An Amphiphilic Dendrimer for Effective Delivery of Small Interfering RNA and Gene Silencing In Vitro and In Vivo

Yu, Tianzhu; Liu, Xiaoxuan; Bolcato-Bellemin, Anne-Laure; Wei, Xiawei; Liu, Cheng; Erbacher, Patrick; Qu, Fengli; Rocchi, Palma; Behr, Jean‐Paul; Peng, Ling

doi:10.1002/anie.201203920

Cited by 230 publications

(233 citation statements)

References 32 publications

(27 reference statements)

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“…17 They have been investigated for biomedical applications as nanocarriers for hydrophobic drug molecules, gene therapy etc. [18][19][20][21][22][23][24][25][26][27] However, studies on parameters which influence their self-assembly have not been attempted very much. In general, there are several factors that govern the self-assembly of amphiphiles, for example, hydrophilic-lipophilic balance (HLB), choice of solvent, etc.…”

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confidence: 99%

Towards engineering of self-assembled nanostructures using non-ionic dendritic amphiphiles

et al. 2015

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confidence: 99%

Towards engineering of self-assembled nanostructures using non-ionic dendritic amphiphiles

et al. 2015

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“…The N/P ratio = 1 needed for efficient DNA compaction is expected to render this new aminofullerene a transfection agent with minimum side effects. 28 Finally, the modular synthetic strategy will provide easy access to a variety of derivatives that are useful for targeting biomolecules such as RNA 29 and proteins. 13,30 This work was supported by KAKENHI (No.…”

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confidence: 99%

DNA Binding of Pentaamino[60]fullerene Synthesized Using Click Chemistry

et al. 2014

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We have synthesized pentaaminofullerene 4 by the introduction of dimethylamino groups using a click reaction. The dendritic fullerene amphiphile showed a low critical micelle concentration of 3.6 « 0.5¯M. 4 is shown to be an efficient DNA binder that compacts DNA into nanoparticles at low nitrogen/phosphorus ratios.Aminofullerenes are protonated in neutral water and aggregate together with DNA 1 and siRNA, 2 serving as a vector 3 both in vitro and in vivo. 4 Tetrapiperazino fullerene epoxide (TPFE) is one of these cationic fullerene vectors that forms subμm-to μm-sized nucleic acid aggregates in a buffer and in serum. 5,6 However, an excess amount of the aminofullerene is required to achieve efficient DNA binding (terminal amine/ phosphate (N/P) ratio of five; the excess reagent is expected a priori to cause more side effects), because the basicity of the secondary amines in TPFE is attenuated by the strong electronwithdrawing effect of the fullerene moiety. In addition, being a little too compact in its structure, TPFE is not easily amenable to further structural modification and functionalization for tuning and targeting of the gene delivery. 7 To remedy these issues, we have designed a modular synthetic route to a new pentaaminofullerene 4 via click cycloaddition chemistry, 8,9 and examined its behavior in micelle formation 10,11 and DNA binding. The dendritic molecule shows high solubility in water to form micelles of ca. 12 nm in diameter. Upon mixing with a doublestranded DNA, it reproducibly forms a spherical aggregate of 50 nm diameter at an N/P ratio as small as 0.51 in a HEPES buffer. This diameter of the fullerene/DNA aggregate was previously shown to be useful for gene delivery across cell membranes. 6,12 The click approach to new pentaaminofullerenes is straightforward, as shown in Scheme 1. 13 A Grignard reagent bearing a terminal acetylene protected by a tris(isopropyl)silyl group (TIPS) was added five times to [60]fullerene in the presence of a stoichiometric amount of copper(I) salt, 14 which was followed by methylation 15 to obtain the pentaacetylenic fullerene 1. The TIPS protection was removed using fluoride anions, and the terminal acetylene 2 was allowed to undergo the Huisgen cycloaddition reaction with 3-(dimethylamino)propyl azide in the presence of copper(I) bromidedimethyl sulfide complex and N,N,N¤,N¤¤,N¤¤-pentamethyldiethylenetriamine (PMDETA) (Scheme 1). 16 This ligand accelerates the reaction and also prevents premature precipitation of the catalyst from the reaction mixture. THF was the solvent of choice, while DMSO gave poor results, perhaps because of charge transfer between the dimethylamino groups and the fullerene moieties in this solvent. 17 The product was purified by the removal of copper contaminants with an aqueous ammonia solution followed by extraction in dichloromethane. Pentaaminofullerene 3 was finally converted into water-soluble hydrochloride salt 4 and used for further studies.Pentaaminofullerene 4 dissolves well in water (>30 g L ¹1or >10 mM) and in a buffer by ...

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“…[9][10][11] Recent studies on dendrons carrying a lipid tail have shown that they hold great promise as non-viral transfectants for genetic materials such as siRNA. [12][13][14] Hence, the ability to form selfassembled structures may be an important feature when applying dendrimers as carriers for drugs and genes.…”

Section: Introductionmentioning

confidence: 99%

Preparation and self-assembly of amphiphilic polylysine dendrons

et al. 2016

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a Herein, we present the synthesis of new amphiphilic polylysine dendrons with variable alkyl chain lengths (C1-C18) at the C-terminal. The dendrons were synthesized in moderate to quantitative yields by divergent solid-phase synthesis (SPS) employing an aldehyde linker. The self-assembling properties of the dendrons in aqueous solutions were studied by small angle neutron scattering (SANS) and dynamic light scattering (DLS). The self-assembling properties were influenced by the length of the alkyl chain and the generation number (Gn). Increasing the temperature and concentration did not have significant impact on the hydrodynamic diameter, but the self-assembling properties were influenced by the pH value. This demonstrated the need for positively charged amines in the head groups for the successful formation of controlled self-assemblies. Dendrons having alkyl chains below C8 did not self-assemble. Well-defined micellar structures observed with SANS were formed with alkyl chain lengths above C12.Large structures detected with DLS for dendrons with alkyl chain lengths above C12 are ascribed to intermicellar aggregates stabilized by hydrophobic and electrostatic forces in accordance with the observed pH effect. Finally, the cytotoxicity of the dendrons was evaluated in mouse fibroblast (NIH/3T3) and human embryonic kidney (HEK 293T) cells at 5, 10 and 20 mM concentrations. The dendrons showed low cytotoxicity, displaying cell viability well above 80%.

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An Amphiphilic Dendrimer for Effective Delivery of Small Interfering RNA and Gene Silencing In Vitro and In Vivo

Cited by 230 publications

References 32 publications

Towards engineering of self-assembled nanostructures using non-ionic dendritic amphiphiles

Towards engineering of self-assembled nanostructures using non-ionic dendritic amphiphiles

DNA Binding of Pentaamino[60]fullerene Synthesized Using Click Chemistry

Preparation and self-assembly of amphiphilic polylysine dendrons

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