Immune-mediated ECM depletion improves tumour perfusion and payload delivery
High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Subjects: | |
| Online Access: | http://purl.org/au-research/grants/nhmrc/1046507 http://hdl.handle.net/20.500.11937/88887 |
| _version_ | 1848765103768338432 |
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| author | Yeow, Y.L. Kotamraju, V.R. Wang, X. Chopra, M. Azme, N. Wu, J. Schoep, T.D. Delaney, D.S. Feindel, K. Li, J. Kennedy, K.M. Allen, W.M. Kennedy, B.F. Larma, I. Sampson, D.D. Mahakian, L.M. Fite, B.Z. Zhang, H. Friman, T. Mann, A.P. Aziz, F.A. Kumarasinghe, M.P. Johansson, M. Ee, H.C. Yeoh, G. Mou, L. Ferrara, K.W. Billiran, H. Ganss, R. Ruoslahti, E. Hamzah, Juliana |
| author_facet | Yeow, Y.L. Kotamraju, V.R. Wang, X. Chopra, M. Azme, N. Wu, J. Schoep, T.D. Delaney, D.S. Feindel, K. Li, J. Kennedy, K.M. Allen, W.M. Kennedy, B.F. Larma, I. Sampson, D.D. Mahakian, L.M. Fite, B.Z. Zhang, H. Friman, T. Mann, A.P. Aziz, F.A. Kumarasinghe, M.P. Johansson, M. Ee, H.C. Yeoh, G. Mou, L. Ferrara, K.W. Billiran, H. Ganss, R. Ruoslahti, E. Hamzah, Juliana |
| author_sort | Yeow, Y.L. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin–nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα. |
| first_indexed | 2025-11-14T11:29:56Z |
| format | Journal Article |
| id | curtin-20.500.11937-88887 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | eng |
| last_indexed | 2025-11-14T11:29:56Z |
| publishDate | 2019 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-888872022-07-27T04:42:55Z Immune-mediated ECM depletion improves tumour perfusion and payload delivery Yeow, Y.L. Kotamraju, V.R. Wang, X. Chopra, M. Azme, N. Wu, J. Schoep, T.D. Delaney, D.S. Feindel, K. Li, J. Kennedy, K.M. Allen, W.M. Kennedy, B.F. Larma, I. Sampson, D.D. Mahakian, L.M. Fite, B.Z. Zhang, H. Friman, T. Mann, A.P. Aziz, F.A. Kumarasinghe, M.P. Johansson, M. Ee, H.C. Yeoh, G. Mou, L. Ferrara, K.W. Billiran, H. Ganss, R. Ruoslahti, E. Hamzah, Juliana extracellular matrix immune cells peptide solid tumour tumour necrosis factor alpha Animals Cell Line Cell Surface Display Techniques Contrast Media Extracellular Matrix Female Ferric Compounds Gadolinium Heterocyclic Compounds Humans Male Mice Nanoparticles Organometallic Compounds Tumor Necrosis Factor-alpha High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin–nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα. 2019 Journal Article http://hdl.handle.net/20.500.11937/88887 10.15252/emmm.201910923 eng http://purl.org/au-research/grants/nhmrc/1046507 http://purl.org/au-research/grants/nhmrc/1058073 http://purl.org/au-research/grants/nhmrc/1121131 http://creativecommons.org/licenses/by/4.0/ fulltext |
| spellingShingle | extracellular matrix immune cells peptide solid tumour tumour necrosis factor alpha Animals Cell Line Cell Surface Display Techniques Contrast Media Extracellular Matrix Female Ferric Compounds Gadolinium Heterocyclic Compounds Humans Male Mice Nanoparticles Organometallic Compounds Tumor Necrosis Factor-alpha Yeow, Y.L. Kotamraju, V.R. Wang, X. Chopra, M. Azme, N. Wu, J. Schoep, T.D. Delaney, D.S. Feindel, K. Li, J. Kennedy, K.M. Allen, W.M. Kennedy, B.F. Larma, I. Sampson, D.D. Mahakian, L.M. Fite, B.Z. Zhang, H. Friman, T. Mann, A.P. Aziz, F.A. Kumarasinghe, M.P. Johansson, M. Ee, H.C. Yeoh, G. Mou, L. Ferrara, K.W. Billiran, H. Ganss, R. Ruoslahti, E. Hamzah, Juliana Immune-mediated ECM depletion improves tumour perfusion and payload delivery |
| title | Immune-mediated ECM depletion improves tumour perfusion and payload delivery |
| title_full | Immune-mediated ECM depletion improves tumour perfusion and payload delivery |
| title_fullStr | Immune-mediated ECM depletion improves tumour perfusion and payload delivery |
| title_full_unstemmed | Immune-mediated ECM depletion improves tumour perfusion and payload delivery |
| title_short | Immune-mediated ECM depletion improves tumour perfusion and payload delivery |
| title_sort | immune-mediated ecm depletion improves tumour perfusion and payload delivery |
| topic | extracellular matrix immune cells peptide solid tumour tumour necrosis factor alpha Animals Cell Line Cell Surface Display Techniques Contrast Media Extracellular Matrix Female Ferric Compounds Gadolinium Heterocyclic Compounds Humans Male Mice Nanoparticles Organometallic Compounds Tumor Necrosis Factor-alpha |
| url | http://purl.org/au-research/grants/nhmrc/1046507 http://purl.org/au-research/grants/nhmrc/1046507 http://purl.org/au-research/grants/nhmrc/1046507 http://hdl.handle.net/20.500.11937/88887 |