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Ovarian cancer immunotherapy using PD-L1 siRNA targeted delivery from folic acid-functionalized polyethylenimine: strategies to enhance T cell killing.
- Source :
-
Advanced healthcare materials [Adv Healthc Mater] 2015 Jun 03; Vol. 4 (8), pp. 1180-9. Date of Electronic Publication: 2015 Apr 11. - Publication Year :
- 2015
-
Abstract
- Adoptive T cell immunotherapy is a promising treatment strategy for epithelial ovarian cancer (EOC). However, programmed death ligand-1 (PD-L1), highly expressed on EOC cells, interacts with programmed death-1 (PD-1), expressed on T cells, causing immunosuppression. This study aims to block PD-1/PD-L1 interactions by delivering PD-L1 siRNA, using various folic acid (FA)-functionalized polyethylenimine (PEI) polymers, to SKOV-3-Luc EOC cells, and investigate the sensitization of the EOC cells to T cell killing. To enhance siRNA uptake into EOC cells, which over express folate receptors, PEI is modified with FA or PEG-FA so that siRNA is complexed into nanoparticles with folate molecules on the surface. PEI modification with a single functional group lowers the polymer cytotoxicity compared to unmodified PEI. FA-conjugated polymers increase siRNA uptake into SKOV-3-luc cells and decrease unspecific uptake into monocytes. All polymers result in 40% to 50% PD-L1 protein knockdown. Importantly, SKOV-3-Luc cells treated with either PEI-FA or PEI- polyethylene glycol (PEG)-FA/PD-L1 siRNA complexes are up to twofold more sensitive to T cell killing compared to scrambled siRNA treated controls. These findings are the first to demonstrate that PD-L1 knockdown in EOC cells, via siRNA/FA-targeted delivery, are able to sensitize cancer cells to T cell killing.<br /> (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- B7-H1 Antigen metabolism
Carcinoma, Ovarian Epithelial
Cell Line, Tumor
Down-Regulation
Female
Genetic Therapy
Humans
Immunotherapy methods
Lysosomal-Associated Membrane Protein 1 genetics
Lysosomal-Associated Membrane Protein 1 metabolism
Nanoparticles chemistry
Neoplasms, Glandular and Epithelial therapy
Ovarian Neoplasms therapy
Particle Size
Polyethylene Glycols chemistry
Polymers chemistry
T-Lymphocytes metabolism
B7-H1 Antigen genetics
Folic Acid metabolism
Gene Expression Regulation, Neoplastic
Neoplasms, Glandular and Epithelial genetics
Ovarian Neoplasms genetics
Polyethyleneimine metabolism
RNA, Small Interfering genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2192-2659
- Volume :
- 4
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Advanced healthcare materials
- Publication Type :
- Academic Journal
- Accession number :
- 25866054
- Full Text :
- https://doi.org/10.1002/adhm.201500089