RESUMO
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.
Assuntos
Neoplasias Encefálicas/terapia , Terapia Genética , Glioma/terapia , Lipossomos/uso terapêutico , Proteínas de Membrana/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Cátions/química , Cátions/farmacocinética , Cátions/uso terapêutico , Linhagem Celular , Glioma/diagnóstico por imagem , Glioma/metabolismo , Glioma/patologia , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Interferência de RNA , RNA Interferente Pequeno/farmacocinéticaRESUMO
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.