Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo.
Ann Hematol
; 98(8): 1905-1918, 2019 Aug.
Article
em En
| MEDLINE
| ID: mdl-31104089
ABSTRACT
Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mielogênica Crônica BCR-ABL Positiva
/
Proteínas de Fusão bcr-abl
/
Sistemas de Liberação de Medicamentos
/
RNA Interferente Pequeno
/
Nanopartículas
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article