Translation of smart contrast agents for brain tumor characterization by MR

MR 脑肿瘤表征智能造影剂的转化

• 批准号: 8105088
• 负责人: Dewan Syed Fahmeed Hyder
• 金额: $ 38.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-05 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105088
• 关键词: Alanine; Amides; Area; Biodistribution; Biological Assay; Biosensor; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Carboxylic Acids; Cell Line; Cell physiology; Cerebral cortex; Charge; Chemical Shift Imaging; Chemicals; Complex; Contrast Media; Data; Deposition; Detection; Development; Diagnosis; Diagnostic; Drug Delivery Systems; Esters; Exclusion; Fever; Frequencies; Future; Goals; Health; Human; Image; Improve Access; In Situ; In Vitro; Ions; Kinetics; Label; Laboratories; Lanthanoid Series Elements; Magnetic Resonance Imaging; Maps; Measurement; Measures; Methods; Neurons; Noise; Normal tissue morphology; Permeability; Phase; Phosphonic Acids; Physiological; Positron-Emission Tomography; Property; Protons; Radio; Rattus; Relaxation; Research Personnel; Resolution; Rodent; Sensitivity and Specificity; Sensory; Signal Transduction; Speed; System; Technology; Temperature; Testing; Time; Tissues; Toxic effect; Toxicology; Translating; Translations; Work; analog; anticancer research; base; bone; cancer therapy; cyclen; cytotoxicity; design; extracellular; improved; in vivo; in vivo Model; magnetic field; molecular imaging; novel; pH gradient; phosphonate; pre-clinical; preclinical study; public health relevance; single photon emission computed tomography; tumor

DESCRIPTION (provided by applicant): Non-invasive pH and temperature mapping is needed for cancer research because these parameters are exploited in tumor diagnosis or therapy. To that goal, smart contrast agents (SCAs) composed of paramagnetic lanthanide ion (Ln3+) with derivatives of 1,4,7,10 tetraazacyclododecane (cyclen) have been developed for MR. We have shown that two commercial Tm3+-based SCAs, TmDOTP5 and TmDOTMA, provide extracellular pH/temperature maps with biosensor imaging of redundant deviation in shifts (BIRDS). These types of SCAs are used as MRS shift agents to separate resonances of endogenous molecules (or ions). However BIRDS maps the 1H signals from non-exchangeable protons (i.e., CHx) of the SCA itself, which is in contrast to the paramagnetic chemical exchange saturation transfer (PARACEST) agent that features exchangeable protons (e.g., OH or NHx). Detection of the non-exchangeable protons by BIRDS provides redundancy to extract temperature/pH, the chemical shift imaging (CSI) data are acquired rapidly for superior signal-to-noise ratio (SNR), and quantification is nearly insensitive to the magnetic field strength (Bo), poor Bo shim conditions, and the SCA's concentration. BIRDS with high speed 2D CSI at 11.7T allows spatial resolution of ~10 <L or better in rat's cerebral cortex with TmDOTP5- (phosphonic acid, high charge) and TmDOTMA- (carboxylic acid, low charge), respectively. Presence of a -CH3 moiety in TmDOTMA- enables about 5W higher SNR. This Yale-Macrocyclics partnership will study four novel Ln3+ cyclen-based complexes. However to map tumors spanning from cortical to subcortical regions in rat brain with ~1 <L spatial resolution - which is within limits of microPET and microSPECT we will first achieve whole brain coverage by combining phased array radio frequency technology with spherically encoded k-space 3D CSI (Aim 1). We will synthesize unique SCAs with improved sensitivity/specificity for pH and/or temperature (Aim 2). These new SCAs (i.e., phosphonate ester and alanine-amide as well as their 19F-labelled analogs) will feature high SNR non-exchangeable protons with two -CH3 moieties, favorable biodistribution by exclusion of phosphonic acids, and improved permeability across the blood-brain barrier (BBB) because of lower SCA charge. Each SCA will then be characterized by MR for its sensitivity to physiological parameter(s), tested for its kinetic inertness, and BBB permeability (Aim 3). Then we will examine their toxicity and biodistribution (Aim 4). Finally we will apply these SCAs to study 9L and CNS-1 tumors in rat brain (Aim 5). The proposed work in rats are the gateway to pre-clinical development and translation to humans is on the horizon because there are clear industrial signs for molecular imaging with BIRDS or PARACEST agents. The final product of the proposed work would help identify the most probable structural features with acceptable toxicology and biodistribution. If this type of pre-clinical development is successful, then it would represent huge paradigms in diagnostic human imaging. PUBLIC HEALTH RELEVANCE: Novel paramagnetic lanthanide macrocyclics will be synthesized and translated for tumor imaging in rat brain. Agents will feature non-exchangeable protons, detectable by biosensor imaging of redundant deviation in shifts (BIRDS), for pH and temperature mapping, where quantification is independent of agent concentration and magnetic field. Each agent, designed for superior sensitivity of BIRDS, will undergo assays for kinetic inertness, brain access, cytotoxicity, and distribution. Results will identify structural features with toxicology and biodistribution suitable for future pre-clinical studies.

