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1.
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
2.
J Control Release ; 221: 62-70, 2016 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-26551344

RESUMO

Sorafenib is a tyrosine kinase inhibitor that has recently been shown to be a potential antifibrotic agent. However, a narrow therapeutic window limits the clinical use and therapeutic efficacy of sorafenib. Herein, we have developed and optimized nanoparticle (NP) formulations prepared from a mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) for the systemic delivery of sorafenib into the fibrotic livers of CCl4-induced fibrosis mouse models. We characterized and compared the pharmaceutical and biological properties of two different PLGA nanoparticles (NPs)--PEG-PLGA NPs (PEG-PLGA/PLGA=10/0) and PEG-PLGA/PLGA NPs (PEG-PLGA/PLGA=5/5). Increasing the PLGA content in the PEG-PLGA/PLGA mixture led to increases in the particle size and drug encapsulation efficacy and a decrease in the drug release rate. Both PEG-PLGA and PEG-PLGA/PLGA NPs significantly prolonged the blood circulation of the cargo and increased the uptake by the fibrotic livers. The systemic administration of PEG-PLGA or PEG-PLGA/PLGA NPs containing sorafenib twice per week for a period of 4 weeks efficiently ameliorated liver fibrosis, as indicated by decreased α-smooth muscle actin (α-SMA) content and collagen production in the livers of CCl4-treated mice. Furthermore, sorafenib-loaded PLGA NPs significantly shrank the abnormal blood vessels and decreased microvascular density (MVD), leading to vessel normalization in the fibrotic livers. In conclusion, our results reflect the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis.


Assuntos
Portadores de Fármacos/química , Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Nanopartículas/química , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Polietilenoglicóis/química , Poliglactina 910/química , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Tetracloreto de Carbono , Células Endoteliais da Veia Umbilical Humana , Ácido Láctico/química , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Nanopartículas/ultraestrutura , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Inibidores de Proteínas Quinases/administração & dosagem , Sorafenibe
3.
Biomaterials ; 67: 194-203, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26218745

RESUMO

Sorafenib, a multikinase inhibitor, has been used as an anti-angiogenic agent against highly vascular hepatocellular carcinoma (HCC) - yet associated with only moderate therapeutic effect and the high incidence of HCC recurrence. We have shown intratumoral hypoxia induced by sorafenib activated C-X-C receptor type 4 (CXCR4)/stromal-derived factor 1α (SDF1α) axis, resulting in polarization toward a tumor-promoting microenvironment and resistance to anti-angiogenic therapy in HCC. Herein, we formulated sorafenib in CXCR4-targeted lipid-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) modified with a CXCR4 antagonist, AMD3100 to systemically deliver sorafenib into HCC and sensitize HCC to sorafenib treatment. We demonstrated that CXCR4-targeted NPs efficiently delivered sorafenib into HCCs and human umbilical vein endothelial cells (HUVECs) to achieve cytotoxicity and anti-angiogenic effect in vitro and in vivo. Despite the increased expression of SDF1α upon the persistent hypoxia induced by sorafenib-loaded CXCR4-targeted NPs, AMD3100 attached to the NPs can block CXCR4/SDF1α, leading to the reduced infiltration of tumor-associated macrophages, enhanced anti-angiogenic effect, a delay in tumor progression and increased overall survival in the orthotopic HCC model compared with other control groups. In conclusion, our results highlight the clinical potential of CXCR4-targeted NPs for delivering sorafenib and overcoming acquired drug resistance in liver cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Láctico/química , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Ácido Poliglicólico/química , Receptores CXCR4/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Nanopartículas/ultraestrutura , Metástase Neoplásica , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Fenótipo , Compostos de Fenilureia/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Sorafenibe , Análise de Sobrevida , Microambiente Tumoral/efeitos dos fármacos
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