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Enhanced specific delivery and targeting of oncolytic Sindbis viral vectors by modulating vascular leakiness in tumor

Abstract

Genetic instability of cancer cells generates resistance after initial responses to chemotherapeutic agents. Several oncolytic viruses have been designed to exploit specific signatures of cancer cells, such as important surface markers or pivotal signaling pathways for selective replication. It is less likely for cancer cells to develop resistance given that mutations in these cancer signatures would negatively impact tumor growth and survival. However, as oncolytic viral vectors are large particles, they suffer from inefficient extravasation from tumor blood vessels. Their ability to reach cancer cells is an important consideration in achieving specific oncolytic targeting and potential vector replication. Our previous studies indicated that the Sindbis viral vectors target tumor cells by the laminin receptor. Here, we present evidence that modulating tumor vascular leakiness, using VEGF and/or metronomic chemotherapy regimens, significantly enhances tumor vascular permeability and directly enhances oncolytic Sindbis vector targeting in tumor models. Because host-derived vascular endothelium cells are genetically stable and less likely to develop resistance to chemotherapeutics, a combined metronomic chemotherapeutics and oncolytic vector regimen should provide a new approach for cancer therapy. This mechanism could explain the synergistic treatment outcomes observed in clinical trials of combined therapies.

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Acknowledgements

We thank Dr Christine Pampeno for critical reading of this paper and helpful discussions and Mr Seth Nickerson for constructing RD-Sindbis/mPlum vector. US Public Health Service Grants CA100687 and CA68498 from the National Cancer Institute, National Institutes of Health and Department of Health and Human Services supported this study. Funding was also provided by a gift from the Litwin Foundation and a Research and License agreement between NYU and CynVec.

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Correspondence to D Meruelo.

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Tseng, JC., Granot, T., DiGiacomo, V. et al. Enhanced specific delivery and targeting of oncolytic Sindbis viral vectors by modulating vascular leakiness in tumor. Cancer Gene Ther 17, 244–255 (2010). https://doi.org/10.1038/cgt.2009.70

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  • DOI: https://doi.org/10.1038/cgt.2009.70

Keywords

  • Sindbis virus
  • viral vector
  • vascular leakiness
  • molecular imaging
  • chemotherapy

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