A multi-functional macrophage and tumor targeting gene delivery system for the regulation of macrophage polarity and reversal of cancer immunoresistance

To achieve effective tumor eradication using anti-tumor immunotherapies, a fusion peptide functionalized gene delivery system for macrophage and tumor targeting delivery of the plasmid DNA encoding the IL-12 gene (pDNA IL-12) was prepared for macrophage re-polarization as well as reversal of cancer...

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Bibliographic Details
Published in:Nanoscale 2018-01, Vol.10 (33), p.15578-15587
Main Authors: He, Xiao-Yan, Liu, Bo-Ya, Xu, Chang, Zhuo, Ren-Xi, Cheng, Si-Xue
Format: Article
Language:English
Subjects:
Animals
Anticancer properties
Calcium carbonate
Cancer
Cell Line
Cell Polarity
Cytokines
Deoxyribonucleic acid
DNA
Gene expression
Gene Transfer Techniques
HEK293 Cells
HeLa Cells
Humans
Hyaluronan Receptors
Hyaluronic Acid
Immunosuppression
Interleukin-12 - genetics
Macrophages - cytology
Mice
Nanoparticles
Neuropilin-1
Peptides
Plasmids
Polarity
Protamines
Receptors
Receptors, Fc
Recombinant Fusion Proteins
Self-assembly
Transfection
Tuftsin
Tumor Microenvironment
Tumors
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Summary:To achieve effective tumor eradication using anti-tumor immunotherapies, a fusion peptide functionalized gene delivery system for macrophage and tumor targeting delivery of the plasmid DNA encoding the IL-12 gene (pDNA IL-12) was prepared for macrophage re-polarization as well as reversal of cancer immunosuppression. A fusion peptide containing the tuftsin sequence that can interact with Fc receptors and neuropilin-1, and hyaluronic acid (HA) that can interact with CD44 were introduced into the delivery system by self-assembly to form peptide/hyaluronic acid/protamine/CaCO3/DNA nanoparticles (PHNP) with both macrophage targeting and tumor targeting capabilities. PHNP provides an efficient immunoregulation on J774A.1 cells to shift the anti-inflammatory M2 phenotype to the anti-tumor M1 phenotype with enhanced secretion of pro-inflammatory cytokines and increased expression of M1 markers. Owing to the improved delivery efficiency caused by the fusion peptide and HA, the transfection mediated by multi-functional PHNP can up-regulate IL-12 as well as down-regulate IL-10 and IL-4 more effectively as compared with the nanoparticles without HA and/or peptide decoration. More importantly, the gene delivery system can also deliver pDNA IL-12 to targeted cancerous HeLa cells to realize the secretion of IL-12. PHNP not only enables tumorous cells to produce pDNA IL-12, but also down-regulates CD47 and up-regulate CD80 and HLA-1 in the malignant cells, indicating that the gene delivery system can effectively reverse tumor induced immunosuppression.
ISSN:2040-3364
2040-3372
DOI:10.1039/c8nr05294h