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Immune‐mediated ECM depletion improves tumour perfusion and payload delivery

Yeow, Yen Ling, Kotamraju, Venkata Ramana, Wang, Xiao, Chopra, Meenu, Azme, Nasibah, Wu, Jiansha, Schoep, Tobias D, Delaney, Derek S, Feindel, Kirk, Li, Ji , Kennedy, Kelsey M, Allen, Wes M, Kennedy, Brendan F, Larma, Irma, Sampson, David D, Mahakian, Lisa M, Fite, Brett Z, Zhang, Hua, Friman, Tomas, Mann, Aman P, Aziz, Farah A, Kumarasinghe, M Priyanthi, Johansson, Mikael, Ee, Hooi C, Yeoh, George, Mou, Lingjun, Ferrara, Katherine W, Billiran, Hector, Ganss, Ruth, Ruoslahti, Erkki and Hamzah, Juliana (2019) Immune‐mediated ECM depletion improves tumour perfusion and payload delivery EMBO Molecular Medicine, e10923. pp. 1-20.

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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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Yeow, Yen Ling
Kotamraju, Venkata Ramana
Wang, Xiao
Chopra, Meenu
Azme, Nasibah
Wu, Jiansha
Schoep, Tobias D
Delaney, Derek S
Feindel, Kirk
Li, Ji
Kennedy, Kelsey M
Allen, Wes M
Kennedy, Brendan F
Larma, Irma
Sampson, David
Mahakian, Lisa M
Fite, Brett Z
Zhang, Hua
Friman, Tomas
Mann, Aman P
Aziz, Farah A
Kumarasinghe, M Priyanthi
Johansson, Mikael
Ee, Hooi C
Yeoh, George
Mou, Lingjun
Ferrara, Katherine W
Billiran, Hector
Ganss, Ruth
Ruoslahti, Erkki
Hamzah, Juliana
Date : 11 November 2019
DOI : 10.15252/emmm.201910923
Copyright Disclaimer : © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Depositing User : Clive Harris
Date Deposited : 18 Nov 2019 11:13
Last Modified : 18 Nov 2019 11:13

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