Abstract LB-165: Early detection of the therapeutic effect in tumors treated with a thermosensitive liposome (TSL) using noninvasive ultrasound and photoacoustic imaging

Abstract

Abstract The ability to assess treatment response on a case-by-case basis in a non-invasive and longitudinal manner has the potential to maximize treatment success. In this work temperature sensitive liposomes (TSLs) have been combined with non-invasive high frequency ultrasound (US) and photoacoustic (PA) imaging to assess structural (cell death) and functional (oxygenation) aspects of tumor response, indicative of therapeutic effect, within a few hours post-treatment in a preclinical model. A TSL is a drug delivery vehicle designed to release its payload at mild-hyperthermic temperatures (39-42°C). The TSL passes through the systemic circulation (37°C), until it reaches a tumor undergoing localized heating (42°C), where it releases its contents rapidly, creating a high local concentration of drug within the tumor vasculature. This leads to high tumoral drug uptake and a number of functional changes within the tumor, resulting in a therapeutic response. Conventional assessment of treatment success is measured by the change in tumor volume over time, but this may not be noticeable until several days post-treatment and no further insight into the biology of the tumor response kinetics is provided. By using US and PA imaging in a non-invasive co-registered manner, structural and functional imaging surrogates of tumor response can be visualized in 3D. These images allow the observation of changes in the first few hours post-treatment and provide both an early indication of overall therapeutic effect and insight into the kinetics of the drug-tumor interaction. Here we have used a simple 2 component TSL called HaT (Heat activated cytoToxic, DPPC/Brij78, 96:4 mol%), designed to deliver doxorubicin (DOX), which has been shown to rapidly release drug at mild-hyperthermic temperatures (100% in <40 s), but has good drug stability at 37°C [Tagami et al. J. Control. Release 2011, 152, 303]. A murine breast cancer model (EMT-6) implanted in the footpad of mice was imaged using the VisualSonics Vevo LAZR system at time points before and after treatment with TSL and localized heating. Co-registered, 3D US and PA images were acquired using a 40 MHz centre frequency transducer. Tumor boundaries were outlined in the US images and used to construct oxygen saturation (sO2) maps of the tumor from the PA data acquired at 750/850 nm to target the endogenous absorption of oxy/deoxy-hemoglobin. Significant changes in sO2 data (p<0.05) were measured within the tumor over the time course studied (0, 1, 2, 5, 24, 48, 168 h), with the greatest variation between HaT-DOX and control groups being observed between 0 and 5 h. The ability to longitudinally monitor the sO2 allows for rapid feedback on functional changes within an individual tumor on much shorter time scales (<5 h) than conventional tumor volume measurements. Mice tumors that received HaT-DOX treatments resulted in a >30% decrease in sO2 within the first 5 h post-treatment and showed >50% tumor regression after 14 days. Furthermore, the extent of tumor regression was observed to be proportional the magnitude of this early decrease in sO2. The observed longitudinal variations in sO2 represent the unique ability of US/PA imaging to monitor structural and functional changes within tumor vasculature and can be used as a rapid, non-invasive early indicator of HaT-DOX treatment efficacy. Citation Format: Jonathan P. May, Eno Hysi, Lauren Wirtzfeld, Elijus Undzys, Michael C. Kolios, Shyh-Dar Li. Early detection of the therapeutic effect in tumors treated with a thermosensitive liposome (TSL) using noninvasive ultrasound and photoacoustic imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-165. doi:10.1158/1538-7445.AM2014-LB-165