1. Nanotechnology-mediated immunochemotherapy with Ingenol-3-Mebutate for Systematic Anti-tumor Effects.
- Author
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Yu M, Zhao M, Yu R, Chu S, Xu J, Xia M, and Wang C
- Subjects
- Animals, Cytokines metabolism, Diterpenes pharmacology, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Micelles, Nanotechnology, Polymers chemistry, Sarcoma, Experimental immunology, Signal Transduction drug effects, Diterpenes administration & dosage, Immunotherapy methods, Nanoparticles, Sarcoma, Experimental drug therapy
- Abstract
Cancer-Immunotherapy was the most exciting topic. However, either insensitivity due to singleness of therapeutic target or immune evasion leads to the failure of the treatment. Ingenol-3-mebutate (I3A) can inhibit cancer through synergy between immunotherapy and chemotherapy, however, the speculation and accurate mechanism haven't been confirmed in vivo limited by its hydrophobicity and pH-instability, which also hindered its clinical translation. Herein we developed a polymeric micelle with 'acidic core' provided by single alcoholic hydroxyl (-CH(CH3)-OH) encapsulating I3A (I3A-PM), which successfully overcome the aforementioned problems and reduce the toxicity in vivo. To test the synergy, S180 tumor-bearing mice were subjected to I3A-PM through intravenous and intratumoral administration, we found I3A-PM presented significant antitumor effect, and promoted Th1 polarization by upregulating the level of Th1 cytokines (IL-12, IL-2, IFN-γ and TNF-α), and accelerated the expansion of CD4
+ and CD8+ T cells, meanwhile, I3A-PM depleted regulatory T cells, Th2 cytokine IL-6 through inhibiting TGF-β signaling pathway. Furthermore, we appealed to virtual screening of tumor target, and found a new pathway of I3A as a TGF-β receptor type I inhibitor to improve immunostimulatory effects. These results demonstrated I3A-PM as a promising nanoagent for cancer immunotherapy strategy. The synergistic therapeutic effects are encouraged to further evaluate in different cancer model compared with commercial products to facilitate research finding (I3A-PM) entering the clinic., (Copyright © 2019. Published by Elsevier B.V.)- Published
- 2019
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