Tumor-specific agents for cancer imaging

用于癌症成像的肿瘤特异性药物

• 批准号: 7789755
• 负责人: MARIA DA GRACA HENRIQUES VICENTE
• 金额: $ 19.31万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-18 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789755
• 关键词: Age related macular degeneration; Antibodies; Antigens; Architecture; Area; Binding; Carcinoembryonic Antigen; Cause of Death; Cells; Cessation of life; Characteristics; Clinical Treatment; Clinical Trials; Colon; Colon Carcinoma; Colonic Neoplasms; Colonoscopy; Colorectal Cancer; Colorectal Neoplasms; Complement; Databases; Development; Disease; Dissociation; Drug Design; Early Diagnosis; Endoscopy; Epidermal Growth Factor Receptor; Fluorescence; Genus Cola; Histology; Human; Image; In Situ; In Vitro; Incidence; Incubated; Investigation; Kinetics; Label; Lasers; Lead; Lesion; Libraries; Ligands; Light; Malignant Epithelial Cell; Malignant Neoplasms; Membrane Proteins; Molecular Conformation; Mucous Membrane; Mus; Neoplasm Metastasis; Nude Mice; Organ Culture Techniques; Patients; Peptides; Pharmaceutical Preparations; Photochemotherapy; Photosensitizing Agents; Porfimer Sodium; Porphyrins; Public Health; Quality of life; Research; Screening procedure; Series; Solid; Solubility; Solutions; Specificity; Staining method; Stains; Surface; Symptoms; Techniques; Tetrapyrroles; Tissues; Toxic effect; Treatment outcome; adenoma; base; cancer cell; cancer imaging; cancer therapy; cell type; cellular targeting; chemotherapeutic agent; colorectal cancer screening; cost; cytotoxicity; design; fluorophore; in vivo; metal complex; mortality; neoplastic; neoplastic cell; novel; phthalocyanine; porphyrin a; programs; protein aminoacid sequence; public health relevance; rectal; response; success; treatment planning; tumor; uptake

DESCRIPTION (provided by applicant): This project proposes to use tetrapyrrole-based conjugates to fluorescently label colorectal tumor foci. Colorectal cancer is the second most common solid internal malignancy and over 50,000 deaths in the U.S. are attributable to this disease. Since the early disease lacks outward signs or symptoms, sensitive recognition of early cancers is key to preventative screening. Current screening techniques, primarily colonoscopy, identify large adenomatous lesions but often miss at least two forms of early colorectal cancer: small adenomas (<5 mm) and flat lesions. Confocal laser endomicroscopy is currently being used for in situ histology as a complement to endoscopy. However up to one-third of adenomas are still missed using this technique, because the fluorescent imaging agents currently in use non-selectively stain normal as well as neoplastic mucosal tissue. In this project we propose to synthesize and investigate new porphyrin and phthalocyanine fluorescent markers that selectively target colon cancer cells. Specifically our strategy involves the targeting of epidermal growth factor receptors (EGF-R) and human carcinoembryonic antigen (CEA), both over-expressed in colon cancer cells. Our proposed research is based on our preliminary investigations of a small library of porphyrin- and phthalocyanine-peptide conjugates and one phthalocyanine-CEA conjugate. Our Specific Aims are: (1a) To synthesize a new series of porphyrins and Pc conjugated to EGF-R peptide ligands and anti-CEA MAb in order to enhance colon cancer targeting; (1b) to evaluate the new conjugates in vitro using human colon carcinoma cells; (2a) to expose promising conjugates to a organ culture of colon cancer with surrounding colon; (2b) to directly inject selected conjugates into colon tumors grown orthotopically in nude mice; and (2c) to instill topically onto rectal mucosa selected imaging agents and investigate their in vivo fluorescence emission and CRC tumor cell selectivity. Porphyrins have been used for over 100 years as labels for biomolecules and as treatment agents by photodynamic therapy, but currently known porphyrins are not tumor-targeted. While naturally occurring porphyrin macrocycles absorb and emit within the 620-660 nm range, phthalocyanines absorb and emit further into the near-IR region (670-750 nm) where light penetrates deeper through tissues and interference from other molecules and autofluorescence is minimized. The proposed studies are of extremely high relevance since they could lead to a much more effective early detection of CRC which could greatly reduce the incidence and mortality of CRC. Furthermore, these studies could form the basis for the development of more efficient tumor-targeted imaging agents and chemotherapeutics. PUBLIC HEALTH RELEVANCE: Our proposed program is of great relevance to public health since cancer is still the second most common cause of death in the Nation and, in particular colorectal cancer, is the second most common solid internal malignancy. The effective early detection of tumors as well as tumor infiltrative areas and tumor metastasis will have an enormous impact on treatment planning, tumor response to treatment and overall treatment outcome, will increase the success of cancer treatment with minimal cost, and will increase the patient's quality of life.

