Designing dendrimers for biological applications

Lee, Cameron C.; MacKay, J. Andrew; Fréchet, Jean M. J.; Szoka, Francis C.

doi:10.1038/nbt1171

Cited by 1,923 publications

(1,434 citation statements)

References 87 publications

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“…Hyperbranched polymers tend to take on a three-dimensional and spherical structure, which differs from those of linear polymers taking on a random coil structure [11][12][13][14][15]. Recently, 3-methyl-glutarylated poly(glycidol) was synthesized by the authors.…”

Section: Synthetic Polymers Of Various Kinds Reportedly Interactmentioning

confidence: 99%

Carboxylated hyperbranched poly(glycidol)s for preparation of pH-sensitive liposomes

Yuba

Harada

Sakanishi

et al. 2011

Journal of Controlled Release

106

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Previous reports by the authors described intracellular delivery using liposomes modified with various carboxylated poly(glycidol) derivatives. These linear polymer-modified liposomes exhibited pH-dependent membrane fusion behavior in cellular acidic compartments. However, the effect of the backbone structure on membrane fusion activity remains unknown. Therefore, this study specifically investigated the backbone structure to obtain pH-sensitive polymers with much higher fusogenic activity and to reveal the effect of the polymer backbone structure on interaction with the membrane.Hyperbranched poly(glycidol) (HPG) derivatives were prepared as a new type of pH-sensitive polymers and modified liposomes using these polymers. The resultant HPG derivatives exhibited high hydrophobicity and intensive interaction with the membrane concomitantly with the increasing degree of polymerization. Furthermore, HPG derivatives showed stronger interaction with the membrane than linear polymers show. Liposomes modified with HPG derivatives of high DP delivered contents into cytosol of DC2.4 cells, a dendritic cell line, more effectively than the linear polymer-modified liposomes do. Results show that the backbone structure of pH-sensitive polymers affected their pH-sensitivity and interaction with liposomal and cellular membranes.

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Section: Synthetic Polymers Of Various Kinds Reportedly Interactmentioning

confidence: 99%

Carboxylated hyperbranched poly(glycidol)s for preparation of pH-sensitive liposomes

Yuba

Harada

Sakanishi

et al. 2011

Journal of Controlled Release

106

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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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“…The crossover between the two regimes occurs at a theoretically well-defined g max 10,12-15 discussed below. Since the first reports of well-characterized dendrimers in 1985 (refs 16-19), thousands of research articles addressed their synthesis, properties and applications [1][2][3][4][5][6][7][8][9][20][21][22][23] . Recent activity in this area reflects a growing interest in biomedical applications such as bio-imaging, gene and drug delivery [24][25][26][27][28] .…”

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confidence: 99%

Synthetic regimes due to packing constraints in dendritic molecules confirmed by labelling experiments

Zhang

Schlüter

et al. 2013

Nat Commun

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Classical theory predicts that branching defects are unavoidable in large dendritic molecules when steric congestion is important. Here we report first experimental evidence of this effect via labelling measurements of an extended homologous series of generations g ¼ 1y6 of dendronized polymers. This system exhibits a single type of defect interrogated specifically by the Sanger reagent thus permitting to identify the predicted upturn in the number of branching defects when g approaches g max and the polymer density approaches close packing. The average number of junctions and defects for each member of the series is recursively obtained from the measured molar concentrations of bound labels and the mass concentrations of the dendritic molecules. The number of defects increases at g ¼ 5 and becomes significant at g ¼ 6 for dendronized polymers where the g max was estimated to occur at 6.1 rg max r 7.1. The combination of labelling measurements with the novel theoretical analysis affords a method for characterizing high g dendritic systems.

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Designing dendrimers for biological applications

Cited by 1,923 publications

References 87 publications

Carboxylated hyperbranched poly(glycidol)s for preparation of pH-sensitive liposomes

Carboxylated hyperbranched poly(glycidol)s for preparation of pH-sensitive liposomes

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

Synthetic regimes due to packing constraints in dendritic molecules confirmed by labelling experiments

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