Preorganized macromolecular gene delivery systems: amphiphilic β-cyclodextrin “click clusters”

Méndez‐Ardoy, Alejandro; Gómez-Garcı́a, Marta; Mellet, Carmen Ortiz; Sevillano, Natalia; Girón, María D.; Salto, Rafael; Santoyo‐González, Francisco; Fernández, José Manuel Garcı́a

doi:10.1039/b903635k

Cited by 77 publications

(46 citation statements)

References 26 publications

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“…Most probably, the transfection efficiency is related to the ability of the individual molecules to self-organize in the corresponding CDplexes and the capability of the later to cross biological membranes, processes that are both intimately related to the stability of the interactions between the clusters and the pDNA chain. [76] …”

Section: Polycationic Cyclodextrins-pdna Complexes (Cdplexes)mentioning

confidence: 99%

Preorganized, Macromolecular, Gene‐Delivery Systems

Mellet

Benito

Fernández

2010

Chemistry A European J

115

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Viruses represent a paradigmatic example of multicomponent, self‐organized supramolecular systems specialized in the delivery and replication of their genetic material. Mimicking their functioning by artificial synthetic molecules represents a fantastic challenge that will lead to the future development of gene therapy. This is only possible if general approaches towards the construction of nanoscale vehicles for DNA are developed and the key rules governing their capacity to compact genetic material and its active transport/delivery through cell membranes are understood. In this area of research, synthetic organic chemistry plays an important role by providing tools to create tailor‐made molecules of increasing complexity. Preorganization of functional elements onto macromolecular platforms has the potential to allow control of the self‐assembling behavior of discrete architectures to produce nanometric objects that can be programmed to complex, compact, deliver, and release plasmid DNA in a target cell.

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Section: Polycationic Cyclodextrins-pdna Complexes (Cdplexes)mentioning

confidence: 99%

Preorganized, Macromolecular, Gene‐Delivery Systems

Mellet

Benito

Fernández

2010

Chemistry A European J

115

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“…More recently, monodisperse polycationic CD conjugates with promising pDNA delivery capabilities were prepared by homogeneous functionalization of the CD primary rim (22)(23)(24). Aiming at merging the virtues of both cationic polymers and cationic lipids in a flexible, well defined framework, we have reported a modular synthetic strategy for the preparation of polycationic amphiphilic CDs (paCDs) that allows the installation of different building blocks onto either face of the truncated-cone structure in a sequential and controlled way, offering a unique opportunity for structure-activity relationship (SAR) studies (25)(26)(27) (Figure 1). The pDNA complexing capabilities and in vitro transfection efficiencies of the corresponding pDNA-paCDs complexes (CDplexes) were found to be dependent on the CD decoration pattern.…”

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 increasing awareness of the potential of polycationic CD derivatives in the design of nonviral gene delivery systems has led several groups to explore the suitability of polycationic CD conjugates to impart, simultaneously, stability and targeting capabilities of the corresponding complexes with plasmid DNA (pDNA), for which the term CDplexes has been coined. [148][149][150][151][152][153][154][155][156][157] Uekama, Arima and co-workers conceived a series of multifunctional CD conjugates consisting of a poly(amidoamine) (PAMAM) starburst dendrimer 102 onto which one-to-two aCD units (103) were randomly attached through a single primary (C-6) position by reaction with the corresponding 6 Itosyl derivative 103. Some of the remaining primary amino groups of the dendrimer were subsequently engaged in thiourea forming reactions with isothiocyanate-armed aMan (104) and aGal derivatives to afford the corresponding polycationic aCD-PAMAM glycoconjugates.…”

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confidence: 99%