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

12 Citations (Scopus)
39 Downloads (Pure)

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 CaO2 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 (PO2) 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 [Treg (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.

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 (in print/issue) - 30 Jun 2021

Bibliographical note

Funding Information:
This authors gratefully acknowledge funding for this work under the Proof of Concept programme administered by InvestNI, Northern Ireland. Both Sian Farrell and Tierna Gillan were in receipt of postgraduate research scholarship awards from the Dept. for the Economy, Northern Ireland. The raw/processed data required to reproduce these findings will be provided on request.

Publisher Copyright:
© 2021

Keywords

  • SDT
  • abscopal
  • cancer
  • immune
  • oxygen
  • pancreatic
  • Oxygen
  • Immune
  • Pancreatic
  • Abscopal
  • Cancer

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