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和温度映射，因为这些参数在肿瘤诊断或治疗中被利用。为此，已经为MR开发了由顺磁性灯笼离子（LN3+）组成的智能对比剂（SCA）（LN3+），MR已开发为MR。我们已经表明，两个基于TM3+的SCAS基于TMDOTP5和TMDOTMA，提供了细胞外pH/温度图，并具有偏移（鸟类）冗余偏差的生物传感器成像。这些类型的SCA被用作MRS Shipt剂，以分离内源分子（或离子）的共振。但是，鸟类映射了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）的顺磁化学交换饱和转移（Paracest）相反。通过鸟类检测非交换质子的质子可为提取温度/pH值，化学位移成像（CSI）数据迅速获取以较高的信噪比（SNR）获取，并且对磁场强度（BO），BO SHIM条件差和SCA的浓度几乎不敏感。在11.7T时具有高速2D CSI的鸟类允许在大鼠的脑皮质中使用TMDOTP5-（磷酸，高电荷）和TMDOTMA-（羧酸，低电荷）的空间分辨率约为10 <l或更好。 TMDOTMA中存在-CH3部分 - 可实现约5W较高的SNR。 这种耶鲁大环（Yale）大环境伙伴关系将研究四个新型LN3+基于Cyclen的复合物。但是，要绘制跨大鼠大脑中皮层到皮层下区域的肿瘤，其空间分辨率〜1 <L-在Micropet和Microspect的范围内，我们将首先通过将相位型阵列射频技术与球形编码的K -Space 3D CSI（AIM 1）相结合，首先实现整个大脑覆盖率（AIM 1）。我们将合成具有提高pH和/或温度的灵敏度/特异性的独特SCA（AIM 2）。这些新的SCA（即磷酸酯和丙氨酸 - 酰胺以及其19F标记的类似物）将具有高SNR不合转的质子，带有两个-CH3部分，通过排斥磷酸含磷酸的生物分布，并且由于跨脑屏障（BBB）的改善（bbb）的渗透性提高了。然后，每个SCA的敏感性对生理参数的敏感性，测试其动力学惰性和BBB渗透性（AIM 3）。然后，我们将检查它们的毒性和生物分布（AIM 4）。最后，我们将将这些SCA应用于大鼠脑中的9L和CNS-1肿瘤（AIM 5）。大鼠中提出的工作是进行临床前发育的门户，而翻译成人类的工作已经上场，因为有明确的工业迹象，用于用鸟类或最偏见的药物进行分子成像。拟议工作的最终产物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，那么它将代表诊断性人体成像中的巨大范例。