Composites of malonic acid diamides and phospholipids — Impact of lipoplex stability on transfection efficiency

Janich, Christopher; Wölk, Christian; Erdmann, Frank; Groth, Thomas; Brezesinski, Gerald; Dobner, Bodo; Langner, Andreas

doi:10.1016/j.jconrel.2015.10.045

Cited by 19 publications

(38 citation statements)

References 52 publications

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“…The existence of three different aggregates indicates phase-separation processes (a phase building curved bilayers that result in vesicles and a phase building planar aggregates such as ribbons and sheets), that could not be demonstrated for these lipid mixtures until now. 16,17 The addition of DNA changes the structure of the lipid aggregates, resulting in lipoplexes with lamellar substructures (parallel ordering) (Fig. 4D, white triangles).…”

Section: Characterization Of Cationic Lipid/dope Mixtures In the Presmentioning

confidence: 99%

“…15 Recently, we published physical-chemical parameters of composites of cationic malonic acid diamides (cytofectine) and phospholipids (co-lipid), and of their lipoplexes, and reported on the influence on the DNA transfer efficiency. 16,17 For these structure-function studies, the two malonic acid diamides, N- (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…16 Moreover, it was demonstrated that the optimal binding strength between the lipid composites and DNA plays an important role in efficient gene transfer into cells, whereby premature DNA release by biological agents is a major parameter influencing the transfection efficiency. 17 The aim of this paper is the investigation of structures formed by the four lipid mixtures and their complexes with DNA. For this purpose, small-and wide-angle X-ray scattering (SAXS and WAXS) experiments were performed.…”

Section: Introductionmentioning

confidence: 99%

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Structures of malonic acid diamide/phospholipid composites and their lipoplexes

et al. 2016

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As a continuation of previous work, the self-assembly process of cationic lipid formulations in the presence and absence of DNA was investigated with respect to binary lipid mixtures suitable as polynucleotide carrier systems. The lipid blends consist of one malonic-acid-based cationic lipid with a varying alkyl chain pattern, either N-{6-amino-1-[N-(9Z)-octadec-9-enylamino]-1-oxohexan-(2S)-2-yl}-N'-{2-[N,N-bis(2-aminoethyl)amino]ethyl}-2-hexadecylpropandiamide () or N-[6-amino-1-oxo-1-(N-tetradecylamino)hexan-(2S)-2-yl]-N'-{2-[N,N-bis(2-aminoethyl)amino]ethyl}-2-hexadecylpropandiamide (), and one neutral co-lipid, either 1,2-di-[(9Z)-octadec-9-enoyl]-sn-glycero-3-phosphocholine (DOPE) or 1,2-di-(hexadecanoyl)-sn-glycero-3-phosphocholine (DPPC). Although the cationic lipids exhibit only slight differences in their structure, the DNA transfer efficiency varies drastically. Therefore, self-assembly was studied in 3D systems by small- and wide-angle X-ray scattering (SAXS and WAXS) and transmission electron microscopy (TEM) as well as in 2D systems by infrared reflection-absorption spectroscopy (IRRAS) on Langmuir films. The investigated lipid mixtures show quite different self-assembly in the absence of DNA, with varying structures from vesicles (/DOPE; /DOPE) and tubes (/DOPE) to discoid structures (/DPPC; /DPPC). Twisted ribbons and sheets, which were stabilized due to hydrogen-bond networks, were found in all investigated lipid mixtures in the absence of DNA. The addition of DNA leads to the formation of lamellar lipoplexes for all the investigated lipid compositions. The lipoplexes differ in crucial parameters, such as the lamellar repeat distance and the spacing between the DNA strands, indicating differences in the binding strength between DNA and the lipid composition. The formation of associates with an ideal charge density might emerge as a key parameter for efficient DNA transfer. Furthermore, the structures observed for the different lipid compositions in the absence of DNA prepare the way for other applications besides gene therapy.

