VALIDATION OF T1-BASED PREDICTIONS OF LIPOSOMAL DRUG CONCENTRATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 每只大鼠的右侧都会有一个直径约1.5厘米的纤维肉瘤。我们已经在动物研究中表明，热疗可以与温敏脂质体(LTSLs)相结合，以增加对肿瘤的药物输送。使用包含磁共振造影剂和药物的多模式LTSLs，我们能够使用MRI可视化脂质体的释放。在之前的一个使用大鼠纤维肉瘤的CIVM项目中，我们已经证明，使用含有硫酸锰和阿霉素的脂质体，T1缩短与给药过程中和给药后的药物浓度呈线性相关。此外，在该模型中，我们还完成了一项基于T1的肿瘤药物浓度和分布模式与肿瘤反应的相关性研究。本研究的目的是使用不同的化疗药物(顺铂)和不同的造影剂(加多特罗)来扩大多模式LTSL的应用。顺铂因其广泛的临床疗效和与热疗的协同作用而被选择。选择加多特罗是因为它的稳定性、安全性和低渗透压。重要的是，我们决定改用一种螯合(并得到FDA批准)的磁共振造影剂，因为与未螯合的锰相关的毒性。因此，这一新配方更有可能被开发用于临床应用。 该项目建议书将使用DeWhirst、Viglianti和Ponce在以前的CIVM项目中使用的相同动物模型(大鼠纤维肉瘤)和T1加权SPGR扫描方法。大鼠腹腔注射麻醉后。注射戊巴比妥钠、尾静脉导管和直肠温度计，动物将被放置在脂肪线圈中。在整个治疗过程中，最初的T1序列(可变翻转角度)之后将是动态图像序列(恒定翻转角度)。治疗结束后，动物将被静脉注射处死。戊巴比妥(经尾静脉导管)。肿瘤将立即被采集并冷冻在液氮中。顺铂和加多特利多在肿瘤中的浓度将在稍后用原子发射光谱分析测定，以及 这些值将与基于T1的预测进行比较。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Each rat will bear a fibrosarcoma on its right flank, ~1.5 cm in diameter at the time of the MRI experiment.We have shown in animal studies that hyperthermia can be combined with temperature sensitive liposomes (LTSLs) to increase drug delivery to tumors. Using multimodal LTSLs containing MR contrast agent and drug, we are able to visualize liposome release using MRI. In a previous CIVM project using rat fibrosarcoma, we have shown that T1 shortening is linearly correlated to drug concentration during and after administration, using a liposome containing manganese sulfate and doxorubicin. In addition, we have completed a study correlating T1-based tumor drug concentrations and distribution patterns with tumor response in this model. The purpose of the current study is to expand the application of the multimodal LTSL using a different chemotherapeutic agent (cisplatin) and a different contrast agent (gadoteridol). Cisplatin was chosen because of its broad clinical efficacy and synergism with hyperthermia. Gadoteridol was chosen because of its stability, safety, and low osmolarity. Importantly, we decided to switch to a chelated (and FDA-approved) MR contrast agent because of the toxicities associated with unchelated manganese. Therefore, this new formulation is more likely to be developed for clinical application. This project proposal will use the same animal model (rat fibrosarcoma) and T1-weighted SPGR scanning method that were used in previous CIVM projects by Dewhirst, Viglianti, and Ponce. After the rat is anesthetized by i.p. injection of pentobarbital, a tail vein catheter and a rectal thermometer will be placed and the animal will be positioned in the fat coil. An initial T1 series (varying flip angle) will be followed by a dynamic series of images (at constant flip angle) throughout therapy. At the end of therapy, the animal will be sacrificed by i.v. pentobarbital (via tail vein catheter). The tumor will be immediately harvested and frozen in liquid nitrogen. The cisplatin and gadoteridol concentrations in the tumor will be measured at a later time by atomic emission spectrometry, and these values will be compared to T1-based predictions.