Bioresponsive MR probes for imaging pancreatic cancer

用于胰腺癌成像的生物响应 MR 探针

• 批准号: 10117201
• 负责人: Megan Kaster
• 金额: $ 4.09万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117201
• 关键词: Address; Affect; Anatomy; Biochemistry; Biodistribution; Biological Markers; Cancer Etiology; Cell Adhesion; Cells; Cellular biology; Cessation of life; Cleaved cell; Clinical; Collagen; Contrast Media; Curative Surgery; Cyclic Peptides; Data; Desmoplastic; Detection; Development; Diagnosis; Diagnostic Imaging; Diagnostic Procedure; Disease; Early Diagnosis; Ensure; Environment; Evaluation; Event; Excision; Exposure to; Funding; Gadolinium; Gelatinase B; Image; Imaging Techniques; In Vitro; Incidence; Integrins; Ionizing radiation; Lanthanoid Series Elements; Ligands; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Mission; Modeling; Molecular; Molecular Probes; Monitor; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Pancreas; Patient-Focused Outcomes; Patients; Penetration; Peptides; Performance; Periodicity; Primary Neoplasm; Prognosis; Proliferating; Publications; Relaxation; Reporting; Resolution; Scanning; Signal Transduction; Site; Stimulus; Survival Rate; Symptoms; Techniques; Testing; Time; Tissues; Tumor Markers; Tumor Tissue; Tumor Volume; base; design; enzyme activity; imaging probe; improved; improved outcome; in vivo; interest; molecular imaging; molecular marker; mortality; mouse model; non-invasive monitor; novel strategies; overexpression; pancreatic cancer model; pancreatic neoplasm; ratiometric; receptor; reconstruction; response; screening; soft tissue; spatiotemporal; targeted agent; translational model; tumor; tumor growth; tumor hypoxia; tumor microenvironment; tumor progression; tumorigenesis

Pancreatic cancer holds the poorest prognosis of any cancer with an incident rate nearly equal to its mortality rate. While significant advances in treatment have been made for many other cancers, the outcomes for pancreatic cancer have only marginally improved. Current diagnostic methods are only able to detect the disease at late stages, at which point the primary tumor is often too advanced for curative surgery and has metastasized. By enabling detection of early stages of pancreatic cancer, the outcome of patients could be drastically improved. By specifically detecting changes in local biochemistry and cell biology through environmental and molecular tumor markers, it is possible to detect a nascent tumor before it has developed enough to cause anatomical or functional disturbances. Key environmental markers of proliferating tumors include a high reduction potential, induced by tumor hypoxia, and collagen-rich desmoplasia. Pancreatic cancer molecular markers of aggressive disease types include high levels of αvβ6 integrin receptor and elevated matrix metalloproteinase-9 (MMP-9) activity. These molecular markers can be detected by bioresponsive magnetic resonance (MR) contrast agents that are targeted to tumor markers. Clinically-approved Gd(III) MR contrast agent (CAs) provide a versatile platform for developing molecular imaging probes for pancreatic cancer through the detection of environmental and molecular markers. The Meade lab has continued to develop responsive Gd(III) CAs with a variety of activation mechanisms that alter the probe's signal in response to specific conditions. Electronic spin relaxation time (T1e) modulated molecular imaging probes provide a promising bioactivatable platform for Gd(III)-based CA with a low r1,off and bright r1,on. Because T1e is the only parameter to affect all coordination spheres of the CA, its modulation can establish a lower background signal than modulation of T1 parameters. Redox-sensitive T1e- modulated probes will use a collagen-targeting cyclic peptide to accumulate in the desmoplastic microenvironment and will be tuned for a tumor specific redox potential. MR shift probes provide a bioactivatable method of distinguishing tumor tissue from healthy tissue based on ratiometric imaging, in which the signal of the probe shifts in response to environmental conditions. Using cyclic RGD to target integrin receptors overexpressed in pancreatic cancer and a short peptide cleaved by MMP-9, this probe will accumulate in pancreatic tumors and provide ratiometric data on MMP-9 activity. The performance of the new probes will be evaluated in vivo using healthy mice and an orthotopic model of pancreatic cancer. This proposal meets the mission statement and funding plans of the NCI. The project involves the development of new imaging probes for molecular detection of pancreatic cancer. Environmental and molecular markers of pancreatic cancer provide a target for early detection. Because of the poor prognosis associated with pancreatic cancer, advances in disease detection could drastically improve patient outcome.

胰腺癌是所有癌症中预后最差的，其发病率几乎等于其死亡率 速度。虽然许多其他癌症的治疗已取得重大进展，但结果 胰腺癌仅略有改善。目前的诊断方法只能检测到 疾病已处于晚期，此时原发肿瘤往往已处于晚期，无法进行根治性手术 已转移。通过检测胰腺癌的早期阶段，患者的结果可能是 显着改善。通过专门检测局部生物化学和细胞生物学的变化 环境和分子肿瘤标志物，可以在新生肿瘤发展之前检测到它 足以引起解剖或功能障碍。增殖肿瘤的关键环境标志物 包括由肿瘤缺氧和富含胶原蛋白的结缔组织引起的高还原电位。胰 侵袭性疾病类型的癌症分子标志物包括高水平的 αvβ6 整合素受体和 基质金属蛋白酶 9 (MMP-9) 活性升高。这些分子标记可以通过以下方式检测： 针对肿瘤标志物的生物响应磁共振 (MR) 造影剂。 临床批准的 Gd(III) MR 造影剂 (CA) 为开发提供了一个多功能平台 通过检测环境和分子水平来检测胰腺癌的分子成像探针 标记。 Meade 实验室继续开发具有多种激活功能的响应性 Gd(III) CA 根据特定条件改变探针信号的机制。电子自旋弛豫时间（T1e） 调制分子成像探针为基于 Gd(III) 的 CA 提供了一个有前途的生物可激活平台 低 r1，关，亮 r1，开。由于 T1e 是影响 CA 所有协调范围的唯一参数，因此它的 调制可以建立比 T1 参数调制更低的背景信号。氧化还原敏感 T1e- 调制探针将使用胶原蛋白靶向环肽在促纤维细胞中积累 微环境并将针对肿瘤特异性氧化还原电位进行调整。 MR 位移探头提供 基于比率成像区分肿瘤组织和健康组织的生物可激活方法，其中 探头的信号会根据环境条件而变化。使用环状 RGD 靶向整合素 胰腺癌中过度表达的受体和 MMP-9 切割的短肽，该探针将 在胰腺肿瘤中积累并提供 MMP-9 活性的比例数据。新机的表现 将使用健康小鼠和胰腺癌原位模型对探针进行体内评估。 该提案符合 NCI 的使命宣言和资助计划。该项目涉及 开发用于胰腺癌分子检测的新型成像探针。环境和 胰腺癌的分子标记物为早期检测提供了目标。由于预后不佳 与胰腺癌相关，疾病检测的进步可以极大地改善患者的治疗结果。