In Vivo Follow-Up of Gene Inhibition in Solid Tumors Using Peptide-Based Nanoparticles for siRNA Delivery

被引:11
作者
Ferreiro, Isabel [1 ]
Genevois, Coralie [1 ,2 ]
Konate, Karidia [3 ]
Vives, Eric [3 ]
Boisguerin, Prisca [3 ]
Deshayes, Sebastien [3 ]
Couillaud, Franck [1 ]
机构
[1] Univ Bordeaux, Imagerie Mol & Therapies Innoyantes Oncol EA 7435, F-33076 Bordeaux, France
[2] Univ Bordeaux, INSERM US 005, ViVIVOPTIC TBM Core, CNRS,UMS 3427, F-33076 Bordeaux, France
[3] Univ Montpellier, PhyMedExp, Inserm U1046, CNRS,UMR 9214, F-34395 Montpellier, France
关键词
cancer therapy; siRNA; gene silencing; peptide-based nanoparticles; optical imaging; CELL-PENETRATING PEPTIDE; MECHANISM; REPORTER;
D O I
10.3390/pharmaceutics13050749
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Small interfering RNA (siRNA) exhibits a high degree of specificity for targeting selected genes. They are efficient on cells in vitro, but in vivo siRNA therapy remains a challenge for solid tumor treatment as siRNAs display difficulty reaching their intracellular target. The present study was designed to show the in vivo efficiency of a new peptide (WRAP5), able to form peptide-based nanoparticles (PBN) that can deliver siRNA to cancer cells in solid tumors. WRAP5:siRNA nanoparticles targeting firefly luciferase (Fluc) were formulated and assayed on Fluc-expressing U87 glioblastoma cells. The mode of action of WRAP5:siRNA by RNA interference was first confirmed in vitro and then investigated in vivo using a combination of bioluminescent reporter genes. Finally, histological analyses were performed to elucidate the cell specificity of this PBN in the context of brain tumors. In vitro and in vivo results showed efficient knock-down of Fluc expression with no toxicity. WRAP5:siFluc remained in the tumor for at least 10 days in vivo. Messenger RNA (mRNA) analyses indicated a specific decrease in Fluc mRNA without affecting tumor growth. Histological studies identified PBN accumulation in the cytoplasm of tumor cells but also in glial and neuronal cells. Through in vivo molecular imaging, our findings established the proof of concept for specific gene silencing in solid tumors. The evidence generated could be translated into therapy for any specific gene in different types of tumors without cell type specificity but with high molecular specificity.
引用
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页数:10
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