Amphiphilic Dendrimers: Novel Self‐Assembling Vectors for Efficient Gene Delivery

Joester, Derk; Losson, Myriam; Pugin, Raphaël; Heinzelmann, H.; Walter, Elke; Merkle, Hans P.; Diederich, François

doi:10.1002/ange.200250284

Cited by 79 publications

(82 citation statements)

References 31 publications

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“…However, the synthetic effort required to obtain dendritic structures in the size-range of the natural protein complex (around 8 nm) is tremendous (12±18 steps) [1] and in some cases a partially destroyed (hydrolyzed) dendritic backbone shows even higher transfection efficiencies than the intact dendrimer. [6,7] More recently, self-assembled amphiphilic dendrons have been prepared [10] that mimic the natural histone complex in size, surface charge, and flexibility and achieve good DNA complexation and high transfection efficiencies. A simple access route to dendritic nanoparticles of different sizes and flexibilities (degree of branching) would allow molecular structure to be correlated with transfection efficiency.…”

Section: Introductionmentioning

confidence: 99%

Dendritic Polyamines: Simple Access to New Materials with Defined Treelike Structures for Application in Nonviral Gene Delivery

et al. 2004

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Polycationic dendrimers are interesting nonviral vectors for in vitro DNA delivery. We describe a simple approach to the synthesis of dendritic polyamines with different molecular weights and adjustable flexibility (degrees of branching; DB). Both parameters influence the transfection efficiency and the cell toxicity of the polymer. Functionalization of hyperbranched polyethylenimine (PEI) by a two-step procedure generated fully branched pseudodendrimers (analogues of polypropylenimine (PPI) and polyamidoamine (PAMAM) dendrimers). The DNA transfection efficiencies observed for these polymers depended on the cell line investigated. The highest efficiencies were observed for polymers whose unfunctionalized PEI cores had molecular weights in the range M(w)=6000-25 000 g mol(-1). The cytotoxicity of the dendrimers generally rises with increasing core size. The data collected for NIH/3T3 and COS-7 cells indicate a maximum transfection efficiency at around 60 % branching for the PPI analogues, and at a PEI-core molecular weight of M(w)=25 000 g mol(-1). PAMAM functionalization of PEI (M(w)=5000 and 21 000 g mol(-1)) leads to polymers with little or no cytotoxity in the cell lines investigated.

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Section: Introductionmentioning

confidence: 99%

Dendritic Polyamines: Simple Access to New Materials with Defined Treelike Structures for Application in Nonviral Gene Delivery

et al. 2004

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“…Their major advantages are the uniform structure, multiple sites of attachment and the versatility to modify their skeletons and surfaces, allowing a precise characterization of the interaction of dendrimer-drug. Potential transfecting agents based on PAMAM, 10 phosphoruscontaining 11 dendrimers or some small amphiphilic dendrimers 12 have shown transfecting activity even in the presence of serum. Although several studies have been published concerning the interaction between PAMAM dendrimers and BSA, 13 however, as far as we know, there is only one study reporting on the interaction between PAMAM-containing dendriplexes and serum proteins.…”

Section: Introductionmentioning

confidence: 99%

Water-soluble carbosilane dendrimers protect phosphorothioate oligonucleotides from binding to serum proteins

et al. 2007

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Treatment of dendriplexes formed between water-soluble carbosilane dendrimers and phosphorothioate oligodeoxynucleotides (ODN) with the anionic detergent sodium dodecyl sulfate disrupted the complexes indicating that the nature of the union in such dendriplexes is merely electrostatic. However, dendriplexes were not dissociated by serum proteins like bovine or human serum albumins, as assessed by gel electrophoresis and fluorescence experiments. This would imply a dendrimer-mediated protective effect able to prevent ODN interactions with serum proteins and additionally could translate into a reduction of the ODN doses needed to achieve the biological effects. The employment of carbosilane dendrimers as carriers may solve the problem of ODN kidnapping by plasmatic proteins as a key drawback for therapeutics involving ODNs. As examples, transfection processes on normal primary peripheral blood cells and diagnosis of HIV infection in the presence of serum have been assayed.

