Iron PARACEST MRI Contrast Agents for Monitoring Hyperthermia-based Therapy

描述（由申请人提供）：项目概述一种有前景的靶向治疗耐药癌症的方法是从热敏脂质体中热诱导药物释放。这种方法将通过追踪脂质体沉积到肿瘤和随后的药物释放作为温度函数的方法来实现。一类新的含铁（Fe(II)）配合物的化合物将被开发出来，以跟踪脂质体对肿瘤的摄取并监测脂质体的温度。我们的铁（II）配合物通过酰胺或氨基吡啶基团上可交换的氢质子的化学交换饱和转移（CEST）产生对比，这些质子共振被顺磁性的铁（II）中心（铁（II）试剂）从大量水的质子共振高度转移。在可交换质子共振频率上应用射频脉冲使这些质子的磁化饱和，并通过交换降低了大量水质子池的磁化。初步研究表明，在30-50℃范围内，我们的ferroCEST试剂的CEST峰位置与温度成正比。这种与浓度无关的位移导致MRI测温剂可以直接校准到温度。我们的具体目标是开发Fe(II) PARACEST试剂，将其纳入脂质双分子层。这些ferroest试剂将含有长长的碳氢化合物尾部，并且总体上是阴离子、中性或阳离子。ferroCEST试剂将与市售脂质结合形成一系列脂质体，其中一些脂质体预计在40-41℃的期望范围内具有热敏性。CEST峰的温度依赖性将在体外通过核磁共振波谱仪和4.7 T核磁共振扫描仪的成像模型来确定。PARACEST测温Fe（II）复合物的初步体内研究将通过对小鼠结肠癌肿瘤进行局部热疗和在治疗期间进行cest成像来进行。水质子频率共振（PFR）测温将用于验证肿瘤温度的变化。长期目标是开发含铁的脂质体，该脂质体无毒，可生物降解，可用于测量脂质体药物传递和热疗或消融治疗期间的MR测温。

DESCRIPTION (provided by applicant): Project Summary A promising approach to target treatment resistant cancers is hyperthermia-induced release of drugs from thermally sensitive liposomes. This approach would be enabled by methods that track liposome deposition into tumor and subsequent drug release as a function of temperature. A new class of compounds containing iron (Fe(II)) coordination complexes will be developed to track liposome uptake into tumors and to monitor the liposome temperature. Our Fe(II) complexes produce contrast through chemical exchange saturation transfer (CEST) of exchangeable NH protons on amide or amino-pyridine groups that have proton resonances which are highly shifted from that of bulk water by the paramagnetic Fe(II) center (ferroCEST agents). Application of a radiofrequency pulse at the exchangeable proton resonance frequency saturates the magnetization of these protons and, through exchange, decreases the magnetization of the bulk water proton pool. Initial studies indicate that the CEST peak position of our ferroCEST agents is directly proportional to temperature over the range of 30-50 oC. This concentration independent shift leads to MRI thermometry agents that can be calibrated directly to temperature. Our specific goals are to develop Fe(II) PARACEST agents for incorporation into the lipid bilayer. These ferroCEST agents will contain long hydrocarbon tails and will be overall anionic, neutral or cationic in charge. The ferroCEST agents will be combined with commercially available lipids to form a series of liposomes, some of which are anticipated to be thermally sensitive over the desired range of 40-41 oC. The temperature dependence of the CEST peak will be determined in vitro by studies on a NMR spectrometer and in imaging phantoms on a 4.7 T MRI scanner. Initial in vivo studies of PARACEST thermometry of the Fe(II) complexes will be carried out by performing localized hyperthermia in murine colon carcinoma tumor in mice and performing CEST-imaging during treatment. Water proton frequency resonance (PFR) thermometry will be used to verify changes in tumor temperature. A long-term goal is to develop ferroCEST containing liposomes that are non-toxic, biodegradable and useful for measuring liposomal drug delivery and MR thermometry during hyperthermia or ablation therapies.