Your browser doesn't support javascript.
loading
Reversal of pancreatic desmoplasia by a tumour stroma-targeted nitric oxide nanogel overcomes TRAIL resistance in pancreatic tumours.
Huang, Hsi-Chien; Sung, Yun-Chieh; Li, Chung-Pin; Wan, Dehui; Chao, Po-Han; Tseng, Yu-Ting; Liao, Bo-Wen; Cheng, Hui-Teng; Hsu, Fu-Fei; Huang, Chieh-Cheng; Chen, Yi-Ting; Liao, Yu-Hui; Hsieh, Hsin Tzu; Shih, Yu-Chuan; Liu, I-Ju; Wu, Han-Chung; Lu, Tsai-Te; Wang, Jane; Chen, Yunching.
Afiliação
  • Huang HC; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Sung YC; Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
  • Li CP; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Wan D; Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
  • Chao PH; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
  • Tseng YT; Division of Clinical Skills Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan.
  • Liao BW; National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan.
  • Cheng HT; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Hsu FF; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Huang CC; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Chen YT; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Liao YH; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Biomedical Park Branch, Zhu Bei City, Taiwan.
  • Hsieh HT; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
  • Shih YC; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
  • Liu IJ; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Wu HC; Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
  • Lu TT; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Wang J; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
  • Chen Y; Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan.
Gut ; 71(9): 1843-1855, 2022 09.
Article em En | MEDLINE | ID: mdl-34921062
ABSTRACT

OBJECTIVE:

Stromal 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.

DESIGN:

Nitric 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.

RESULTS:

The 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.

CONCLUSION:

The 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.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Gut Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Carcinoma Ductal Pancreático Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Gut Ano de publicação: 2022 Tipo de documento: Article