Exploiting a Rose Bengal-bearing, oxygen-producing nanoparticle for SDT and associated immune-mediated therapeutic effects in the treatment of pancreatic cancer

Dean Nicholas, Heather Nesbitt, Sian Farrell, Keiran Logan, Eva McMullin, Tierna Gillan, Paul Kelly, Declan O'Rourke, Simon Porter, Keith Thomas, Barry M G O'Hagan, Nikolitsa Nomikou, Bridgeen Callan, John F Callan, Anthony P McHale

Research output: Contribution to journalArticlepeer-review

Abstract

Sonodynamic therapy (SDT) is an emerging stimulus-responsive approach for the targeted treatment of solid tumours. However, its ability to generate stimulus-responsive cytotoxic reactive oxygen species (ROS), is compromised by tumour hypoxia. Here we describe a robust means of preparing a pH-sensitive polymethacrylate-coated CaO nanoparticle that is capable of transiently alleviating tumour hypoxia. Systemic administration of particles to animals bearing human xenograft BxPC3 pancreatic tumours increases oxygen partial pressures (PO ) to 20 - 50 mmHg for over 40 min. RT-qPCR analysis of expression of selected tumour marker genes in treated animals suggests that the transient production of oxygen is sufficient to elicit effects at a molecular genetic level. Using particles labelled with the near infra-red (nIR) fluorescent dye, indocyanine green, selective uptake of particles by tumours was observed. Systemic administration of particles containing Rose Bengal (RB) at concentrations of 0.1 mg/mg of particles are capable of eliciting nanoparticle-induced, SDT-mediated antitumour effects using the BxPC3 human pancreatic tumour model in immuno-compromised mice. Additionally, a potent abscopal effect was observed in off-target tumours in a syngeneic murine bilateral tumour model for pancreatic cancer and an increase in tumour cytotoxic T cells (CD8 ) and a decrease in immunosuppressive tumour regulatory T cells [T (CD4 , FoxP3 )] was observed in both target and off-target tumours in SDT treated animals. We suggest that this approach offers significant potential in the treatment of both focal and disseminated (metastatic) pancreatic cancer. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
Original languageEnglish
Pages (from-to)49-59
Number of pages11
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume163
Early online date31 Mar 2021
DOIs
Publication statusPublished - 30 Jun 2021

Keywords

  • SDT
  • abscopal
  • cancer
  • immune
  • oxygen
  • pancreatic

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