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“…Vectors based on cationic polymers (polycations) are particularly attractive because of their synthetic maneuverability, allowing incorporation of multiple functional elements within the same molecule without compromising DNA-binding ability (11)(12)(13). And yet, available polycations are handicapped by their low potencies (14, 15), prompting the search for new ones with better transfection efficiencies (16)(17)(18)(19)(20). It is likely that major improvements may be brought about by elucidating the mechanism of gene delivery by those vectors already relatively competent, followed by their targeted chemical derivatization to overcome extra-and͞or intracellular barriers to nonviral gene delivery (10).…”

mentioning

confidence: 99%

Conjugation to gold nanoparticles enhances polyethylenimine's transfer of plasmid DNA into mammalian cells

Thomas

Klibanov

2003

Proc. Natl. Acad. Sci. U.S.A.

521

322

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Branched polyethylenimine (PEI) chains with an average molecular mass of 2 kDa (PEI2) have been covalently attached to gold nanoparticles (GNPs), and the potency of the resulting PEI2-GNPs conjugates as vectors for the delivery of plasmid DNA into monkey kidney (COS-7) cells in the presence of serum in vitro has been systematically investigated. The transfection efficiencies vary as a function of the PEI͞gold molar ratio in the conjugates, with the best one (PEI2-GNPII) being 12 times more potent than the unmodified polycation. This potency can be further doubled by adding amphiphilic N-dodecyl-PEI2 during complex formation with DNA. The resulting ternary complexes are at least 1 order of magnitude more efficient than the 25-kDa PEI, one of the premier polycationic gene-delivery vectors. Importantly, although unmodified PEI2 transfects just 4% of the cells, PEI2-GNPII transfects 25%, and the PEI2-GNPII͞dodecyl-PEI2 ternary complex transfects 50% of the cells. The intracellular trafficking of the DNA complexes of these vectors, monitored by transmission electron microscopy, has detected the complexes in the nucleus <1 h after transfection.G ene therapy holds great promise for treating diseases ranging from inherited disorders to acquired conditions and cancer (1-4). The most common vectors (carriers) in current clinical trials are recombinant viruses, wherein the gene of interest is covalently inserted into the viral genome. Unfortunately, such severe side reactions encountered in patients as immune response and insertional mutagenesis leading to death, carcinogenesis, or germ-cell-line alterations pose serious concerns about the clinical application of viral vectors (5-7) and have prompted development of nonviral delivery systems (8-10). Unlike viral vectors, nonviral ones rely on the formation of noncovalent assemblies between DNA (a polyanion) and cationic polymers or liposomes. Vectors based on cationic polymers (polycations) are particularly attractive because of their synthetic maneuverability, allowing incorporation of multiple functional elements within the same molecule without compromising DNA-binding ability (11)(12)(13). And yet, available polycations are handicapped by their low potencies (14, 15), prompting the search for new ones with better transfection efficiencies (16)(17)(18)(19)(20). It is likely that major improvements may be brought about by elucidating the mechanism of gene delivery by those vectors already relatively competent, followed by their targeted chemical derivatization to overcome extra-and͞or intracellular barriers to nonviral gene delivery (10). For these reasons, polyethylenimine (PEI), a synthetic ''proton-sponge'' polycation (21-24) introduced for transfection a few years ago, is an ideal candidate for such a quest.The transfection efficiency and toxicity of PEI correlate strongly with its molecular mass. For example, PEI2 is some 2 orders of magnitude less efficient than its 25-kDa counterpart (PEI25) at the same concentration, presumably because of its inability to condense...

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Amphiphilic Dendrimers: Novel Self‐Assembling Vectors for Efficient Gene Delivery

Cited by 79 publications

References 31 publications

Dendritic Polyamines: Simple Access to New Materials with Defined Treelike Structures for Application in Nonviral Gene Delivery

Dendritic Polyamines: Simple Access to New Materials with Defined Treelike Structures for Application in Nonviral Gene Delivery

Water-soluble carbosilane dendrimers protect phosphorothioate oligonucleotides from binding to serum proteins

Conjugation to gold nanoparticles enhances polyethylenimine's transfer of plasmid DNA into mammalian cells

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