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Published OnlineFirst June 6, 2017; DOI: 10.1158/1541-7786.MCR-17-0164 Near-Infrared Photoimmunotherapy Targeting PSMA Figure 2. In vivo fluorescence imaging of PC3pip-luc tumor. A, In vivo anti-PSMA-IR700 fluorescence real-time imaging of tumor-bearing mice (right dorsum). The tumor showed high fluorescence intensity after injection and the intensity was gradually decreased over days. Most of the excess agent was excreted to the urine immediately after injection. ROIs were placed on the tumor and liver, then ROIs were also placed in the adjacent nontumor region as background (left dorsum; blue circle and lower abdomen; green circle). B, Time course of NIR fluorescence signal of IR700 in tumors and livers (n 1⁄4 10). The IR700 fluorescence intensity of tumor and liver showed high intensities within 1 day after anti-PSMA-IR700 injection but this decreased gradually over days. C, Time course of NIR fluorescence signal of TBR in tumors and livers (n 1⁄4 10). TBR of tumor and liver showed high within four days after anti-PSMA-IR700 injection, then the TBR was gradually decreased over the following days. representing necrotic cell death was observed in PC3pip-luc cells (Supplementary Video). Most of these morphologic changes were observed within 15 minutes of light exposure (Fig. 1C), indicating rapid induction of necrotic cell death. On the other hand, PC3flu cells showed no obvious change after NIR light exposure. Bioluminescence showed a decrease of luciferase activity in a light dose-dependent manner (Fig. 1D). BLI also showed significant decreases of luciferase activity in NIR-PIT–treated cells (Fig. 1E). On the basis of incorporation of PI, although no NIR-PIT effects were shown in PC3flu cells (Fig. 1F), percentage of cell death increased in a light dose- dependent manner in PC3pip-luc cells (Fig. 1G). Over 80% of PC3pip-luc cells died when exposed to 8 J/cm2 of NIR light. There was no significant cytotoxicity associated with NIR light exposure alone in the absence of anti-PSMA-IR700 and with anti-PSMA-IR700 alone without NIR light exposure. In vivo fluorescence imaging studies The fluorescence intensity of anti-PSMA-IR700 in PC3pip-luc tumor showed high intensities within 1 day after anti-PSMA- IR700 injection but this decreased gradually over the following www.aacrjournals.org days (Fig. 2A and B). On the other hand, target-to-background ratio (TBR) of anti-PSMA-IR700 in tumor and liver was high immediately after APC injection, following which the TBR did not change for several days (Fig. 2C). TBR of anti-PSMA-IR700 was high in tumor due to specific APC binding to PSMA expressing PC3pip-luc cells, while TBR was high in liver likely due to nonspecific accumulation of anti-PSMA–IR700 conjugate as the liver is not known to express PSMA. To obtain the maximal therapeutic effect, the tumor fluorescence caused by binding of the APC should be high in tumor and low in background. Tumor fluorescence was high after APC injection, while fluorescence signal of background including liver decreased beginning 9 hours after APC injection. Thus, we used 1 day of incubation with APC to get the maximal difference between tumor and background normal tissue. In vivo NIR-PIT The treatment and imaging regimen is shown in Fig. 3A. One day after injection of anti-PSMA-IR700, the tumors showed higher fluorescence intensity than did the tumor with no anti- PSMA-IR700. After exposure to 50 J/cm2 of NIR light, IR700 Mol Cancer Res; 15(9) September 2017 1157 Downloaded from mcr.aacrjournals.org on December 1, 2020. © 2017 American Association for Cancer Research.PDF Image | Near-Infrared Photoimmunotherapy Targeting Prostate Cancer
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