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Section: Characterization Of Cationic Lipid/dope Mixtures In the Presmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structures of malonic acid diamide/phospholipid composites and their lipoplexes

et al. 2016

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“…20 Some representatives are able to form highly efficient nucleic acid carriers. 21,22 The third generation is characterized by an expansion of the lipophilic part by introducing a third alkyl chain (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Relationship between structure and molecular interactions in monolayers of specially designed aminolipids

et al. 2019

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Artificial cationic lipids are already recognized as highly efficient gene therapy tools. Here, we focus on another potential use of aminolipids, in their electrically-uncharged state, for the formation of covalently cross-linked, one-molecule-thin films at interfaces. Such films are envisioned for future (bio-)materials applications. To this end, Langmuir monolayers of structurally different aminolipids are comprehensively characterized with the help of highly sensitive surface characterization techniques. Pressure-area isotherms, Brewster angle microscopy, grazing-incidence X-ray diffraction and infrared reflectionabsorption spectrometry experiments provide a detailed, comparative molecular picture of the formed monolayers. This physico-chemical study highlights the relationship between chemical structures and intermolecular interactions, which can serve as a basis for the rational design of cross-linked thin films with precisely controlled properties. Fig. 4 (A-E) (top row) Representative GIXD plots (intensity as a function of the out-of-plane component Q z and the in-plane component Q xy of the scattering vector) characterizing the monolayer LC phases of all studied aminolipids. Superimposed as white lines are the Q z -integrated Bragg peak intensities as a function of Q xy . White dots: experimental data; white lines: Lorentzian fits. (bottom row) Schematic illustrations of the chain tilt. Inset bottom right in panel (E): schematic top-view representation of the lattice formed by DiTT4. The positions of chains and headgroups are indicated with black dots and yellow stars, respectively. Red, black, and blue triangles indicate the repeating unit cell of the alkyl chains. The dashed parallelogram indicates the molecular unit cell. Purple line: schematic delimitation of the molecules. 3532 | Nanoscale Adv., 2019, 1, 3529-3536 This journal is

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“…Among cationic lipids, the number of lipopolyamines (LPAs) available is increasing due to ease of synthesis, high transfection efficiency and low toxicity. Indeed spreading the cationic charge with primary and secondary amines improves interaction with nucleic acid and reduces the toxicity associated with the localized cationic charge of tertiary amines and the ether linkage, while the amide linker improves serum compatibility and biodegradability [50] , [51] , [52] , [53] , [54] , [55] .…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 2 promiscuity is responsible for the immunostimulatory activity of nucleic acid nanocarriers

Pizzuto

Gangloff

Scherman

et al. 2017

Journal of Controlled Release

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Lipopolyamines (LPAs) are cationic lipids; they interact spontaneously with nucleic acids to form lipoplexes used for gene delivery. The main hurdle to using lipoplexes in gene therapy lies in their immunostimulatory properties, so far attributed to the nucleic acid cargo, while cationic lipids were considered as inert to the immune system. Here we demonstrate for the first time that di-C18 LPAs trigger pro-inflammatory responses through Toll-like receptor 2 (TLR2) activation, and this whether they are bound to nucleic acids or not. Molecular docking experiments suggest potential TLR2 binding modes reminiscent of bacterial lipopeptide sensing. The di-C18 LPAs share the ability of burying their lipid chains in the hydrophobic cavity of TLR2 and, in some cases, TLR1, at the vicinity of the dimerization interface; the cationic headgroups form multiple hydrogen bonds, thus crosslinking TLRs into functional complexes. Unravelling the molecular basis of TLR1 and TLR6-driven heterodimerization upon LPA binding underlines the highly collaborative and promiscuous ligand binding mechanism. The prevalence of non-specific main chain-mediated interactions demonstrates that potentially any saturated LPA currently used or proposed as transfection agent is likely to activate TLR2 during transfection. Hence our study emphasizes the urgent need to test the inflammatory properties of transfection agents and proposes the use of docking analysis as a preliminary screening tool for the synthesis of new non-immunostimulatory nanocarriers.

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Composites of malonic acid diamides and phospholipids — Impact of lipoplex stability on transfection efficiency

Cited by 19 publications

References 52 publications

Structures of malonic acid diamide/phospholipid composites and their lipoplexes

Structures of malonic acid diamide/phospholipid composites and their lipoplexes

Relationship between structure and molecular interactions in monolayers of specially designed aminolipids

Toll-like receptor 2 promiscuity is responsible for the immunostimulatory activity of nucleic acid nanocarriers

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