VALIDATION OF T1-BASED PREDICTIONS OF LIPOSOMAL DRUG CONCENTRATION

点击翻译按钮获取中文摘要

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.