently achieved using planar fluorescence imaging. The new imaging paradigm will be demonstrated by conducting experiments using relatively deep-tissue animal models of spontaneous prostate cancer and orthotopic colon cancer. Chemiluminescence imaging will be used to locate the tumor tissue that is targeted by the nanoparticles, and fluorescence microscopy of thin histology sections taken from the same specimen will quantify uptake into the tumor parenchyma. The power of this new imaging technology will be employed to answer questions concerning the ability of the tumor vascular-penetrating peptide iRGD to promote nanoparticle entry into tumors. PUBLIC HEALTH RELEVANCE: High performance imaging probes for cell death will facilitate the diagnosis and treatment of disease in diverse medical fields such as oncology, cardiology, organ transplantation, neurology, ophthalmology, and autoimmune disease. New chemiluminescent and fluorescent probes for planar optical imaging will accelerate efforts to develop effective tumor imaging and treatment methods.

描述（由申请人提供）：目标是为临床前生物医学研究和人类临床应用生产新的成像探针和相关方案。第一个具体目标是发现选择性靶向暴露有磷脂酰丝氨酸的阴离子细胞膜表面的合成小分子，并将其与健康细胞的近中性膜表面区分开来。一个应用是细胞死亡成像，作为检测疾病和测量治疗效果的方法。初步工作表明，荧光锌配位复合物家族可以作为各种细胞和动物模型中死亡和垂死组织的光学成像探针。尽管对暴露的磷脂酰丝氨酸的结合亲和力适中（低微摩尔解离常数），但对健康组织的选择性非常高。为了提高临床应用的细胞靶向性能，将采用系统的合成和筛选循环来寻找对磷脂酰丝氨酸的结合亲和力高出 500 倍的下一代化合物。这将实现微剂量，这是成功翻译的关键。先导化合物的成像能力将在细胞培养物和细胞死亡动物模型中进行评估，重点是生产第一套实用的光学成像探针，用于非侵入性评估抗癌疗法的功效。第二个具体目标是使用近红外化学发光和荧光（CLF）纳米粒子创建肿瘤平面光学成像的新范例。化学发光是热激活的（即不需要化学或电刺激），这意味着纳米颗粒可以在低温下储存，并且只有在升温至体温时才变得化学发光。小鼠的初步结果表明，化学发光成像可以识别动物表面以下两厘米以上的目标位点，比目前使用平面荧光成像所实现的深度大约五倍。新的成像范例将通过使用自发性前列腺癌和原位结肠癌的相对深层组织动物模型进行实验来证明。化学发光成像将用于定位纳米颗粒靶向的肿瘤组织，而从同一样本中获取的薄组织学切片的荧光显微镜将量化肿瘤实质的吸收。这种新成像技术的力量将被用来回答有关肿瘤血管穿透肽 iRGD 促进纳米颗粒进入肿瘤的能力的问题。 公共健康相关性：用于细胞死亡的高性能成像探针将促进肿瘤学、心脏病学、器官移植、神经病学、眼科和自身免疫性疾病等不同医学领域疾病的诊断和治疗。用于平面光学成像的新型化学发光和荧光探针将加速开发有效的肿瘤成像和治疗方法。