Polyplex-mediated inhibition of chemokine receptor CXCR4 and chromatin-remodeling enzyme NCOA3 impedes pancreatic cancer progression and metastasis.
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.
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198.
Yan
Y
Wang
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States.
Sushil
S
Kumar
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States.
Satyanarayana
S
Rachagani
Department of Radiology, University of Nebraska Medical Center, Nebraska, United States.
Balasrinivasa R
BR
Sajja
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198.
Ying
Y
Xie
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198.
Yu
Y
Hang
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States.
Maneesh
M
Jain
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198.
Jing
J
Li
Department of Radiology, University of Nebraska Medical Center, Nebraska, United States.
Michael D
MD
Boska
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Nebraska, United States.
Surinder K
SK
Batra
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198.
David
D
Oupický
D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D056921:Nuclear Receptor Coactivator 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D011108:Polymers; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3
CXCR4; Metastasis; Mucin; NCOA3; Pancreatic cancer; Polyplexes; Tumor perfusion; siRNA delivery