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Statements

Subject Item
n2:RIV%2F44555601%3A13440%2F11%3A43878440%21RIV12-MSM-13440___
rdf:type
skos:Concept n18:Vysledek
rdfs:seeAlso
http://www.sciencedirect.com/science?_ob=MiamiImageURL&_cid=271103&_user=640945&_pii=S0168365911001015&_check=y&_origin=&_coverDate=15-Jul-2011&view=c&wchp=dGLzVlV-zSkzS&md5=83f002ff8b371e9ba8bb36169e9d3ff8/1-s2.0-S0168365911001015-main.pdf
dcterms:description
This study aimed to identify suitable siRNA delivery systems based on flexible generation 2-4 triazine dendrimers by correlating physico-chemical and biological in vitro and in vivo properties of the complexes with thermodynamic parameters calculated using molecular modeling. The siRNA binding properties of the dendrimers and PEI 25 kDa were simulated, binding and stability were measured in SYBR Gold assays, and hydrodynamic diameters, zeta potentials, and cytotoxicity were quantified. These parameters were compared with cellular uptake of the complexes and their ability to mediate RNAi. Radiolabeled complexes were administered intravenously, and pharmacokinetic profiles and biodistribution of these polyplexes were assessed both invasively and non-invasively. All flexible triazine dendrimers formed thermodynamically more stable complexes than PEI. While PEI and the generation 4 dendrimer interacted more superficially with siRNA, generation 2 and 3 virtually coalesced with siRNA, forming a tightly intertwined structure. These dendriplexes were therefore more efficiently charge-neutralized than PEI complexes, reducing agglomeration. This behavior was confirmed by results of hydrodynamic diameters (72.0 nm153.5 nm) and zeta potentials (4.9 mV-21.8 mV in 10 mM HEPES) of the dendriplexes in comparison to PEI complexes (312.8 nm-480.0 nm and 13.7 mV-17.4 mV in 10 mM HEPES). All dendrimers, even generation 3 and 4, were less toxic than PEI. All dendriplexes were efficiently endocytosed and showed significant and specific luciferase knockdown in HeLa/Luc cells. Scintillation counting confirmed that the generation 2 triazine complexes showed more than twofold prolonged circulation times as a result of their good thermodynamic stability. This study aimed to identify suitable siRNA delivery systems based on flexible generation 2-4 triazine dendrimers by correlating physico-chemical and biological in vitro and in vivo properties of the complexes with thermodynamic parameters calculated using molecular modeling. The siRNA binding properties of the dendrimers and PEI 25 kDa were simulated, binding and stability were measured in SYBR Gold assays, and hydrodynamic diameters, zeta potentials, and cytotoxicity were quantified. These parameters were compared with cellular uptake of the complexes and their ability to mediate RNAi. Radiolabeled complexes were administered intravenously, and pharmacokinetic profiles and biodistribution of these polyplexes were assessed both invasively and non-invasively. All flexible triazine dendrimers formed thermodynamically more stable complexes than PEI. While PEI and the generation 4 dendrimer interacted more superficially with siRNA, generation 2 and 3 virtually coalesced with siRNA, forming a tightly intertwined structure. These dendriplexes were therefore more efficiently charge-neutralized than PEI complexes, reducing agglomeration. This behavior was confirmed by results of hydrodynamic diameters (72.0 nm153.5 nm) and zeta potentials (4.9 mV-21.8 mV in 10 mM HEPES) of the dendriplexes in comparison to PEI complexes (312.8 nm-480.0 nm and 13.7 mV-17.4 mV in 10 mM HEPES). All dendrimers, even generation 3 and 4, were less toxic than PEI. All dendriplexes were efficiently endocytosed and showed significant and specific luciferase knockdown in HeLa/Luc cells. Scintillation counting confirmed that the generation 2 triazine complexes showed more than twofold prolonged circulation times as a result of their good thermodynamic stability.
dcterms:title
Molecular modeling and in vivo imaging can identify successful flexible triazine dendrimer-based siRNA delivery systems Molecular modeling and in vivo imaging can identify successful flexible triazine dendrimer-based siRNA delivery systems
skos:prefLabel
Molecular modeling and in vivo imaging can identify successful flexible triazine dendrimer-based siRNA delivery systems Molecular modeling and in vivo imaging can identify successful flexible triazine dendrimer-based siRNA delivery systems
skos:notation
RIV/44555601:13440/11:43878440!RIV12-MSM-13440___
n18:predkladatel
n20:orjk%3A13440
n3:aktivita
n13:P
n3:aktivity
P(OC10053)
n3:cisloPeriodika
1
n3:dodaniDat
n10:2012
n3:domaciTvurceVysledku
n16:2991098
n3:druhVysledku
n17:J
n3:duvernostUdaju
n8:S
n3:entitaPredkladatele
n6:predkladatel
n3:idSjednocenehoVysledku
213503
n3:idVysledku
RIV/44555601:13440/11:43878440
n3:jazykVysledku
n21:eng
n3:klicovaSlova
SPECT imaging; Pharmacokinetics; Biodistribution; Molecular modeling; RNA interference; Triazine dendrimers
n3:klicoveSlovo
n9:Biodistribution n9:SPECT%20imaging n9:Molecular%20modeling n9:RNA%20interference n9:Pharmacokinetics n9:Triazine%20dendrimers
n3:kodStatuVydavatele
NL - Nizozemsko
n3:kontrolniKodProRIV
[B6D797133429]
n3:nazevZdroje
Journal of Controlled Release
n3:obor
n19:BO
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
10
n3:projekt
n7:OC10053
n3:rokUplatneniVysledku
n10:2011
n3:svazekPeriodika
153
n3:tvurceVysledku
Zheng, Mengyao Höffken, Helmut Librizzi, Damiano Malý, Marek Mintzer, Meredith A. Danani, Andrea Pavan, Giovanni M. Merkel, Olivia M. Kissel, Thomas Simanek, Eric E.
n3:wos
000293433500004
s:issn
0168-3659
s:numberOfPages
11
n14:doi
10.1016/j.jconrel.2011.02.016
n15:organizacniJednotka
13440