TY - JOUR
T1 - Targeting the Tumor Core
T2 - Hypoxia-Responsive Nanoparticles for the Delivery of Chemotherapy to Pancreatic Tumors
AU - Confeld, Matthew I.
AU - Mamnoon, Babak
AU - Feng, Li
AU - Jensen-Smith, Heather
AU - Ray, Priyanka
AU - Froberg, James
AU - Kim, Jiha
AU - Hollingsworth, Michael A.
AU - Quadir, Mohiuddin
AU - Choi, Yongki
AU - Mallik, Sanku
N1 - Funding Information:
This research was supported by an NIH grant [1 R01GM 114080 (NIGMS)] and a Ready-to-Go award from the DaCCoTA Center (NIGMS U54 GM128729) to S.M. S.M. also acknowledges support from the Grand Challenge Initiative and the Office of the Dean, College of Health Professions, North Dakota State University. M.A.H. was supported by NCI Research Specialist 5R50CA211462, SPORE in pancreatic cancer P50CA127297, NCI Cancer Center Support P30CA36727, and Pancreatic Cancer Detection Consortium U01CA210240. We thank Dr. Paul M. Grandgenett, Director, Rapid Autopsy Program, University of Nebraska Medical Center Tissue Bank for providing the human pancreatic cancer samples.The Animal Core Facility is partly supported by the NIH COBRE award 1P20 GM109024.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/8/3
Y1 - 2020/8/3
N2 - In pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, increased cell survival, the formation of cancer stem cells, and drug resistance. Hypoxia in PDAC is also associated with the development of collagen-rich, fibrous extracellular stroma (desmoplasia), resulting in severely impaired drug penetration. To overcome these daunting challenges, we created polymer nanoparticles (polymersomes) that target and penetrate pancreatic tumors, reach the hypoxic niches, undergo rapid structural destabilization, and release the encapsulated drugs. In vitro studies indicated a high cellular uptake of the polymersomes and increased cytotoxicity of the drugs under hypoxia compared to unencapsulated drugs. The polymersomes decreased tumor growth by nearly 250% and significantly increased necrosis within the tumors by 60% in mice compared to untreated controls. We anticipate that these polymer nanoparticles possess a considerable translational potential for delivering drugs to solid hypoxic tumors.
AB - In pancreatic ductal adenocarcinoma (PDAC), early onset of hypoxia triggers remodeling of the extracellular matrix, epithelial-to-mesenchymal transition, increased cell survival, the formation of cancer stem cells, and drug resistance. Hypoxia in PDAC is also associated with the development of collagen-rich, fibrous extracellular stroma (desmoplasia), resulting in severely impaired drug penetration. To overcome these daunting challenges, we created polymer nanoparticles (polymersomes) that target and penetrate pancreatic tumors, reach the hypoxic niches, undergo rapid structural destabilization, and release the encapsulated drugs. In vitro studies indicated a high cellular uptake of the polymersomes and increased cytotoxicity of the drugs under hypoxia compared to unencapsulated drugs. The polymersomes decreased tumor growth by nearly 250% and significantly increased necrosis within the tumors by 60% in mice compared to untreated controls. We anticipate that these polymer nanoparticles possess a considerable translational potential for delivering drugs to solid hypoxic tumors.
KW - hypoxia-responsive
KW - nanoparticles
KW - pancreatic cancer
KW - polymersomes
KW - tumor-penetrating
UR - http://www.scopus.com/inward/record.url?scp=85089613305&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089613305&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.0c00247
DO - 10.1021/acs.molpharmaceut.0c00247
M3 - Article
C2 - 32521162
AN - SCOPUS:85089613305
SN - 1543-8384
VL - 17
SP - 2849
EP - 2863
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 8
ER -