Targeting mesothelin receptors with drug-loaded bacterial nanocells suppresses human mesothelioma tumour growth in mouse xenograft models
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 populati...
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Published in | PloS one Vol. 12; no. 10; p. e0186137 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Public Library of Science
23.10.2017
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Abstract | 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. |
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AbstractList | 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. 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. |
Audience | Academic |
Author | Alfaleh, Mohamed A Weiss, Jocelyn Vanegas, Natasha Mahler, Stephen M Howard, Christopher B de Bakker, Christopher J Suurbach, Julia H Rumballe, Bree A Sedliarou, Ilya Gudhka, Reema Brahmbhatt, Himanshu Jones, Martina L Milne, Michael R MacDiarmid, Jennifer A |
AuthorAffiliation | Wayne State University, UNITED STATES 1 Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia 5 Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia 6 Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Queensland, Australia 2 Faculty of Pharmacy; King Abdulaziz University, Jeddah, Saudi Arabia 3 Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland, Australia 4 Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia |
AuthorAffiliation_xml | – name: 5 Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – name: 2 Faculty of Pharmacy; King Abdulaziz University, Jeddah, Saudi Arabia – name: 4 Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia – name: 6 Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Queensland, Australia – name: 3 Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland, Australia – name: 1 Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia – name: Wayne State University, UNITED STATES |
Author_xml | – sequence: 1 givenname: Mohamed A surname: Alfaleh fullname: Alfaleh, Mohamed A organization: Faculty of Pharmacy; King Abdulaziz University, Jeddah, Saudi Arabia – sequence: 2 givenname: Christopher B orcidid: 0000-0001-9797-8686 surname: Howard fullname: Howard, Christopher B organization: Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia – sequence: 3 givenname: Ilya surname: Sedliarou fullname: Sedliarou, Ilya organization: Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – sequence: 4 givenname: Martina L surname: Jones fullname: Jones, Martina L organization: Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia – sequence: 5 givenname: Reema surname: Gudhka fullname: Gudhka, Reema organization: Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – sequence: 6 givenname: Natasha surname: Vanegas fullname: Vanegas, Natasha organization: Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – sequence: 7 givenname: Jocelyn surname: Weiss fullname: Weiss, Jocelyn organization: Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – sequence: 8 givenname: Julia H surname: Suurbach fullname: Suurbach, Julia H organization: Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – sequence: 9 givenname: Christopher J surname: de Bakker fullname: de Bakker, Christopher J organization: Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, Queensland, Australia – sequence: 10 givenname: Michael R surname: Milne fullname: Milne, Michael R organization: Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Queensland, Australia – sequence: 11 givenname: Bree A surname: Rumballe fullname: Rumballe, Bree A organization: Queensland Brain Institute (QBI), The University of Queensland, Brisbane, Queensland, Australia – sequence: 12 givenname: Jennifer A surname: MacDiarmid fullname: MacDiarmid, Jennifer A organization: Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – sequence: 13 givenname: Himanshu surname: Brahmbhatt fullname: Brahmbhatt, Himanshu organization: Cancer Therapeutics, EnGeneIC Ltd, Sydney, New South Wales, Australia – sequence: 14 givenname: Stephen M surname: Mahler fullname: Mahler, Stephen M organization: Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland, Brisbane, Queensland, Australia |
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Copyright | COPYRIGHT 2017 Public Library of Science 2017 Alfaleh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2017 Alfaleh et al 2017 Alfaleh et al |
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Notes | Competing Interests: J. MacDiarmid and H. Brahmbhatt are Co-Directors and shareholders and I.S., J.H.S., J.W., N.V., R.G., J.M.D. and H.B. are employees in EnGeneIC Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The rest of the authors declare no conflict of interest. |
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Snippet | Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant... |
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SubjectTerms | 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 |
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Title | Targeting mesothelin receptors with drug-loaded bacterial nanocells suppresses human mesothelioma tumour growth in mouse xenograft models |
URI | https://www.ncbi.nlm.nih.gov/pubmed/29059207 https://www.proquest.com/docview/1954729902 https://pubmed.ncbi.nlm.nih.gov/PMC5653298 https://doaj.org/article/3cc239526a9745e480d90eda76e8be15 http://dx.doi.org/10.1371/journal.pone.0186137 |
Volume | 12 |
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