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: 8408792
• 负责人: Dewan Syed Fahmeed Hyder
• 金额: $ 32.85万
• 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/8408792
• 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 Targeting; Esters; Exclusion; Frequencies; Future; Goals; Health; Human; Hyperthermia; 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.

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，智能造影剂（SCA）组成的顺磁性镧系离子（Ln 3+）与衍生物的1，4，7，10四氮杂环十二烷（cyclen）已开发用于MR。我们已经表明，两个商业Tm 3+为基础的SCA，TmDOTP 5和TmDOTMA，提供细胞外pH/温度图与生物传感器成像的冗余偏差的变化（BIRDS）。这些类型的SCA用作MRS移位剂以分离内源性分子（或离子）的共振。然而，BIRDS映射来自不可交换质子的1H信号（即，CHx），这与具有可交换质子（例如，OH或NHx）。通过BIRDS对不可交换质子的检测提供了提取温度/pH的冗余，化学位移成像（CSI）数据被快速获取以获得上级信噪比（SNR），并且定量对磁场强度（Bo）、不良Bo匀场条件和SCA浓度几乎不敏感。在11.7T下具有高速2D CSI的BIRDS允许在分别具有TmDOTP 5-（膦酸，高电荷）和TmDOTMA-（羧酸，低电荷）的大鼠大脑皮层中具有约10 μ L或更好的空间分辨率。TmDOTMA中-CH 3部分的存在能够实现约5 W的更高SNR。 这个耶鲁-Macrocyclics合作伙伴关系将研究四种新型的基于Ln 3 + cyclen的复合物。然而，为了以~1 <L的空间分辨率（其在microPET和microSPECT的限制内）映射大鼠大脑中从皮层到皮层下区域的肿瘤，我们将首先通过将相控阵射频技术与球形编码的k空间3D CSI相结合来实现全脑覆盖（目标1）。我们将合成对pH和/或温度具有改进的灵敏度/特异性的独特SCA（目标2）。这些新的管制计划协议（即，膦酸酯和丙氨酸-酰胺以及它们的19 F-标记的类似物）的特征将在于具有两个-CH 3部分的高SNR不可交换质子、通过排除膦酸而有利的生物分布以及由于较低的SCA电荷而改善的穿过血脑屏障（BBB）的渗透性。然后通过MR表征每种SCA对生理参数的敏感性，检测其动力学惰性和BBB渗透性（目标3）。然后，我们将研究其毒性和生物分布（目标4）。最后，我们将应用这些SCA研究大鼠脑中的9 L和CNS-1肿瘤（目的5）。在大鼠中进行的拟议工作是临床前开发的门户，并且即将转化为人类，因为BIRDS或PARACEST试剂的分子成像有明确的工业迹象。拟议工作的最终产品将有助于确定最可能的结构特征以及可接受的毒理学和生物分布。如果这种类型的临床前开发是成功的，那么它将代表诊断人类成像的巨大范例。