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. Chemotherapy has long been used to provide tumor control during cancer treatment. However, there are several limitations of chemotherapy. First, free chemotherapeutic agents tend to distribute to the whole body, causing the familiar treatment side effects associated with chemotherapy. Second, a lack of a noninvasive manner to assess chemotherapy drug concentration post treatment has hindered study of how drug distribution/dose affects tumor control. Temperature sensitive liposomes (TSLs) may provide a way to overcome both of these hurdles because they localized drug release at the tumor site and allow noninvasive imaging of the drug concentration distribution. However, in order to have local drug release, and accurate measurement of drug concentration, local hyperthermia (HT) must be applied and the temperature must be accurately measured. The hyperthermia causes the lipid membrane of the liposome to break down, and the increased permeability in concert with the absolute temperature quantitatively influence the signal received from the imaging. Consequently, the project we are proposing will help explain the relationship between tissue temperature and drug release were in previous experiments the temperature from the hyperthermia device was estimated but not measured. The primary goal of our TSL research is to develop a technology that can be moved from the lab/animal domain into the clinic/human domain. Our initial work with the CIVM in Viglianti et al. 2004 and 2006 demonstrated that we could image and quantify drug distribution delivered with TSL. From this work the measured signal was dependent on drug/TSL concentration in addition to temperature. Temperature data from animals that were not imaged allowed us to make assumptions about the animal's temperature that were necessary to convert the measured signal to absolute concentration of drug. Although a first approximation, the previous work allowed Ponce et al. (2007) to demonstrate that the temperature distribution was just as important as total drug delivered in the efficacy of TSL. This was possible by changing the sequence of the applied hyperthermia and the administration of the TSL. In our experiment, the effects of HT are necessary for multiple reasons. Biologically, HT causes the vascular system of the tumor to become more """"""""leaky"""""""" and increased the perfusion of the tumor. This effect is taken advantage of in the clinic in order to improve tumor oxygenation, which in turn leads to improved radiation response. To maximize the benefits of this effect, accurate temperature monitoring is essential. Attempts to do this non-invasively are currently on going. The method that is suitable for our purposes utilizes the proton resonant frequency (PRF) shift that occurs with changing temperature. To do this, we will use a spoiled gradient recalled acquisition in steady state (spoiled GRASS) pulse sequence. By using the pre and post heating phase data of a given ROI and the temperature independent phase data from an oil standard, the temperature of the tissue can be derived. The oil standards are used because they allow us to map the field inhomogenity and to correct for phase drift of the sample in the magnet. In our experiment hyperthermia is used for targeting of the liposome contents through TSL release. The rat will be treated with HT while inside the magnet, and the LTSL will be injected after HT. The study that we are proposing overcomes one of the main limitations of previous studies by Viglianti et al. (2004,2006) by actively monitoring the temperature of the animal instead of using steady state heat flow equations to estimate it. By noninvasively monitoring the temperature of the tissue during liposome content release, we can see how the temperature maps of the tissue will help predict the final destination of the chemotherapy drug release. This will potentially enable one to """"""""paint"""""""" chemotherapy drug onto the tumor by altering the temperature maps so that the desired end doxorubicin concentration is received. The project that we are proposing uses a rat fibrosarcoma model with liposomes injected before hyperthermia. We will then attempt to relate a non-invasive temperature map obtained from a spoiled gradient recalled echo pulse sequence in a 2T magnet to the T1 based DOX concentration measurements in order to better understand how heating affects in vivo drug concentration and further demonstrate the translation of the imagable liposome system to the clinic.
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