RESUMEN
The correct affiliation no 2 is presented in this paper.
RESUMEN
Glioblastoma is one of the most aggressive types of brain tumor. Epidermal growth factor receptors (EGFRs) are overexpressed in glioma, and EGFR amplifications and mutations lead to rapid proliferation and invasion. EGFR-targeted therapy might be an effective treatment for glioma. Gefitinib (Ge) is an EGFR tyrosine kinase inhibitor (TKI), and Golgi phosphoprotein 3 (GOLPH3) expression is associated with worse glioma prognosis. Downregulation of GOLPH3 could promote EGFR degradation. Here, an angiopep-2 (A2)-modified cationic lipid-poly (lactic-co-glycolic acid) (PLGA) nanoparticle (A2-N) was developed that can release Ge and GOLPH3 siRNA (siGOLPH3) upon entering glioma cells and therefore acts as a combinatorial anti-tumor therapy. The in vitro and in vivo studies proved that A2-N/Ge/siGOLPH3 successfully crossed the blood-brain barrier (BBB) and targeted glioma. Released siGOLPH3 effectively silenced GOLPH3 mRNA expression and further promoted EGFR and p-EGFR degradation. Released Ge also markedly inhibited EGFR signaling. This combined EGFR-targeted action achieved remarkable anti-glioma effects and could be a safe and effective treatment for glioma. KEY MESSAGES: Angiopep-2-modified cationic lipid polymer can penetrate the BBB. Gefitinib can inhibit EGFR signaling and block the autophosphorylation of critical tyrosine residues on EGFR. GOLPH3 siRNA can be transfected into glioma and downregulate GLOPH3 expression. A2-N/Ge/siGOLPH3 can inhibit glioma growth.
Asunto(s)
Receptores ErbB/metabolismo , Gefitinib/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/metabolismo , Proteínas de la Membrana/metabolismo , Nanopartículas/química , Fosfoproteínas/metabolismo , ARN Interferente Pequeño/metabolismo , Animales , Proliferación Celular/genética , Proliferación Celular/fisiología , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfoproteínas/genética , ARN Interferente Pequeño/genéticaRESUMEN
The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH2s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Glioma/terapia , Nanopartículas/administración & dosificación , Péptidos/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Temozolomida/administración & dosificación , Animales , Antineoplásicos Alquilantes/síntesis química , Antineoplásicos Alquilantes/metabolismo , Línea Celular Tumoral , Terapia Combinada/métodos , Sistemas de Liberación de Medicamentos/métodos , Glioma/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Desnudos , Nanopartículas/química , Nanopartículas/metabolismo , Péptidos/síntesis química , Péptidos/metabolismo , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/administración & dosificación , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/síntesis química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/metabolismo , Profármacos/administración & dosificación , Profármacos/química , Profármacos/metabolismo , Fármacos Sensibilizantes a Radiaciones/síntesis química , Fármacos Sensibilizantes a Radiaciones/metabolismo , Radioterapia/métodos , Temozolomida/síntesis química , Temozolomida/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
PURPOSE: GOLPH3 has been shown to be involved in glioma proliferation. In this study, we aimed to demonstrate that GOLPH3 can serve as a target for glioma gene therapy. METHODS: During the experiment, cationic liposomes with angiopep-2 (A2-CL) were used to deliver siGOLPH3 crossing the blood-brain barrier and reaching the glioma. RESULTS: At the cellular level, the A2-CL/siGOLPH3 could silence GOLPH3 and then effectively inhibited the proliferation of cells. In vivo experiments, using U87-GFP-Luci-bearing BALB/c mouse models, we demonstrated that A2-CL could deliver GOLPH3-siRNA specifically to glioma and effectively inhibit glioma growth. CONCLUSIONS: This study shows that GOLPH3 has great potential as a target for the gene therapy of glioma and is of great value in precise medical applications.