Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

• Published in: PloS one Vol. 11; no. 4; p. e0151832
• Main Authors: MacDiarmid, Jennifer A, Langova, Veronika, Bailey, Dale, Pattison, Scott T, Pattison, Stacey L, Christensen, Neil, Armstrong, Luke R, Brahmbhatt, Vatsala N, Smolarczyk, Katarzyna, Harrison, Matthew T, Costa, Marylia, Mugridge, Nancy B, Sedliarou, Ilya, Grimes, Nicholas A, Kiss, Debra L, Stillman, Bruce, Hann, Christine L, Gallia, Gary L, Graham, Robert M, Brahmbhatt, Himanshu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.04.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Animal experimentation; Animals; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Antibodies, Monoclonal - therapeutic use; Bacteria; Biochemistry; Bioindicators; Biology and Life Sciences; Blood-brain barrier; Brain; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain research; Brain tumors; Cancer; Cancer therapies; Care and treatment; Cell Proliferation - drug effects; Chemotherapy; Computed tomography; Cytotoxicity; Diagnosis; Disease Models, Animal; Dogs; Dosage and administration; Doxorubicin; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug Delivery Systems; Emission analysis; Epidermal growth factor; Epidermal growth factor receptors; Female; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - mortality; Glioblastoma - pathology; Hematology; Humans; Inflammation; Intravenous administration; Magnetic resonance; Magnetic resonance imaging; Male; Medical diagnosis; Medical prognosis; Medical research; Medicine; Medicine and Health Sciences; Minicells; Molecular Targeted Therapy; Nanoparticles; Neoplasm Staging; Neuroimaging; Oncology; Patients; Permeability; Photon emission; Receptor, Epidermal Growth Factor; Regression analysis; Remission; Research and Analysis Methods; Single photon emission computed tomography; Studies; Survival Rate; Therapeutic applications; Tissue Distribution; Tissues; Toxicity; Toxicology; Tumor Cells, Cultured; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151832

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. 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). 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.