Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours
| العنوان: | Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours |
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| المؤلفون: | Hsi-Chien Huang, Yun-Chieh Sung, Chung-Pin Li, Dehui Wan, Po-Han Chao, Yu-Ting Tseng, Bo-Wen Liao, Hui-Teng Cheng, Fu-Fei Hsu, Chieh-Cheng Huang, Yi-Ting Chen, Yu-Hui Liao, Hsin Tzu Hsieh, Yu-Chuan Shih, I-Ju Liu, Han-Chung Wu, Tsai-Te Lu, Jane Wang, Yunching Chen |
| المصدر: | Gut. 71:1843-1855 |
| بيانات النشر: | BMJ, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Pancreatic Neoplasms, TNF-Related Apoptosis-Inducing Ligand, Mice, Tumor Microenvironment, Gastroenterology, Animals, Humans, Nanogels, Nitric Oxide, Carcinoma, Pancreatic Ductal |
| الوصف: | ObjectiveStromal barriers, such as the abundant desmoplastic stroma that is characteristic of pancreatic ductal adenocarcinoma (PDAC), can block the delivery and decrease the tumour-penetrating ability of therapeutics such as tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), which can selectively induce cancer cell apoptosis. This study aimed to develop a TRAIL-based nanotherapy that not only eliminated the extracellular matrix barrier to increase TRAIL delivery into tumours but also blocked antiapoptotic mechanisms to overcome TRAIL resistance in PDAC.DesignNitric oxide (NO) plays a role in preventing tissue desmoplasia and could thus be delivered to disrupt the stromal barrier and improve TRAIL delivery in PDAC. We applied an in vitro–in vivo combinatorial phage display technique to identify novel peptide ligands to target the desmoplastic stroma in both murine and human orthotopic PDAC. We then constructed a stroma-targeted nanogel modified with phage display-identified tumour stroma-targeting peptides to co-deliver NO and TRAIL to PDAC and examined the anticancer effect in three-dimensional spheroid cultures in vitro and in orthotopic PDAC models in vivo.ResultsThe delivery of NO to the PDAC tumour stroma resulted in reprogramming of activated pancreatic stellate cells, alleviation of tumour desmoplasia and downregulation of antiapoptotic BCL-2 protein expression, thereby facilitating tumour penetration by TRAIL and substantially enhancing the antitumour efficacy of TRAIL therapy.ConclusionThe co-delivery of TRAIL and NO by a stroma-targeted nanogel that remodels the fibrotic tumour microenvironment and suppresses tumour growth has the potential to be translated into a safe and promising treatment for PDAC. |
| تدمد: | 1468-3288 0017-5749 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c6a72fbcd366b404de8eb8cd0c287f5c https://doi.org/10.1136/gutjnl-2021-325180 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c6a72fbcd366b404de8eb8cd0c287f5c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14683288 00175749 |
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