Vascular targeting to the SST2 receptor improves the therapeutic response to near-IR two-photon activated PDT for deep-tissue cancer treatment |
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Authors: | Jean R Starkey Elizabeth M Pascucci Mikhail A Drobizhev Aleisha Elliott Aleksander K Rebane |
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Institution: | 1. Montana State University, Department of Microbiology, Bozeman, MT 59717, USA;2. Montana State University, Department of Physics, Bozeman, MT 59717, USA;3. National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallin, Estonia |
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Abstract: | BackgroundBroader clinical acceptance of photodynamic therapy is currently hindered by (a) poor depth efficacy, and (b) predisposition towards establishment of an angiogenic environment during the treatment. Improved depth efficacy is being sought by exploiting the NIR tissue transparency window and by photo-activation using two-photon absorption (2PA). Here, we use two-photon activation of PDT sensitizers, untargeted and targeted to SST2 receptors or EGF receptors, to achieve deep tissue treatment.MethodsHuman tumor lines, positive or negative for SST2r expression were used, as well as murine 3LL cells and bovine aortic endothelial cells. Expression of SST2 receptors on cancer cells and tumor vasculature was evaluated in vitro and frozen xenograft sections. PDT effects on tumor blood flow were followed using in vivo scanning after intravenous injection of FITC conjugated dextran 150 K. Dependence of the PDT efficacy on the laser pulse duration was evaluated. Effectiveness of targeting to vascular SST2 receptors was compared to that of EGF receptors, or no targeting.ResultsTumor vasculature stained for SST2 receptors even in tumors from SST2 receptor negative cell lines, and SST2r targeted PDT led to tumor vascular shutdown. Stretching the pulse from ~ 120 fs to ~ 3 ps led to loss of the PDT efficacy especially at greater depth. PDT targeted to SST2 receptors was much more effective than untargeted PDT or PDT targeted to EGF receptors.General significanceThe use of octreotate to target SST2 receptors expressed on tumor vessels is an excellent approach to PDT with few recurrences and some long term cures. |
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Keywords: | PDT photodynamic therapy NIR near infrared UCNP upconversion nanoparticle VEGF vascular endothelial growth factor ATCC American type culture collection SST2r somatostatin type 2 receptor EGF epidermal growth factor BAE bovine aortic endothelial DMEM Dulbecco's minimal essential medium EDTA Ethylenediaminetetraacetic acid SCID severe combined immunodeficient FITC fluorescein isothiocyanate EDC 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride PBS phosphate buffered saline CMF calcium and magnesium free saline GE11 peptide YHWYGYTPQNVI |
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