1. Combined delivery of a TGF-β inhibitor and an adenoviral vector expressing interleukin-12 potentiates cancer immunotherapy.
- Author
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Jiang J, Zhang Y, Peng K, Wang Q, Hong X, Li H, Fan G, Zhang Z, Gong T, and Sun X
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Benzodioxoles pharmacology, Cell Line, Tumor, Cell Movement, Combined Modality Therapy, Female, Imidazoles pharmacology, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Melanoma, Experimental therapy, Mice, Inbred C57BL, Neoplasm Invasiveness, Neoplasms immunology, Polyethyleneimine chemistry, Pyridines pharmacology, Transduction, Genetic, beta-Cyclodextrins chemistry, Adenoviridae metabolism, Benzodioxoles administration & dosage, Drug Delivery Systems, Genetic Vectors administration & dosage, Imidazoles administration & dosage, Immunotherapy, Interleukin-12 therapeutic use, Neoplasms therapy, Pyridines administration & dosage, Transforming Growth Factor beta antagonists & inhibitors
- Abstract
Cancer immunotherapy appears to have a promising future, but it can be thwarted by secretion of immunosuppressive factors, such as transforming growth factor-β (TGF-β), which inhibits local immune responses to tumors. To weaken immune resistance of tumors and simultaneously strengthen immune responses, we developed a multifunctional polymer that could co-deliver hydrophobic TGF-β inhibitor and an adenovirus gene vector to tumor sites. This co-delivery system sustainably released TGF-β inhibitor SB-505124 and effectively transferred the adenovirus vector carrying the interleukin-12 gene. In addition, it significantly delayed growth of B16 melanoma xenografts in mice and increased animal survival. Mechanistic studies showed that this combination therapy enhanced anti-tumor immune response by activating CD4
+ and CD8+ T cells, natural killer cells and interferon-γ secretion in the tumor microenvironment., Statement of Significance: To weaken immune resistance of tumors and simultaneously strengthen tumors' immune responses, we synthesized a structurally simple, low-toxic but functional polymer β-cyclodextrin-PEI to encapsulate a hydrophobic TGF-β inhibitor SB-505124 and to complex adenovirus vectors expressing IL-12. This is the first report demonstrating that combining TGF-β inhibitor with IL-12 could provide effective immunotherapy against melanoma by the sustainable release of SB-505124 and the effectible transduction of IL-12 gene in tumor cells. The rational delivery system presented a comprehensive and valued platform to be a candidate vector for co-delivering hydrophobic small-molecule drugs and therapeutic genes for treating cancer, providing a new approach for cancer immunotherapy., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)- Published
- 2017
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