Targeting mesothelin receptors with drug-loaded bacterial nanocells suppresses human mesothelioma tumour growth in mouse xenograft models

• Published in: PloS one Vol. 12; no. 10; p. e0186137
• Main Authors: Alfaleh, Mohamed A, Howard, Christopher B, Sedliarou, Ilya, Jones, Martina L, Gudhka, Reema, Vanegas, Natasha, Weiss, Jocelyn, Suurbach, Julia H, de Bakker, Christopher J, Milne, Michael R, Rumballe, Bree A, MacDiarmid, Jennifer A, Brahmbhatt, Himanshu, Mahler, Stephen M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.10.2017; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Antibodies; Anticancer properties; Apoptosis; Asbestos; Bacteria; Biocompatibility; Bioengineering; Biology and Life Sciences; Bispecific antibodies; Breast cancer; Cancer; Cancer therapies; Cell division; Cell growth; Cell Proliferation; Cell receptors; Cell surface; Chemotherapy; Clinical trials; Confocal microscopy; Councils; Cytometry; Cytotoxic agents; Cytotoxicity; Doxorubicin; Drug delivery systems; Drug dosages; Drug efficacy; Drug resistance; Drug therapy; Drugs; Flow cytometry; Genetic aspects; Health aspects; Humans; Hypoxia; Immunoglobulins; Immunohistochemistry; Internalization; Medical research; Medicine and Health Sciences; Mesothelioma; Mesothelioma - pathology; Mice; Microscopy; Nanotechnology; Physiological aspects; Receptors; Receptors, Cell Surface - metabolism; Research and Analysis Methods; Selectivity; Side effects; Toxicity; Training; Tumors; Xenograft Model Antitumor Assays; Xenografts; Australia; Queensland Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0186137

Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant mesothelioma incidence rates in European countries are still rising and Australia has one of the highest burdens of malignant mesothelioma on a population basis in the world. Therapy using systemic delivery of free cytotoxic agents is associated with many undesirable side effects due to non-selectivity, and is thus dose-limited which limits its therapeutic potential. Therefore, increasing the selectivity of anti-cancer agents has the potential to dramatically enhance drug efficacy and reduce toxicity. EnGeneIC Dream Vectors (EDV) are antibody-targeted nanocells which can be loaded with cytotoxic drugs and delivered to specific cancer cells via bispecific antibodies (BsAbs) which target the EDV and a cancer cell-specific receptor, simultaneously. BsAbs were designed to target doxorubicin-loaded EDVs to cancer cells via cell surface mesothelin (MSLN). Flow cytometry was used to investigate cell binding and induction of apoptosis, and confocal microscopy to visualize internalization. Mouse xenograft models were used to assess anti-tumour effects in vivo, followed by immunohistochemistry for ex vivo evaluation of proliferation and necrosis. BsAb-targeted, doxorubicin-loaded EDVs were able to bind to and internalize within mesothelioma cells in vitro via MSLN receptors and induce apoptosis. In mice xenografts, the BsAb-targeted, doxorubicin-loaded EDVs suppressed the tumour growth and also decreased cell proliferation. Thus, the use of MSLN-specific antibodies to deliver encapsulated doxorubicin can provide a novel and alternative modality for treatment of mesothelioma.