title: Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model.
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.
  
  
  RESULTS
  EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage 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
  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.
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: MacDiarmid
authors.affiliation: Small Animal Specialist Hospital, Sydney, New South Wales, Australia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Langova
authors.affiliation: Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia.
authors.forename: Dale
authors.initials: D
authors.lastname: Bailey
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Pattison
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Pattison
authors.affiliation: Small Animal Specialist Hospital, Sydney, New South Wales, Australia.
authors.forename: Neil
authors.initials: N
authors.lastname: Christensen
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Armstrong
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Vatsala N
authors.initials: VN
authors.lastname: Brahmbhatt
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Smolarczyk
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Harrison
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Marylia
authors.initials: M
authors.lastname: Costa
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Mugridge
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Ilya
authors.initials: I
authors.lastname: Sedliarou
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Grimes
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Kiss
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Stillman
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.|University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.affiliation: Cancer Therapeutics, EnGeneIC Pty Ltd, Sydney, New South Wales, Australia.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Brahmbhatt
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D066246:ErbB Receptors; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D015996:Survival Rate; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D004317:Doxorubicin; C512478:EGFR protein, human; D066246:ErbB Receptors