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Re: Tumor Radiation Response Enhancement by Acoustical Stimulation of the Vasculature
URO-SCIENCE
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Re: Tumor Radiation Response Enhancement by Acoustical Stimulation of the Vasculature G. J. Czarnota, R. Karshafian, P. N. Burns, S. Wong, A. Al Mahrouki, J. W. Lee, A. Caissie, W. Tran, C. Kim, M. Furukawa, E. Wong and A. Giles Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada Proc Natl Acad Sci U S A 2012; 109: E2033–E2041.
We have discovered that ultrasound-mediated microbubble vascular disruption can enhance tumor responses to radiation in vivo. We demonstrate this effect using a human PC3 prostate cancer xenograft model. Results indicate a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate with experiments in vivo that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication. Editorial Comment: The authors show that low mechanical index ultrasound mediated excitation of microbubbles can enhance the effects of radiation in vitro and supra-additively in vivo using histological and functional assays of cell death and tumor growth delay experiments. Data obtained from experiments in vitro indicate that under these ultrasound exposure conditions ceramide formation is induced by microbubble interactions with cells and associated with endothelial cell apoptosis. This is a known mechanism for radiation based, ceramide related endothelial cell death. Endothelial cell death in vivo caused by microbubble perturbation of tumor microvasculature leads to a pronounced vascular disruption and a tenfold enhancement of tumor cell death when combined with single radiation treatments. Experiments indicate that single 2 Gy doses of radiation can lead to more than 40% tumor volume kill. Treatments with multiple fractions of the combined modalities demonstrate that ineffective doses of radiation can be made more effective in terms of tumor growth delay and mouse survival. The authors propose that such combined treatments lead to vascular cell death, which then secondarily induces tumor cell kill, and that such therapy can be used to increase the efficacy of cancer treatments. Anthony Atala, M.D.
Re: Synapse-Directed Delivery of Immunomodulators Using T-Cell-Conjugated Nanoparticles M. T. Stephan, S. B. Stephan, P. Bak, J. Chen and D. J. Irvine Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts Biomaterials 2012; 33: 5776 –5787.
Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the
1163
Re: Tumor Radiation Response Enhancement by Acoustical Stimulation of the Vasculature G. J. Czarnota, R. Karshafian, P. N. Burns, S. Wong, A. Al Mahrouki, J. W. Lee, A. Caissie, W. Tran, C. Kim, M. Furukawa, E. Wong and A. Giles Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada Proc Natl Acad Sci U S A 2012; 109: E2033–E2041.
We have discovered that ultrasound-mediated microbubble vascular disruption can enhance tumor responses to radiation in vivo. We demonstrate this effect using a human PC3 prostate cancer xenograft model. Results indicate a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate with experiments in vivo that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication. Editorial Comment: The authors show that low mechanical index ultrasound mediated excitation of microbubbles can enhance the effects of radiation in vitro and supra-additively in vivo using histological and functional assays of cell death and tumor growth delay experiments. Data obtained from experiments in vitro indicate that under these ultrasound exposure conditions ceramide formation is induced by microbubble interactions with cells and associated with endothelial cell apoptosis. This is a known mechanism for radiation based, ceramide related endothelial cell death. Endothelial cell death in vivo caused by microbubble perturbation of tumor microvasculature leads to a pronounced vascular disruption and a tenfold enhancement of tumor cell death when combined with single radiation treatments. Experiments indicate that single 2 Gy doses of radiation can lead to more than 40% tumor volume kill. Treatments with multiple fractions of the combined modalities demonstrate that ineffective doses of radiation can be made more effective in terms of tumor growth delay and mouse survival. The authors propose that such combined treatments lead to vascular cell death, which then secondarily induces tumor cell kill, and that such therapy can be used to increase the efficacy of cancer treatments. Anthony Atala, M.D.
Re: Synapse-Directed Delivery of Immunomodulators Using T-Cell-Conjugated Nanoparticles M. T. Stephan, S. B. Stephan, P. Bak, J. Chen and D. J. Irvine Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts Biomaterials 2012; 33: 5776 –5787.
Regulating molecular interactions in the T-cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T-cell membrane proteins enables efficient delivery of compounds into the T-cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition. To translate these findings into a therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T-cell receptor activation in the synapse, in the