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Métodos Terapêuticos e Terapias MTCI
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1.
Sci Adv ; 6(3): eaax5032, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31998834

RESUMO

While immunotherapy holds great promise for combating cancer, the limited efficacy due to an immunosuppressive tumor microenvironment and systemic toxicity hinder the broader application of cancer immunotherapy. Here, we report a combinatorial immunotherapy approach that uses a highly efficient and tumor-selective gene carrier to improve anticancer efficacy and circumvent the systemic toxicity. In this study, we engineered tumor-targeted lipid-dendrimer-calcium-phosphate (TT-LDCP) nanoparticles (NPs) with thymine-functionalized dendrimers that exhibit not only enhanced gene delivery capacity but also immune adjuvant properties by activating the stimulator of interferon genes (STING)-cGAS pathway. TT-LDCP NPs delivered siRNA against immune checkpoint ligand PD-L1 and immunostimulatory IL-2-encoding plasmid DNA to hepatocellular carcinoma (HCC), increased tumoral infiltration and activation of CD8+ T cells, augmented the efficacy of cancer vaccine immunotherapy, and suppressed HCC progression. Our work presents nanotechnology-enabled dual delivery of siRNA and plasmid DNA that selectively targets and reprograms the immunosuppressive tumor microenvironment to improve cancer immunotherapy.


Assuntos
Biomarcadores Tumorais , Fenômenos Imunogenéticos , Terapia de Alvo Molecular , Nanopartículas , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Nanomedicina Teranóstica , Animais , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores/metabolismo , Fosfatos de Cálcio/química , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Terapia Genética , Humanos , Imunoterapia , Lipídeos/química , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Nanotecnologia , Neoplasias/patologia , Plasmídeos/administração & dosagem , Plasmídeos/química , Plasmídeos/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Transdução de Sinais
2.
Sci Rep ; 7: 44123, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276530

RESUMO

Sorafenib is a RAF inhibitor approved for several cancers, including hepatocellular carcinoma (HCC). Inhibition of RAF kinases can induce a dose-dependent "paradoxical" upregulation of the downstream mitogen-activated protein kinase (MAPK) pathway in cancer cells. It is unknown whether "paradoxical" ERK activation occurs after sorafenib therapy in HCC, and if so, if it impacts the therapeutic efficacy. Here, we demonstrate that RAF inhibition by sorafenib rapidly leads to RAF dimerization and ERK activation in HCCs, which contributes to treatment evasion. The transactivation of RAF dimers and ERK signaling promotes HCC cell survival, prevents apoptosis via downregulation of BIM and achieves immunosuppression by MAPK/NF-kB-dependent activation of PD-L1 gene expression. To overcome treatment evasion and reduce systemic effects, we developed CXCR4-targeted nanoparticles to co-deliver sorafenib with the MEK inhibitor AZD6244 in HCC. Using this approach, we preferentially and efficiently inactivated RAF/ERK, upregulated BIM and down-regulated PD-L1 expression in HCC, and facilitated intra-tumoral infiltration of cytotoxic CD8+ T cells. These effects resulted in a profound delay in tumor growth. Thus, this nano-delivery strategy to selectively target tumors and prevent the paradoxical ERK activation could increase the feasibility of dual RAF/MEK inhibition to overcome sorafenib treatment escape in HCC.


Assuntos
Benzimidazóis , Carcinoma Hepatocelular/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/uso terapêutico , Proteínas de Neoplasias/imunologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases , Receptores CXCR4/imunologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos , Niacinamida/farmacocinética , Niacinamida/farmacologia , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe
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