¹⁸F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal cancer therapy

Within the field of nanoparticle-assisted photothermal cancer therapy, focus has mostly been on developing novel heat-generating nanoparticles with the right optical and dimensional properties. Comparison and evaluation of their performance in tumor-bearing animals are commonly assessed by changes in tumor volume; however, this is usually a late-occurring event. This study implements 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging to perform early evaluation of the treatment outcome of photothermal therapy. Silica-gold nanoshells (NS) are administered intravenously to nude mice bearing human neuroendocrine tumor xenografts and the tumors are irradiated by a near-infrared laser. The animals are positron emission tomography scanned with 2-deoxy-2-[F-18]fluoro-D-glucose one day before and one day after treatment. Using this setup, a significant decrease in tumor uptake of 2-deoxy-2-[F-18]fluoro-D-glucose is found already one day after therapy in the group receiving NS and laser treatment compared to control animals. At this time point no change in tumor volume can be detected. Moreover, the change in tumor uptake, is used to stratify the animals into responders and non-responders, where the responding group matched improved survival. Overall, these findings support the use of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography imaging for preclinical and clinical evaluation and optimization of photothermal therapy

Photo-absorption properties and biodistribution of 150 nm NS.

<p>(a) Absorbance spectrum of NS measured in water using UV-vis spectrophotometry (<i>insert</i>: TEM image and illustration of a NS). The dotted line represents the wavelength of the NIR excitation laser (807 nm). (b) The mean Au content measured using ICP-MS in different tissues and (c) the corresponding number of NS measured 24 hours after intravenous injection. The biodistribution data is plotted on a log-scale to better resolve the Au content in tissues with very low uptake. Data shown is the mean ± S.E.M., <i>n</i> = 4.</p

Stratification of animals based on their ýG value.

<p>Animals with a ýG lower than 100% (<i>n</i> = 11) had a significant (<i>p</i> value < 0.01) improved survival compared to animals with a ýG equal to or above 100% (<i>n</i> = 12).</p

Autoradiography, H&E histological and immunohistochemical staining of a NS and saline treated tumor.

<p>Autoradiography of the ¹⁸F-FDG distribution in a NS and saline treated tumor. The dashed line marks the border between tumor and skin tissue. The NS treated tumor had a lower uptake of ¹⁸F-FDG than the saline treated tumor. From H&E staining of sections from the same tumors, the tissue in the NS treated tumor was found to be highly porous and necrotic whereas the saline treated tumor had a core with central necrosis but otherwise the tissue appeared normal. Finally, immunohistochemical staining with macrophage marker CD68 showed an increased level of macrophage infiltration in the NS treated tumor compared to the saline treated tumor.</p

Evaluation of photothermal treatment.

<p>(a) Representative thermographic images showing the temperature at the surface of the tumor during 5 min treatment of animals from each group. (b) Mean temperature at the tumor surface as a function of time for all animals included in the study, i.e., PET and survival evaluation, immunohistochemistry, and autoradiography. (c-d) The tumors that were treated with NS and laser showed a delayed growth and improved survival compared to the saline and sham groups. In (b-d) data shown in blue circles/lines; <i>n</i> = 9 represents the NS group, data shown in black squares/lines; <i>n</i> = 9 represents the saline group, and data shown in grey triangles/lines; <i>n</i> = 5 represents the sham group. Data shown is mean ± S.E.M. Each growth curve in (c) is shown until <i>n</i> = 3.</p

PET-based treatment evaluation.

<p>(a) Representative ¹⁸F-FDG-PET/CT images showing an animal from each group at baseline and day 1. Tumors are marked by white arrows. The ¹⁸F-FDG uptake is markedly reduced at day 1 compared to baseline for the NS treated animal. (b) The mean ¹⁸F-FDG uptake at day 1 relative to baseline for all three groups. * denotes <i>p</i> value < 0.05, ** denotes <i>p</i> value < 0.01 and data represents mean ± S.E.M. (c) The individual ¹⁸F-FDG uptake at day 1 relative to baseline for the NS group (blue; <i>n</i> = 9), saline group (black; <i>n</i> = 9), and sham group (grey; <i>n</i> = 5).</p