Photoacoustic Imaging of Cancer Treatment Response: Early Detection of Therapeutic Effect from Thermosensitive Liposomes

Abstract

Imaging methods capable of indicating the potential for success of an individualized treatment course, during or immediately following the treatment, could improve therapeutic outcomes. Temperature Sensitive Liposomes (TSLs) provide an effective way to deliver chemotherapeutics to a localized tumoral area heated to mild-hyperthermia (HT). The high drug levels reached in the tumor vasculature lead to increased tumor regression via the cascade of events during and immediately following treatment. For a TSL carrying doxorubicin (DOX) these include the rapid and intense exposure of endothelial cells to high drug concentrations, hemorrhage, blood coagulation and vascular shutdown. In this study, ultrasound-guided photoacoustic imaging was used to probe the changes to tumors following treatment with the TSL, HaT-DOX (Heat activated cytoToxic). Levels of oxygen saturation (sO2) were studied in a longitudinal manner, from 30 min pre-treatment to 7 days post-treatment. The efficacious treatments of HT-HaT-DOX were shown to induce a significant drop in sO2 (>10%) as early as 30 min post-treatment that led to tumor regression (in 90% of cases); HT-Saline and non-efficacious HT-HaT-DOX (10% of cases) treatments did not show any significant change in sO2 at these timepoints. The changes in sO2 were further corroborated with histological data, using the vascular and perfusion markers CD31 and FITC-lectin. These results allowed us to further surmise a plausible mechanism of the cellular events taking place in the TSL treated tumor regions over the first 24 hours post-treatment. The potential for using photoacoustic imaging to measure tumor sO2 as a surrogate prognostic marker for predicting therapeutic outcome with a TSL treatment is demonstrated.

Photoacoustic signal characterization of cancer treatment response: Correlation with changes in tumor oxygenation

“…This non-responder mouse was treated in an identical fashion and was included in this data set as its oxygenation and QUS/QPA behavior was significantly different from HaT-DOX responders. As reported in our previous study for a larger subset of animals, a 90% regression rate was observed 25 days after HaT-DOX treatment [43].…”

“…These animals all responded to the HaT-DOX treatment (as assessed by caliper measurements) and experienced a 2 h post-treatment, 22% drop in oxygenation (as assessed by the sO 2 mode). This drop in oxygenation was present as early as 30 min post-treatment and was sustained for the first 24 h. Tumor oxygenation histograms can be used to quantify changes in blood vessel oxygenation throughout the entire tumor [43]. The early changes in blood vessel oxygenation correlate with treatment response: responders’ sO 2 decreased 30 mins post-treatment.…”

“…The recently published study by our group examined the correlation between sO 2 and vascular damage due to a single dose of HaT-DOX released during mild-hyperthermia [43]. At the 2 h timepoint, the drop in sO 2 was correlated with an increase in FITC-lectin leakage within the tumor interstitium.…”

“…Normal tissue is the teal color surrounding the tumor and the slide background is light gray. For more details on how these images were obtained refer to reference [43]. (c) Distribution of the size of tumor blood vessels for HaT-DOX and Saline measured at the 2 h timepoint.…”

“…The use of PA imaging for cancer treatment monitoring is a relatively new endeavor [43], [44], [45]. In this study, we correlate the spectral information of the PA RF data (QPA) with the oxygen saturation (sO 2 ) of in-vivo tumors treated with a novel thermosensitive liposome.…”