Abstract
PurposeRecently we showed that a number of carboxylated near-infrared fluorescent (NIRF) cyanine dyes possess strong necrosis avid properties in vitro as well as in different mouse models of spontaneous and therapy-induced tumor necrosis, indicating their potential use for cancer diagnostic- and prognostic purposes. In the previous study, the detection of the cyanines was achieved by whole body optical imaging, a technique that, due to the limited penetration of near-infrared light, is not suitable for investigations deeper than 1 cm within the human body. Therefore, in order to facilitate clinical translation, the purpose of the present study was to generate a necrosis avid cyanine-based NIRF probe that could also be used for single photon emission computed tomography (SPECT). For this, the necrosis avid NIRF cyanine HQ4 was radiolabeled with 111indium, via the chelate diethylene triamine pentaacetic acid (DTPA).ProceduresThe necrosis avid properties of the radiotracer [111In]DTPA-HQ4 were examined in vitro and in vivo in different breast tumor models in mice using SPECT and optical imaging. Moreover, biodistribution studies were performed to examine the pharmacokinetics of the probe in vivo.ResultsUsing optical imaging and radioactivity measurements, in vitro, we showed selective accumulation of [111In]DTPA-HQ4 in dead cells. Using SPECT and in biodistribution studies, the necrosis avidity of the radiotracer was confirmed in a 4T1 mouse breast cancer model of spontaneous tumor necrosis and in a MCF-7 human breast cancer model of chemotherapy-induced tumor necrosis.ConclusionsThe radiotracer [111In]DTPA-HQ4 possessed strong and selective necrosis avidity in vitro and in various mouse models of tumor necrosis in vivo, indicating its potential to be clinically applied for diagnostic purposes and to monitor anti-cancer treatment efficacy.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-0972-7) contains supplementary material, which is available to authorized users.
Highlights
Necrosis is a form of cell death characterized by severe cell swelling, denaturation and coagulation of cytoplasmic proteins, and disruption of the cell membrane, causing the release of its intracellular content
Antibodies are relatively large in size, have long circulation time, could induce an immune response, and expensive to develop in good manufacturing practices (GMP) quality, and the photosensitizer hypericin is phototoxic, poorly soluble, and tend to aggregate rapidly [16, 18, 19]
Using whole body optical imaging in mice, we showed that these cyanines can be employed to image areas of spontaneous necrosis in solid tumors and to determine the efficacy of chemotherapy by monitoring therapy-induced tumor necrosis [23]
Summary
Necrosis is a form of cell death characterized by severe cell swelling, denaturation and coagulation of cytoplasmic proteins, and disruption of the cell membrane, causing the release of its intracellular content. Agents that bind to necrotic tumor tissue can contribute to a more accurate disease diagnosis and can be exploited to predict early treatment outcome of anti-cancer treatments [12] To this end, back in 1988, Epstein and colleagues [13] developed so-called tumor necrosis targeting (TNT) antibodies that are directed towards nuclear proteins and labeled with radioactive iodine for imaging and anti-cancer treatment purposes. Antibodies are relatively large in size, have long circulation time, could induce an immune response, and expensive to develop in good manufacturing practices (GMP) quality, and the photosensitizer hypericin is phototoxic, poorly soluble, and tend to aggregate rapidly [16, 18, 19] All these issues hamper the clinical translation of these compounds [14, 20,21,22]
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