TY - JOUR
T1 - Bolaamphiphiles as carriers for siRNA delivery
T2 - From chemical syntheses to practical applications
AU - Gupta, Kshitij
AU - Afonin, Kirill A.
AU - Viard, Mathias
AU - Herrero, Virginia
AU - Kasprzak, Wojciech
AU - Kagiampakis, Ioannis
AU - Kim, Taejin
AU - Koyfman, Alexey Y.
AU - Puri, Anu
AU - Stepler, Marissa
AU - Sappe, Alison
AU - Kewalramani, Vineet N.
AU - Grinberg, Sarina
AU - Linder, Charles
AU - Heldman, Eliahu
AU - Blumenthal, Robert
AU - Shapiro, Bruce A.
N1 - Funding Information:
This work is dedicated to Sarina Grinberg who recently passed away. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD and the National Cancer Institute's Advanced Biomedical Computing Center (ABCC) of the Frederick National Laboratory, Frederick. We thank Dr. Bindu Lakshman and Dr. Andrew Stephen, Protein Chemistry Laboratory, Cancer Research Technology Program, Leidos Biomedical Inc. Frederick, MD for their help in using the fluorescent anisotropy technique. This publication has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health , under contract HHSN 261200800001E to WKK. This research was supported in part by the National Institutes of Health P41GM103832 and the Postdoctoral Training Fellowship from the Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia to A.Y.K. (CPRIT grant no. RP101489 ). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research . 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 U.S. Government.
PY - 2015/7/18
Y1 - 2015/7/18
N2 - Abstract In this study we have investigated a new class of cationic lipids - "bolaamphiphiles" or "bolas" - for their ability to efficiently deliver small interfering RNAs (siRNAs) to cancer cells. The bolas of this study consist of a hydrophobic chain with one or more positively charged head groups at each end. Recently, we reported that micelles of the bolas GLH-19 and GLH-20 (derived from vernonia oil) efficiently deliver siRNAs, while having relatively low toxicities in vitro and in vivo. Our previous studies validated that; bolaamphiphiles can be designed to vary the magnitude of siRNA shielding, its delivery, and its subsequent release. To further understand the structural features of bolas critical for siRNAs delivery, new structurally related bolas (GLH-58 and GLH-60) were designed and synthesized from jojoba oil. Both bolas have similar hydrophobic domains and contain either one, in GLH-58, or two, in GLH-60 positively charged head groups at each end of the hydrophobic core. We have computationally predicted and experimentally validated that GLH-58 formed more stable nano sized micelles than GLH-60 and performed significantly better in comparison to GLH-60 for siRNA delivery. GLH-58/siRNA complexes demonstrated better efficiency in silencing the expression of the GFP gene in human breast cancer cells at concentrations of 5 μg/mL, well below the toxic dose. Moreover, delivery of multiple different siRNAs targeting the HIV genome demonstrated further inhibition of virus production.
AB - Abstract In this study we have investigated a new class of cationic lipids - "bolaamphiphiles" or "bolas" - for their ability to efficiently deliver small interfering RNAs (siRNAs) to cancer cells. The bolas of this study consist of a hydrophobic chain with one or more positively charged head groups at each end. Recently, we reported that micelles of the bolas GLH-19 and GLH-20 (derived from vernonia oil) efficiently deliver siRNAs, while having relatively low toxicities in vitro and in vivo. Our previous studies validated that; bolaamphiphiles can be designed to vary the magnitude of siRNA shielding, its delivery, and its subsequent release. To further understand the structural features of bolas critical for siRNAs delivery, new structurally related bolas (GLH-58 and GLH-60) were designed and synthesized from jojoba oil. Both bolas have similar hydrophobic domains and contain either one, in GLH-58, or two, in GLH-60 positively charged head groups at each end of the hydrophobic core. We have computationally predicted and experimentally validated that GLH-58 formed more stable nano sized micelles than GLH-60 and performed significantly better in comparison to GLH-60 for siRNA delivery. GLH-58/siRNA complexes demonstrated better efficiency in silencing the expression of the GFP gene in human breast cancer cells at concentrations of 5 μg/mL, well below the toxic dose. Moreover, delivery of multiple different siRNAs targeting the HIV genome demonstrated further inhibition of virus production.
KW - Bolaamphiphiles
KW - Cryo-EM
KW - FRET
KW - Molecular dynamics simulations
KW - RNAi induced gene silencing
KW - siRNA drug delivery
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U2 - 10.1016/j.jconrel.2015.06.041
DO - 10.1016/j.jconrel.2015.06.041
M3 - Article
C2 - 26151705
AN - SCOPUS:84937217327
SN - 0168-3659
VL - 213
SP - 142
EP - 151
JO - Journal of Controlled Release
JF - Journal of Controlled Release
M1 - 7746
ER -