Dendritic vectors for gene transfection

Guillot‐Nieckowski, Marine; Eisler, Sara; Diederich, François

doi:10.1039/b614877h

Cited by 164 publications

(81 citation statements)

References 135 publications

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“…Novel strategies have been implemented to build up well defined constructs featuring selfassembling capabilities in the presence of nucleic acids. In this context, the unique characteristics of dendrimers and other highly ordered clusters, such as uniformity, monodispersity and multivalency, have attracted increasing attention (5)(6)(7)(8). Homogeneous external functionalization of these platforms becomes, however, exponentially more complicated as the dendrimer generation increases (9)(10).…”

Section: Introductionmentioning

confidence: 99%

Insights in cellular uptake mechanisms of pDNA–polycationic amphiphilic cyclodextrin nanoparticles (CDplexes)

Díaz‐Moscoso

Vercauteren

Rejman

et al. 2010

Journal of Controlled Release

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have equally contributed to the reported work. Abstr actIt is generally recognized that the major obstacle to efficient gene delivery is cellular internalization and endosomal escape of the DNA. Recently, we have developed a modular strategy for the preparation of well-defined polycationic amphiphilic cyclodextrins (paCDs) capable of complexing and compacting DNA into homogeneous nanoparticles (<70 nm).Since paCDs resemble both cationic polymers and cationic lipids, it is conceivable that the corresponding pDNA-paCD nanoparticles (CDplexes) might use the cell uptake and endosomal escape mechanisms described for both lipoplexes and polyplexes. To verify this hypothesis, we have now investigated the uptake and transfection efficiencies of CDplexes in the presence of several inhibitors of endocytosis, namely chlorpromazine, genistein, dynasore and methylated β-cyclodextrin (MbCD). Our data show that CDplexes obtained from paCD 1, which ranks among the most efficient paCD gene vectors reported up to date, are internalized by both clathrin-dependent (CDE) and clathrin-independent endocytosis (CIE), both processes being cholesterol-and dynamin-dependent. We observed that the largest fraction of gene complexes is taken up via CDE, but this fraction is less relevant for transfection. The smaller fraction that is internalized via the CIE pathway is predominantly responsible for successful transfection. Intr oductionThe successful delivery of therapeutic genes into cells and their availability at the intracellular site of action are crucial requirements for successful gene therapy. During the last decade, under the advent of nanotechnology, a broad diversity of creative materials featuring promising properties for nonviral gene delivery applications has emerged, (1). Cationic polymers and lipids, or their combinations, have shown the ability to bind nucleic acids through electrostatic interactions and condense them into complexes that can be readily internalized by cells (2-3). The gene delivering capabilities of many of these systems have been thoroughly investigated. Yet, drawing firm conclusions that might serve to provide feedback for the design of improved delivery entities is a delicate issue as a consequence of the essentially polydisperse nature of such structures (4).The control of the architecture of multifunctional macromolecules is a major determinant in the rational design of successful nonviral gene delivery systems. Novel 3 strategies have been implemented to build up well defined constructs featuring selfassembling capabilities in the presence of nucleic acids. In this context, the unique characteristics of dendrimers and other highly ordered clusters, such as uniformity, monodispersity and multivalency, have attracted increasing attention (5-8). Homogeneous external functionalization of these platforms becomes, however, exponentially more complicated as the dendrimer generation increases (9-10). The use of preorganized macrocyclic scaffolds, such as calixarenes, to achieve a precise alignment of functiona...

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Section: Introductionmentioning

confidence: 99%

Insights in cellular uptake mechanisms of pDNA–polycationic amphiphilic cyclodextrin nanoparticles (CDplexes)

Díaz‐Moscoso

Vercauteren

Rejman

et al. 2010

Journal of Controlled Release

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“…38 It has also been proposed that larger generation dendrimer nanoparticles and/or doses can cause the endosome to rupture (endosomolysis), via the so-called proton pump mechanism. 39,40,41 Supported by the fact that after ~16hrs the PAMAM dendrimers have been seen to be located in the mitochondria, 22,38 whereupon the oxidative stress is further increased, resulting in further MMPD, which can culminate in apoptosis. A similar inflammatory cascade has been reported in murine macrophages, although the evolution of the responses was observed to be somewhat slower.…”

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confidence: 99%

Numerical simulations of in vitro nanoparticle toxicity – The case of poly(amido amine) dendrimers

Maher¹,

Naha²,

Mukherjee³

et al. 2014

Toxicology in Vitro

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A phenomenological rate equation model is constructed to numerically simulate nanoparticle uptake and subsequent cellular response. Polyamidoamine dendrimers (generations 4-6) are modelled and the temporal evolution of the intracellular cascade of; increased levels of reactive oxygen species, intracellular antioxidant species, caspase activation, mitochondrial membrane potential decay, tumour necrosis factor and interleukin generation is simulated, based on experimental observations. The model serves as a tool to interpolate and visualise the range of dose and temporal dependences and elucidate the mechanisms underlying the in vitro cytotoxic response to nanoparticle exposure and describes the interaction in terms of independent nanoparticle properties and cellular parameters, based on reaction rates. Such an approach could be a valid alternative to that of effective concentrations for classification of nanotoxicity and may lay the foundation for future quantitative structure activity relationships and predictive nanotoxicity models.3

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“…It has therefore been suggested that PAMAM dendrimers can be considered as a potential drug carrier of ketoprofen with a sustained release behavior under suitable conditions (Na et al, 2006). PAMAM dendrimers have also been shown to be a potent transfection agent for DNA and oligonucleotides (GuillotNieckowski et al, 2007). It is reported that PAMAM dendrimers help in the delivery of siRNA, and protect it from enzymatic degradation.…”

Section: Introductionmentioning

confidence: 99%

In vitro mammalian cytotoxicological study of PAMAM dendrimers – Towards quantitative structure activity relationships

Mukherjee¹,

Davoren²,

Byrne³

2010

Toxicology in Vitro

134

114

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Dendritic vectors for gene transfection

Cited by 164 publications

References 135 publications

Insights in cellular uptake mechanisms of pDNA–polycationic amphiphilic cyclodextrin nanoparticles (CDplexes)

Insights in cellular uptake mechanisms of pDNA–polycationic amphiphilic cyclodextrin nanoparticles (CDplexes)

Numerical simulations of in vitro nanoparticle toxicity – The case of poly(amido amine) dendrimers

In vitro mammalian cytotoxicological study of PAMAM dendrimers – Towards quantitative structure activity relationships

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