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Bacteriophage‐mediated therapy of chondrosarcoma by selective delivery of the tumor necrosis factor alpha (TNFα) gene

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Title: Bacteriophage‐mediated therapy of chondrosarcoma by selective delivery of the tumor necrosis factor alpha (TNFα) gene
Authors: Chongchai, A
Waramit, S
Suwan, K
Al-Bahrani, M
Udomruk, S
Phitak, T
Kongtawelert, P
Pothacharoen, P
Hajitou, A
Item Type: Journal Article
Abstract: Chondrosarcoma is a cartilage‐forming bone tumor, well known for intrinsic resistance to chemotherapy and radiotherapy. We have designed a targeted chondrosarcoma gene therapy using a bacteriophage (phage) particle to deliver therapeutic genes. Phage has no tropism for mammalian cells, allowing engineered phage to be targeted to specific cell surface receptors in cancer. We modified the phage capsid to display the RGD4C ligand on the pIII minor coat proteins to specifically bind to αvβ3 or αvβ5 integrin receptors. The endosomal escape peptide, H5WYG, was also displayed on recombinant pVIII major coat proteins to enhance gene delivery. Finally, a human tumor necrosis factor alpha (TNFα) therapeutic transgene expression cassette was incorporated into the phage genome. First, we found that human chondrosarcoma cells (SW1353) have high expression of αvβ3, αvβ5 integrin receptors, and both TNFα receptors. Targeted particle encoding a luciferase reporter gene efficiently and selectively mediated gene delivery to these cells. When SW1353 cells were treated with the targeted particle encoding a TNFα transgene, significant cell killing was evident and was associated with high expression of TNFα and apoptosis‐related genes. In vivo, mice with established human chondrosarcoma showed suppression of tumors upon repetitive intravenous administrations of the targeted phage. These data show that our phage‐based particle is a promising, selective, and efficient tool for targeted chondrosarcoma therapy.
Issue Date: 1-May-2021
Date of Acceptance: 15-Feb-2021
URI: http://hdl.handle.net/10044/1/88106
DOI: 10.1096/fj.202002539R
ISSN: 0892-6638
Publisher: Federation of American Society of Experimental Biology (FASEB)
Journal / Book Title: The FASEB Journal
Volume: 35
Issue: 5
Copyright Statement: © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Medical Research Council (MRC)
Children with Cancer UK
Cancer Research UK
Medical Research Council (MRC)
Funder's Grant Number: G0701159
Keywords: chondrosarcoma
integrins αvβ3 and αvβ5 apoptosis
phage-based particle
targeted gene therapy
tumor necrosis factor alpha (TNFα)
Biochemistry & Molecular Biology
0601 Biochemistry and Cell Biology
0606 Physiology
1116 Medical Physiology
Publication Status: Published
Article Number: ARTN e21487
Online Publication Date: 2021-04-03
Appears in Collections:Department of Brain Sciences

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