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.

中文翻译：

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免疫介导的ECM耗竭可改善肿瘤灌注和有效载荷输送。

实体癌中高的细胞外基质（ECM）含量会损害肿瘤灌注，从而损害成像和治疗剂的可及性。我们设计了一种新的降解肿瘤ECM的方法，可改善循环化合物的摄取。我们使用称为CSG的新发现肽配体将免疫调节细胞因子肿瘤坏死因子α（TNFα）靶向肿瘤。该肽与小鼠和人类癌症的ECM中的层粘连蛋白-Nidogen复合物结合，而在正常组织中几乎没有或没有检测到该肽，并且它在肿瘤小鼠中选择性地将重组TNFα-CSG融合蛋白递送至肿瘤ECM。静脉注射TNFα-CSG在小鼠肿瘤中，尤其是在富含ECM的区域中，触发了强大的免疫细胞浸润。免疫细胞的大量涌入伴随着ECM的大量降解，肿瘤僵硬度的降低，扩张肿瘤血管，改善造影剂加多度多和氧化铁纳米颗粒的灌注并增加肿瘤内摄取。观察到荷瘤小鼠的肿瘤生长受到抑制和存活时间延长。在没有TNFα通常严重的毒副作用的情况下，可以获得这些效果。