TY - JOUR
T1 - Characterization of Cationic Bolaamphiphile Vesicles for siRNA Delivery into Tumors and Brain
AU - Popov, Mary
AU - Linder, Charles
AU - Heldman, Eliahu
N1 - Funding Information:
This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick. This work has been funded with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
Funding Information:
This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick . This work has been funded with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health , under contract no. HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
Publisher Copyright:
© 2020
PY - 2020/6/5
Y1 - 2020/6/5
N2 - Small interfering RNAs (siRNAs) are potential therapeutic substances due to their gene silencing capability as exemplified by the recent approval by the US Food and Drug Administration (FDA) of the first siRNA therapeutic agent (patisiran). However, the delivery of naked siRNAs is challenging because of their short plasma half-lives and poor cell penetrability. In this study, we used vesicles made from bolaamphiphiles (bolas), GLH-19 and GLH-20, to investigate their ability to protect siRNA from degradation by nucleases while delivering it to target cells, including cells in the brain. Based on computational and experimental studies, we found that GLH-19 vesicles have better delivery characteristics than do GLH-20 vesicles in terms of stability, binding affinity, protection against nucleases, and transfection efficiency, while GLH-20 vesicles contribute to efficient release of the delivered siRNAs, which become available for silencing. Our studies with vesicles made from a mixture of the two bolas (GLH-19 and GLH-20) show that they were able to deliver siRNAs into cultured cancer cells, into a flank tumor and into the brain. The vesicles penetrate cell membranes and the blood-brain barrier (BBB) by endocytosis and transcytosis, respectively, mainly through the caveolae-dependent pathway. These results suggest that GLH-19 strengthens vesicle stability, provides protection against nucleases, and enhances transfection efficiency, while GLH-20 makes the siRNA available for gene silencing.
AB - Small interfering RNAs (siRNAs) are potential therapeutic substances due to their gene silencing capability as exemplified by the recent approval by the US Food and Drug Administration (FDA) of the first siRNA therapeutic agent (patisiran). However, the delivery of naked siRNAs is challenging because of their short plasma half-lives and poor cell penetrability. In this study, we used vesicles made from bolaamphiphiles (bolas), GLH-19 and GLH-20, to investigate their ability to protect siRNA from degradation by nucleases while delivering it to target cells, including cells in the brain. Based on computational and experimental studies, we found that GLH-19 vesicles have better delivery characteristics than do GLH-20 vesicles in terms of stability, binding affinity, protection against nucleases, and transfection efficiency, while GLH-20 vesicles contribute to efficient release of the delivered siRNAs, which become available for silencing. Our studies with vesicles made from a mixture of the two bolas (GLH-19 and GLH-20) show that they were able to deliver siRNAs into cultured cancer cells, into a flank tumor and into the brain. The vesicles penetrate cell membranes and the blood-brain barrier (BBB) by endocytosis and transcytosis, respectively, mainly through the caveolae-dependent pathway. These results suggest that GLH-19 strengthens vesicle stability, provides protection against nucleases, and enhances transfection efficiency, while GLH-20 makes the siRNA available for gene silencing.
KW - Blood Brain Barrier (BBB)
KW - Bolaamphiphiles
KW - Delivery Systems
KW - Gene Silencing
KW - Molecular Dynamics
KW - RNA Nanotechnology
KW - Targeting
KW - Transfection
KW - Vesicles
KW - siRNA
UR - http://www.scopus.com/inward/record.url?scp=85081740961&partnerID=8YFLogxK
U2 - 10.1016/j.omtn.2020.02.011
DO - 10.1016/j.omtn.2020.02.011
M3 - Article
C2 - 32200271
AN - SCOPUS:85081740961
SN - 2162-2531
VL - 20
SP - 359
EP - 372
JO - Molecular Therapy - Nucleic Acids
JF - Molecular Therapy - Nucleic Acids
ER -