Targeted doxorubicin delivery to brain tumors via minicells: Proof of principle using dogs with spontaneously occurring tumors as a model

Jennifer A. MacDiarmid, Veronika Langova, Dale Bailey, Scott T. Pattison, Stacey L. Pattison, Neil Christensen, Luke R. Armstrong, Vatsala N. Brahmbhatt, Katarzyna Smolarczyk, Matthew T. Harrison, Marylia Costa, Nancy B. Mugridge, Ilya Sedliarou, Nicholas A. Grimes, Debra L. Kiss, Bruce Stillman, Christine Hann, Gary L Gallia, Robert M. Graham, Himanshu Brahmbhatt

Research output: Contribution to journalArticle

Abstract

Background: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. Methodology/Principle Findings: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with latestage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Conclusions/Significance: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma.

Original languageEnglish (US)
Article numbere0151832
JournalPLoS One
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2016

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    MacDiarmid, J. A., Langova, V., Bailey, D., Pattison, S. T., Pattison, S. L., Christensen, N., Armstrong, L. R., Brahmbhatt, V. N., Smolarczyk, K., Harrison, M. T., Costa, M., Mugridge, N. B., Sedliarou, I., Grimes, N. A., Kiss, D. L., Stillman, B., Hann, C., Gallia, G. L., Graham, R. M., & Brahmbhatt, H. (2016). Targeted doxorubicin delivery to brain tumors via minicells: Proof of principle using dogs with spontaneously occurring tumors as a model. PLoS One, 11(4), [e0151832]. https://doi.org/10.1371/journal.pone.0151832