| Autor: |
Azambuja JH; Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil. julianahazambuja@hotmail.com., Schuh RS; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil., Michels LR; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil., Gelsleichter NE; Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil., Beckenkamp LR; Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil., Iser IC; Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil., Lenz GS; Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil., de Oliveira FH; Departamento de Patologia, UFRGS, Porto Alegre, RS, Brazil., Venturin G; Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., Greggio S; Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., daCosta JC; Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil., Wink MR; Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil., Sevigny J; Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, QC, Québec, Canada.; Centre de recherche du CHU de Québec, Université Laval, Québec City, QC, G1V 4G2, Canada., Stefani MA; Departamento de Morfologia, UFRGS, Porto Alegre, RS, Brazil., Battastini AMO; Departamento de Bioquímica, UFRGS, Porto Alegre, RS, Brazil., Teixeira HF; Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil., Braganhol E; Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil. |
| Abstrakt: |
Glioblastoma is the most devastating primary brain tumor. Effective therapies are not available, mainly due to high tumor heterogeneity, chemoresistance, and the difficulties imposed by blood-brain barrier. CD73, an enzyme responsible for adenosine (ADO) production, is overexpressed in cancer cells and emerges as a target for glioblastoma treatment. Indeed, ADO causes a variety of tumor-promoting actions, particularly by inducing tumor immune escape, whereas CD73 inhibition impairs tumor progression. Here, a cationic nanoemulsion to deliver CD73siRNA (NE-siRNA CD73R) via nasal route aiming glioblastoma treatment was developed. NE-siRNA CD73R was uptaken by glioma cells in culture, resulting in a parallel 60-80% decrease in AMPase activity and 30-50% in cell viability. Upon nasal delivery, NE-siRNA CD73R was detected in rat brain and serum. Notably, treatment with CD73siRNA complexes of glioma-bearing Wistar rats reduced tumor growth by 60%. Additionally, NE-siRNA CD73R treatment decreased 95% ADO levels in liquor and tumor CD73 expression, confirming in vivo CD73 silencing. Finally, no toxicity was observed in either primary astrocytes or rats with this cationic nanoemulsion. These results suggest that nasal administration of cationic NE as CD73 siRNA delivery system represents a novel potential treatment for glioblastoma. Graphical Abstract Glioblastoma is the most common and devastating form of primary brain tumor. CD73, a protein involved in cell-cell adhesion and migration processes and also responsible for extracellular adenosine (ADO) production, is overexpressed by glioma cells and emerges as an important target for glioma treatment. Indeed, ADO participates in tumor immune escape, cell proliferation, and angiogenesis, and CD73 inhibition impairs those processes. Here, a cationic nanoemulsion to deliver CD73 siRNA (NE-siRNA CD73R) via nasal route aiming glioblastoma treatment was developed. NE-siRNA CD73R knockdown in vitro and in vivo CD73. Upon nasal delivery of NE-siRNA CD73R, the treatment markedly reduced tumor volume by 60% in a rat preclinical glioblastoma model. The treatment was well tolerated, and did not induce kidney, liver, lung, olfactory, bone marrow, or behavior alterations. These results indicate that the nasal administration of NE as a CD73 siRNA delivery system offered an efficient means of gene knockdown and may represent a potential alternative for glioblastoma treatment. |
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