Combined intracranial Acriflavine, temozolomide and radiation extends survival in a rat glioma model

Riccardo Serra, Antonella Mangraviti, Noah L. Gorelick, Tovi Shapira-Furman, Safwan Alomari, Arba Cecia, Namrata Darjee, Henry Brem, Yakir Rottenberg, Abraham J. Domb, Betty Tyler

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Glioblastomas have been historically difficult to treat with poor long-term survival. With novel strategies focused on targeting hypoxia-inducible factor (HIF) regulatory pathways, recent evidence has shown that Acriflavine (ACF) can effectively target glioma invasiveness and recurrence. However, local delivery of ACF and its combinatory effects with Temozolomide (TMZ) and radiation therapy (XRT) have not yet been optimized. In this study we test a novel polymeric matrix that can gradually release ACF at the tumor bed site in combination with systemic TMZ and XRT. In vitro cytotoxicity assays of ACF in combination with TMZ and XRT were performed on rodent and human cell lines with CCK-8 and flow cytometry. In vitro drug release was measured and intracranial safety was assessed in tumor-free animals. Finally, efficacy was assessed in an intracranial gliosarcoma model and combination therapy with TMZ and XRT evaluated. Combination therapy of ACF, TMZ, and XRT was able to reduce cell viability and induce apoptosis in glioma cells. In vitro and in vivo release of ACF was measured in benchtop and animal models. Efficacy was established in an in vivo gliosarcoma model in which intracranial ACF (p < 0.01) significantly improved median survival and the combination therapy of ACF, TMZ and XRT (p < 0.01) significantly improved median survival and led to long-term survival (LTS). We provide evidence that ACF, combined with TMZ and XRT, led to LTS in an intracranial model of rat gliosarcoma. These findings, in combination with the use of a novel polymeric matrix that allows more gradual drug delivery, constitute a first step in the translation of this novel strategy to human use.

Original languageEnglish
Pages (from-to)179-186
Number of pages8
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume170
DOIs
StatePublished - Jan 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 Elsevier B.V.

Funding

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. However, Dr. H. Brem is a paid consultant to Insightec and chairman of the company's Medical Advisory Board. Insightec is developing focused ultrasound treatments for brain tumors. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. Research funding from NIH, Johns Hopkins University, Acuity Bio Corp* and philanthropy. Consultant for AsclepiX Therapeutics, StemGen, InSightec*, Accelerating Combination Therapies*, Catalio Nexus Fund II, LLC*, LikeMinds, Inc.*, Galen Robotics, Inc.* and Nurami Medical (*includes equity or options). B. Tyler has research funding from NIH and is a co-owner for Accelerating Combination Therapies*. Ashvattha Therapeutics Inc. has also licensed one of her patents (*includes equity or options).

FundersFunder number
National Institutes of Health
Johns Hopkins University

    Keywords

    • Acriflavine
    • Glioma
    • Radiation therapy
    • Temozolomide

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