In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery
Specific small interfering RNAs (siRNAs) designed to silence different oncogenic pathways can be used for cancer therapy. However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biological membranes due to their negative charge. These obstacles...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-01-01
|
| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225311630138X |
| _version_ | 1818515462427770880 |
|---|---|
| author | Taejin Kim Kirill A. Afonin Mathias Viard Alexey Y Koyfman Selene Sparks Eliahu Heldman Sarina Grinberg Charles Linder Robert P Blumenthal Bruce A Shapiro |
| author_facet | Taejin Kim Kirill A. Afonin Mathias Viard Alexey Y Koyfman Selene Sparks Eliahu Heldman Sarina Grinberg Charles Linder Robert P Blumenthal Bruce A Shapiro |
| author_sort | Taejin Kim |
| collection | DOAJ |
| description | Specific small interfering RNAs (siRNAs) designed to silence different oncogenic pathways can be used for cancer therapy. However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biological membranes due to their negative charge. These obstacles can be overcome by using siRNAs complexed with bolaamphiphiles, consisting of two positively charged head groups that flank an internal hydrophobic chain. Bolaamphiphiles have relatively low toxicities, long persistence in the blood stream, and most importantly, in aqueous conditions can form poly-cationic micelles thus, becoming amenable to association with siRNAs. Herein, two different bolaamphiphiles with acetylcholine head groups attached to an alkyl chain in two distinct configurations are compared for their abilities to complex with siRNAs and deliver them into cells inducing gene silencing. Our explicit solvent molecular dynamics (MD) simulations showed that bolaamphiphiles associate with siRNAs due to electrostatic, hydrogen bonding, and hydrophobic interactions. These in silico studies are supported by various in vitro and in cell culture experimental techniques as well as by some in vivo studies. Results demonstrate that depending on the application, the extent of siRNA chemical protection, delivery efficiency, and further intracellular release can be varied by simply changing the type of bolaamphiphile used. |
| first_indexed | 2024-12-11T00:29:10Z |
| format | Article |
| id | doaj.art-d85cc7457486442b920c8a084c31aba4 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-11T00:29:10Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-d85cc7457486442b920c8a084c31aba42022-12-22T01:27:26ZengElsevierMolecular Therapy: Nucleic Acids2162-25312013-01-012C10.1038/mtna.2013.5In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs DeliveryTaejin Kim0Kirill A. Afonin1Mathias Viard2Alexey Y Koyfman3Selene Sparks4Eliahu Heldman5Sarina Grinberg6Charles Linder7Robert P Blumenthal8Bruce A Shapiro9Center for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USACenter for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USACenter for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USANational Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USACenter for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USABasic Science Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USABen-Gurion University of the Negev, Beer Sheva, IsraelBen-Gurion University of the Negev, Beer Sheva, IsraelCenter for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USACenter for Cancer Research Nanobiology Program, National Cancer Institute, Frederick, Maryland, USASpecific small interfering RNAs (siRNAs) designed to silence different oncogenic pathways can be used for cancer therapy. However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biological membranes due to their negative charge. These obstacles can be overcome by using siRNAs complexed with bolaamphiphiles, consisting of two positively charged head groups that flank an internal hydrophobic chain. Bolaamphiphiles have relatively low toxicities, long persistence in the blood stream, and most importantly, in aqueous conditions can form poly-cationic micelles thus, becoming amenable to association with siRNAs. Herein, two different bolaamphiphiles with acetylcholine head groups attached to an alkyl chain in two distinct configurations are compared for their abilities to complex with siRNAs and deliver them into cells inducing gene silencing. Our explicit solvent molecular dynamics (MD) simulations showed that bolaamphiphiles associate with siRNAs due to electrostatic, hydrogen bonding, and hydrophobic interactions. These in silico studies are supported by various in vitro and in cell culture experimental techniques as well as by some in vivo studies. Results demonstrate that depending on the application, the extent of siRNA chemical protection, delivery efficiency, and further intracellular release can be varied by simply changing the type of bolaamphiphile used.http://www.sciencedirect.com/science/article/pii/S216225311630138Xbolaamphiphilescryo-EMmolecular dynamics simulationsFRETpoly-cationic micellesRNA-based therapeuticssiRNA deliveryspecific gene silencing |
| spellingShingle | Taejin Kim Kirill A. Afonin Mathias Viard Alexey Y Koyfman Selene Sparks Eliahu Heldman Sarina Grinberg Charles Linder Robert P Blumenthal Bruce A Shapiro In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery Molecular Therapy: Nucleic Acids bolaamphiphiles cryo-EM molecular dynamics simulations FRET poly-cationic micelles RNA-based therapeutics siRNA delivery specific gene silencing |
| title | In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery |
| title_full | In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery |
| title_fullStr | In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery |
| title_full_unstemmed | In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery |
| title_short | In Silico, In Vitro, and In Vivo Studies Indicate the Potential Use of Bolaamphiphiles for Therapeutic siRNAs Delivery |
| title_sort | in silico in vitro and in vivo studies indicate the potential use of bolaamphiphiles for therapeutic sirnas delivery |
| topic | bolaamphiphiles cryo-EM molecular dynamics simulations FRET poly-cationic micelles RNA-based therapeutics siRNA delivery specific gene silencing |
| url | http://www.sciencedirect.com/science/article/pii/S216225311630138X |
| work_keys_str_mv | AT taejinkim insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT kirillaafonin insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT mathiasviard insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT alexeyykoyfman insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT selenesparks insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT eliahuheldman insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT sarinagrinberg insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT charleslinder insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT robertpblumenthal insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery AT bruceashapiro insilicoinvitroandinvivostudiesindicatethepotentialuseofbolaamphiphilesfortherapeuticsirnasdelivery |