描述（由申请人提供）：癌症研究需要非侵入性 pH 和温度绘图，因为这些参数用于肿瘤诊断或治疗。为了实现这一目标，我们开发了由顺磁性镧系离子 (Ln3+) 和 1,4,7,10 四氮杂环十二烷 (cyclen) 衍生物组成的用于 MR 的智能造影剂 (SCAs)。我们已经证明，两种基于 Tm3+ 的商业 SCA（TmDOTP5 和 TmDOTMA）可提供细胞外 pH/温度图，以及班次冗余偏差 (BIRDS) 的生物传感器成像。这些类型的 SCA 用作 MRS 位移剂来分离内源分子（或离子）的共振。然而，BIRDS 绘制了来自 SCA 本身的不可交换质子（即 CHx）的 1H 信号，这与具有可交换质子（例如 OH 或 NHx）特征的顺磁化学交换饱和转移 (PARACEST) 剂形成对比。 BIRDS 对不可交换质子的检测提供了提取温度/pH 的冗余，快速采集化学位移成像 (CSI) 数据以获得卓越的信噪比 (SNR)，并且定量对磁场强度几乎不敏感(Bo)、较差的 Bo 垫片条件以及 SCA 的浓度。具有 11.7T 高速 2D CSI 的 BIRDS 分别使用 TmDOTP5-（膦酸，高电荷）和 TmDOTMA-（羧酸，低电荷）在大鼠大脑皮层中实现约 10 <L 或更好的空间分辨率。 TmDOTMA- 中存在 -CH3 部分，可使 SNR 提高约 5W。 耶鲁大学与 Macrocyclos 的合作伙伴关系将研究四种新型 Ln3+ Cyclen 复合物。然而，为了以约 1 <L 的空间分辨率绘制大鼠大脑中从皮质到皮质下区域的肿瘤图谱（这在 microPET 和 microSPECT 的限制之内），我们将首先通过将相控阵射频技术与球形编码 k 空间 3D 相结合来实现全脑覆盖CSI（目标 1）。我们将合成独特的 SCA，提高 pH 和/或温度的灵敏度/特异性（目标 2）。这些新的 SCA（即膦酸酯和丙氨酸酰胺及其 19F 标记的类似物）将具有具有两个 -CH3 部分的高 SNR 不可交换质子、通过排除膦酸实现有利的生物分布以及改善的血液渗透性。由于 SCA 电荷较低，导致脑屏障 (BBB)。然后，每个 SCA 将通过 MR 表征其对生理参数的敏感性，测试其动力学惰性和 BBB 渗透性（目标 3）。然后我们将检查它们的毒性和生物分布（目标 4）。最后，我们将应用这些 SCA 研究大鼠脑中的 9L 和 CNS-1 肿瘤（目标 5）。拟议的在大鼠身上的工作是临床前开发的大门，并且向人类的转化即将到来，因为使用 BIRDS 或 PARACEST 试剂进行分子成像有明显的工业迹象。拟议工作的最终产品将有助于确定具有可接受的毒理学和生物分布的最可能的结构特征。如果这种类型的临床前开发成功，那么它将代表诊断人体成像的巨大范例。 公共卫生相关性：将合成新型顺磁性镧系元素大环化合物并转化为大鼠脑肿瘤成像。药剂将具有不可交换的质子，可通过生物传感器成像的位移冗余偏差 (BIRDS) 进行检测，用于 pH 和温度绘图，其中量化独立于药剂浓度和磁场。每种试剂均专为 BIRDS 的卓越灵敏度而设计，将接受动力学惰性、大脑通路、细胞毒性和分布测定。结果将确定适合未来临床前研究的毒理学和生物分布的结构特征。