Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells

Kim, H. Ryoung; Gil, Sophie; Andrieux, Karine; Nicolas, Valérie; Appel, M.; Chacun, Hélène; Desmaële, Didier; Taran, Frédéric; Georgin, Dominique; Couvreur, P.

doi:10.1007/s00018-007-6390-x

Cited by 153 publications

(85 citation statements)

References 49 publications

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“…Phenylarsine oxide has been reported to be an inhibitor of clathrin-mediated endocytosis [23]. Filipin blocks the caveolae-mediated process in non-specific adsorptive endocytosis [24]. Colchicine is known to inhibit macropinocytosis [25], which provides non-specific endocytosis of macromolecules, whereas cationic poly-L-Lysine acts as an uptake inhibitor for cationic delivery systems.…”

Section: Mechanisms Of Cellular Uptake Of Dna Complexed To Dab-lf Denmentioning

confidence: 99%

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Somani

Robb

Pickard

et al. 2015

Journal of Controlled Release

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The possibility of using gene therapy for the treatment of brain diseases such as brain cancer, Alzheimer's and Parkinson's diseases, is currently hampered by the lack of gene delivery systems able to cross the blood-brain barrier and deliver DNA to the brain following intravenous administration. On the basis that lactoferrin can effectively reach the brain by using specific receptors for crossing the blood-brain barrier, we propose to investigate if a lactoferrin-bearing generation 3-diaminobutyric polypropylenimine (DAB) dendrimer would allow the transport of plasmid DNA to the brain after intravenous administration.In this work, we demonstrated that the conjugation of lactoferrin to the dendrimer led to an enhanced DNA uptake by 2.1-fold in bEnd.3 murine brain capillary endothelial cells compared to the unmodified dendriplex in vitro. In vivo, the intravenous administration of lactoferrin-bearing DAB dendriplex resulted in a significantly increased gene expression in the brain, by more than 6.4-fold compared to that of DAB dendriplex, while decreasing gene expression in the lung and the kidneys. Gene expression in the brain was significantly higher than in any other major organs of the body. Lactoferrin-bearing generation 3 polypropylenimine dendrimer is therefore a highly promising delivery system for systemic gene delivery to the brain. KEYWORDSBrain delivery; blood-brain barrier; gene expression; dendrimer; lactoferrin 2 1. Introduction Brain diseases, including glioma, Alzheimer's and Parkinson's diseases, currently represent one of the largest and fastest growing area of unmet clinical need. Brain cancer is the leading cause of cancer death in young people and accounts for more than one third of cancer deaths in children aged under 10. Alzheimer's disease is the most common type of dementia, affecting almost 500 000 people in the UK. The symptoms of this disease develop gradually and become more severe over the course of several years. In addition, there is currently no cure for Parkinson's disease, which affects 127 000 people in the UK [1][2][3][4]. Gene therapy has emerged as a promising therapeutic strategy, as the genetic basis for many of these diseases is known. However, the possibility of using genes as medicines to treat brain pathologies is limited by the lack of safe and efficacious delivery systems able to cross the blood-brain barrier (BBB) and to deliver DNA to the brain after intravenous administration, without secondary effects to healthy tissues. In addition, locally administered treatments fail to achieve a widespread gene expression in the target cells throughout the entire brain, which is necessary for a successful treatment of most brain pathologies [2-3, 5]. There is therefore an urgent need to develop safe and efficacious non-viral gene-based nanomedicines able to cross the BBB after intravenous administration, in order to ultimately provide better treatment options for brain diseases than currently available. Despite acting as an entrance gateway to the brain, the BBB does...

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Section: Mechanisms Of Cellular Uptake Of Dna Complexed To Dab-lf Denmentioning

confidence: 99%

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Somani

Robb

Pickard

et al. 2015

Journal of Controlled Release

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“…The medium was removed and the cells were pretreated with PhAsO (10 mmol/L), filipin (5 mg/mL), colchicine (10 mmol/L), excessive Lf (100 mmol/L), and polylysine (400 mg/mL) for 10 mins at 371C. PhAsO is reported to inhibit clathrindependent endocytosis (Visser et al, 2004), and filipin is known to block the caveolae-mediated process (Kim et al, 2007). Colchicine is an inhibitor of macropinocytosis (Liu and Shapiro, 2003), whereas cationic polylysine could inhibit the uptake of cationic vectors.…”

Section: Treatments With Inhibitorsmentioning

confidence: 99%

Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles

Huang

Han

et al. 2009

J Cereb Blood Flow Metab

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Ligand-mediated brain-targeting drug delivery is one of the focuses at present. Elucidation of exact targeting mechanisms serves to efficiently design these drug delivery systems. In our previous studies, lactoferrin (Lf) was successfully exploited as a brain-targeting ligand to modify cationic dendrimer-based nanoparticles (NPs). The mechanisms of Lf-modified NPs to the brain were systematically investigated in this study for the first time. The uptake of Lf-modified vectors and NPs by brain capillary endothelial cells (BCECs) was related to clathrin-dependent endocytosis, caveolae-mediated endocytosis, and macropinocytosis. The intracellular trafficking results showed that Lf-modified NPs could rapidly enter the acidic endolysosomal compartments within 5 mins and then partly escape within 30 mins. Both Lf-modified vectors and NPs showed higher blood-brain barrier-crossing efficiency than unmodified counterparts. All the results suggest that both receptorand adsorptive-mediated mechanisms contribute to the cellular uptake of Lf-modified vectors and NPs. Enhanced brain-targeting delivery could be achieved through the synergistic effect of the macromolecular polymers and the ligand.

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“…For the detailed set-up of the DPD simulation, the readers are referred to our previous studies [71,109]. For the model of NPs, we consider that the NP is formed by a rigid core with a surface coated polymer [110]. A typical model system will be the PEGylated Au NPs, with the core and shell representing Au NP and PEG polymer, respectively.…”

Section: Model and Methodologymentioning

confidence: 99%

Cell and nanoparticle transport in tumour microvasculature: the role of size, shape and surface functionality of nanoparticles

et al. 2016

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Through nanomedicine, game-changing methods are emerging to deliver drug molecules directly to diseased areas. One of the most promising of these is the targeted delivery of drugs and imaging agents via drug carrier-based platforms. Such drug delivery systems can now be synthesized from a wide range of different materials, made in a number of different shapes, and coated with an array of different organic molecules, including ligands. If optimized, these systems can enhance the efficacy and specificity of delivery compared with those of non-targeted systems. Emerging integrated multiscale experiments, models and simulations have opened the door for endless medical applications. Current bottlenecks in design of the drug-carrying particles are the lack of knowledge about the dispersion of these particles in the microvasculature and of their subsequent internalization by diseased cells (Bao et al . 2014 J. R. Soc. Interface 11 , 20140301 ( doi:10.1098/rsif.2014.0301 )). We describe multiscale modelling techniques that study how drug carriers disperse within the microvasculature. The immersed molecular finite-element method is adopted to simulate whole blood including blood plasma, red blood cells and nanoparticles. With a novel dissipative particle dynamics method, the beginning stages of receptor-driven endocytosis of nanoparticles can be understood in detail. Using this multiscale modelling method, we elucidate how the size, shape and surface functionality of nanoparticles will affect their dispersion in the microvasculature and subsequent internalization by targeted cells.

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Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells

Cited by 153 publications

References 49 publications

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Enhanced gene expression in the brain following intravenous administration of lactoferrin-bearing polypropylenimine dendriplex

Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles

Cell and nanoparticle transport in tumour microvasculature: the role of size, shape and surface functionality of nanoparticles

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