Researchers working on new therapies and drug developments for pancreatic cancer and groups working on preclinical studies with interest in noninvasive monitoring technique will benefit from this work. Pancreatic cancer is the fourth leading cause of cancer mortality rates in the United States. Current treatment options are of limited benefit with a five-year survival rate following diagnosis of less than 5% (1). Dense stroma and poor vascular perfusion limits drug penetration and uptake into the tumor tissue. Growing evidence suggests that hyperthermia can decrease drug resistance by enhancing cellular uptake (2). MR-guided heating methods enable accurate and precise spatial and temporal control of heating, and when coupled with temperature sensitive liposomes (TSLs), could result in tightly targeted drug delivery (3,4). The goal of the study was to evaluate enhanced drug delivery to treat pancreatic tumor in a clinically relevant transgenic mouse model using Magnetic Resonance-guided High Intensity Focused Ultrasound (MR-HIFU) in conjunction with a heat triggered drug delivery system. Two different mouse models of pancreatic ductal adenocarcinoma were analyzed for these studies: a transgenic mouse model (KPC) and an induced orthotopic model. An animal positioning system with an integrated 4-channel small animal Magnetic Resonance Imaging (MRI) coil (Philips Medical Systems, Helsinki, Finland) was used with the MR-HIFU system (Sonalleve®, Philips Healthcare) to hold, image and treat the mice assigned to the experimental group. The mild hyperthermia heating algorithm resulted in a tight target temperature range (41 ± 0.5°C, target = 40 - 41°C) which was homogeneous within the ROI (Figure 1). Approximately 20 s were required to achieve the target temperature (Figure 2). Defined tumor tissue was treated by targeted sonications (1.2 MHz frequency, 7W acoustic power) in 5-10 minute increments with a total time of 30 minutes after injection of free doxorubicin (Dox) or TSLs loaded with Dox (ThermoDox®, Celcion Corporation). Temperature elevation during sonications was monitored by a gradient echo based echo planar imaging (EPI) sequence with an EPI factor of 5, a TE/TR value of 16/25 ms, a flip angle of 20 degree, and a dynamic scan time of 1.8 s. A small gel phantom placed beside the mouse was used to monitor the magnetic drift for temperature correction. Mice were flushed before sacrifice and tumor tissue was removed for evaluation. Tumor drug uptake was evaluated by fluorescence microscopy and high performance liquid chromatography (HPLC).The median increase in tumor doxorubicin concentration in the treated region is 9-fold greater than the concentration in untreated regions of the tumor (up-to a maximum 16-fold increase). Figure 3 shows the concentration of drug in tissue measured by HPLC for HIFU treated and untreated tumors (Fig. 3A) as well as fluorescence microscopy images qualitatively demonstrating the difference in drug concentration in untreated (Fig. 3B) and treated (Fig. 3C) regions of the tumor in the same animal. Fluorescence evaluation of the tumor tissue revealed increased focal nuclear uptake of Dox in regions treated with MR-HIFU hyperthermia with systemically administered Dox loaded TSLs. Quantitative measurement of tissue drug concentrations using HPLC, indicated an increase in Dox uptake from TSL compared to free Dox and Dox loaded TSLs without hyperthermia application.This method provides precise and non-invasive hyperthermia treatment in a small animal using a clinically available MR-HIFU system. The combination of hyperthermia with Dox loaded TSLs resulted in higher concentration of doxorubicin compared to free Dox and Dox loaded TSLs without hyperthermia. These results are encouraging as we move into survival studies. The clinical translation would offer a new non-invasive and local treatment option for this type of cancer.