Abstract
Optical fluorescence-guided imaging is increasingly used to guide surgery and endoscopic procedures. Activatable probes are particularly useful because of high target-to-background ratios that increase sensitivity for tiny cancer foci. However, green fluorescent activatable probes suffer from interference from autofluorescence found in biological tissue. The purpose of this study was to determine if dynamic imaging can be used to differentiate specific fluorescence arising from an activated probe in a tumor from autofluorescence in background tissues especially when low concentrations of the dye are applied. Serial fluorescence imaging was performed using various concentrations of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) which was sprayed on the peritoneal surface with tiny implants of SHIN3-DsRed ovarian cancer tumors. Temporal differences in signal between specific green fluorescence in cancer foci and non-specific autofluorescence in background tissue were measured at 5, 10, 20 and 30 min after application of gGlu-HMRG and were processed into three kinetic maps reflecting maximum fluorescence signal (MF), wash-in rate (WIR), and area under the curve (AUC), respectively. Using concentrations up to 10 μM of gGlu-HMRG, the fluorescence intensity of cancer foci was significantly higher than that of small intestine but only at 30 min. However, on kinetic maps derived from dynamic fluorescence imaging, the signal of cancer foci was significantly higher than that of small intestine after only 5 min even at concentrations as low as 2.5 μM of gGlu-HMRG (p < 0.01). At lower concentrations, kinetic maps derived from dynamic fluorescence imaging were superior to unprocessed images for cancer detection.
Highlights
IntroductionThe ability to completely resect tumors is important for long term durable responses
In many oncologic procedures, the ability to completely resect tumors is important for long term durable responses
Fluorescence intensity of the small intestine did not change after spraying gGlu-HMRG and there was no significant difference (p = 0.41, 0.47, 0.41 and 0.30 at 5, 10, 20 and 30 min after spraying gGlu-HMRG, respectively) (Figure 2, Supplementary Figures S1, S2 and Supplementary Video S1)
Summary
The ability to completely resect tumors is important for long term durable responses. Optical fluorescence-guided imaging is increasingly used as an aid to surgery or endoscopy to guide the detection of tiny tumor foci. Optical fluorescence imaging offers high sensitivity, low cost, portability, realtime capabilities, and importantly, absence of ionizing radiation [1,2,3,4,5] and there is much interest in this topic. Always-on probes fluoresce regardless of whether they are bound to the target tissue and have the disadvantage of high background signal. Activatable probes only become fluorescent after they come in contact with the target tissue. This class of optical probes have lower background signals, but require rapid activation to be practical in the clinical environment [7]. One www.impactjournals.com/oncotarget common approach for activating optical probes is to make use of specific enzymatic activity found in the tumor microenvironment but not in normal tissues [8]
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