Selecting the optimal parameters for sonoporation of pancreatic cancer in a pre-clinical model

Christopher W. Schultz, Gorka Ruiz de Garibay, Anika Langer, Ji Bin Liu, Teena Dhir, Calum Leitch, Corinne E. Wessner, Mireia Mayoral, Bo Zhang, Mihaela Popa, Chunwang Huang, Spiros Kotopoulis, Xianghong Luo, Yanhua Zhen, Sihua Niu, Mehnoosh Torkzaban, Kirk Wallace, John R. Eisenbrey, Jonathan R. Brody, Emmet McCormackFlemming Forsberg

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the modern world, in part due to poor delivery of chemotherapeutics. Sonoporation can be used to enhance the efficacy of standard of care therapies for PDAC. Using xenograft models of PDAC we investigate sonoporation using four ifferent ultrasound contrast agents (UCAs) and two ultrasound regimens to identify the ideal parameters to increase therapeutic efficacy. MIA-PaCa2 xenografts in over 175 immunodeficient mice were treated with gemcitabine and paclitaxel and subjected to low or high power ultrasound (60 and 200 mW/cm2 respectively) in conjunction with one of four different UCAs. The UCAs investigated were Definity®, SonoVue®, Optison™ or Sonazoid™. Tumor volumes, vascularity, hemoglobin, and oxygenation were measured and compared to controls. High power treatment in conjunction with Sonazoid sonoporation led to significantly smaller tumors when started early (tumors ~50mm3; p = .0105), while no UCAs significantly increased efficacy in the low power cohort. This trend was also found in larger tumors (~250mm3) where all four UCA agents significantly increased therapeutic efficacy in the high power group (p < .01), while only Definity and SonoVue increased efficacy in the low power cohort (p < .03). Overall, the higher power ultrasound treatment modality was more consistently effective at decreasing tumor volume and increasing vascularity characteristics. In conclusion, Sonazoid was the most consistently effective UCA at decreasing tumor volume and increasing vascularity. Thus, we are pursuing a larger phase II clinical trial to validate the increased efficacy of sonoporation in conjunction with chemotherapy in PDAC patients.

Original languageEnglish (US)
JournalCancer Biology and Therapy
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • drug delivery
  • novel therapeutic
  • Pancreatic Ductal Adenocarcinoma
  • sonoporation
  • ultrasound contrast agent

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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