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J Control Release ; 304: 242-258, 2019 06 28.
Artigo em Francês | MEDLINE | ID: mdl-31071376

RESUMO

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-ß signaling pathway. Furthermore, we appealed to virtual screening of tumor target, and found a new pathway of I3A as a TGF-ß 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.


Assuntos
Diterpenos/administração & dosagem , Imunoterapia/métodos , Nanopartículas , Sarcoma Experimental/tratamento farmacológico , Animais , Citocinas/metabolismo , Diterpenos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Micelas , Nanotecnologia , Polímeros/química , Sarcoma Experimental/imunologia , Transdução de Sinais/efeitos dos fármacos
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