描述（由申请人提供）：本项目提出使用基于四吡咯的缀合物来荧光标记结直肠肿瘤病灶。结直肠癌是第二常见的实体内部恶性肿瘤，在美国有超过50，000例死亡可归因于这种疾病。由于早期疾病缺乏外在的体征或症状，早期癌症的敏感识别是预防性筛查的关键。目前的筛查技术，主要是结肠镜检查，可以识别大的腺瘤性病变，但通常会错过至少两种形式的早期结直肠癌：小腺瘤（<5 mm）和扁平病变。共聚焦激光显微内镜目前正用于原位组织学检查，作为内窥镜检查的补充。然而，由于目前使用的荧光成像剂非选择性地染色正常和肿瘤性粘膜组织，因此使用该技术仍然错过了多达三分之一的腺瘤。在这个项目中，我们建议合成和研究新的卟啉和酞菁荧光标记物，选择性地靶向结肠癌细胞。具体而言，我们的策略涉及靶向表皮生长因子受体（EGF-R）和人癌胚抗原（CEA），两者都在结肠癌细胞中过表达。我们提出的研究是基于我们的初步调查的一个小图书馆的卟啉和酞菁肽共轭物和酞菁CEA共轭物。我们的具体目标是：（1a）合成一系列新的卟啉和酞菁偶联EGF-R肽配体和抗CEA单克隆抗体，以增强结肠癌靶向性;（1b）使用人结肠癌细胞体外评价新偶联物;（2a）将有希望的偶联物暴露于具有周围结肠的结肠癌器官培养物;（2b）将选择的缀合物直接注射到裸鼠中原位生长的结肠肿瘤中;和（2c）将选择的成像剂局部滴注到直肠粘膜上，并研究它们的体内荧光发射和CRC肿瘤细胞选择性。卟啉作为生物分子的标记物和作为光动力疗法的治疗剂已经使用了100多年，但是目前已知的卟啉不是肿瘤靶向的。虽然天然存在的卟啉大环在620-660 nm范围内吸收和发射，但酞菁吸收和发射进一步进入近红外区域（670-750 nm），其中光更深地穿透组织，并且来自其他分子和自发荧光的干扰最小化。拟议的研究具有极高的相关性，因为它们可能导致更有效地早期发现CRC，从而大大降低CRC的发病率和死亡率。此外，这些研究可以为开发更有效的肿瘤靶向成像剂和化疗药物奠定基础。 公共卫生关系：我们提出的计划与公共卫生密切相关，因为癌症仍然是全国第二大常见的死亡原因，特别是结直肠癌，是第二大常见的实体内部恶性肿瘤。肿瘤以及肿瘤浸润区域和肿瘤转移的有效早期检测将对治疗计划、肿瘤对治疗的反应和总体治疗结果产生巨大影响，将以最小的成本增加癌症治疗的成功，并将提高患者的生活质量。