Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway

Takahiro Seki, Fionnadh Carroll, Sam Illingworth, Nicky Green, Ryan Cawood, Houria Bachtarzi, Vladimir Subr, Kerry Fisher, Leonard W. Seymour

Research output: Contribution to journalArticle

Abstract

Tumour Necrosis Factor alpha (TNF) is a pleiotropic pro-inflammatory cytokine with known vascular permeabilising activity. It is employed during isolated limb perfusion to enhance delivery of chemotherapeutic drugs into tumour tissue. The use of conditionally-replicating lytic viruses, so called ‘oncolytic virotherapy’, provides a new approach to cancer treatment that is currently limited by the low efficiency of extravasation of viral particles into tumours. We report here evidence that TNF significantly enhances the delivery of virus particles through the endothelial layer to allow access to tumour cells both in vitro and in vivo. Intravenous administration of TNF resulted in a 3- to 6-fold increase in EL4 tumour uptake of Evans Blue/Albumin, adenovirus and long-circulating polymer coated adenovirus. Interestingly, endothelial permeabilisation could be suppressed in vitro and in vivo by Y-27632, a Rho kinase inhibitor, without inhibiting viral infection. These data indicate that TNF can enhance the delivery of virus particles into tumours through a Rho A/Rho kinase dependent mechanism and may be a valuable strategy for increasing the delivery of oncolytic viruses and other therapeutic agents.
Original languageEnglish
Pages (from-to)381-389
Number of pages9
JournalJournal of Controlled Release
Volume156
Issue number3
Publication statusPublished - 22 Dec 2011

Keywords

  • Drug delivery
  • Adenovirus
  • Vascular permeability
  • Tumour necrosis factor-α
  • Rho A/Rho kinase inhibitor
  • EPR-effect

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    Seki, T., Carroll, F., Illingworth, S., Green, N., Cawood, R., Bachtarzi, H., Subr, V., Fisher, K., & Seymour, L. W. (2011). Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway. Journal of Controlled Release, 156(3), 381-389.