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Polyplex-mediated inhibition of chemokine receptor CXCR4 and chromatin-remodeling enzyme NCOA3 impedes pancreatic cancer progression and metastasis.
- Source :
-
Biomaterials [Biomaterials] 2016 Sep; Vol. 101, pp. 108-120. Date of Electronic Publication: 2016 May 27. - Publication Year :
- 2016
-
Abstract
- Pancreatic cancer (PC) is one of the most aggressive malignancies due to intense desmoplasia, extreme hypoxia and inherent chemoresistance. Studies have implicated the expression of chemokine receptor CXCR4 and nuclear receptor co-activator-3 (NCOA3) in the development of desmoplasia and metastatic spread of PC. Using a series of polymeric CXCR4 antagonists (PCX), we optimized formulation of PCX/siNCOA3 polyplexes to simultaneously target CXCR4 and NCOA3 in PC. Cholesterol-modified PCX showed maximum CXCR4 antagonism, NCOA3 silencing and inhibition of PC cell migration in vitro. The optimized PCX/siNCOA3 polyplexes were used in evaluating antitumor and antimetastatic activity in orthotopic mouse model of metastatic PC. The polyplexes displayed significant inhibition of primary tumor growth, which was accompanied by a decrease in tumor necrosis and increased tumor perfusion. The polyplexes also showed significant antimetastatic effect and effective suppression of metastasis to distant organs. Overall, dual-function PCX/siNCOA3 polyplexes can effectively regulate tumor microenvironment to decrease progression and dissemination of PC.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Cell Line, Tumor
Disease Progression
Female
Humans
Mice, Nude
Neoplasm Metastasis genetics
Neoplasm Metastasis pathology
Nuclear Receptor Coactivator 3 genetics
Pancreas metabolism
Pancreas pathology
Pancreatic Neoplasms genetics
Pancreatic Neoplasms pathology
Polymers administration & dosage
Polymers chemistry
RNA, Small Interfering administration & dosage
RNA, Small Interfering genetics
Neoplasm Metastasis prevention & control
Nuclear Receptor Coactivator 3 antagonists & inhibitors
Pancreatic Neoplasms therapy
Polymers therapeutic use
RNA, Small Interfering therapeutic use
Receptors, CXCR4 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5905
- Volume :
- 101
- Database :
- MEDLINE
- Journal :
- Biomaterials
- Publication Type :
- Academic Journal
- Accession number :
- 27267632
- Full Text :
- https://doi.org/10.1016/j.biomaterials.2016.05.042