A symmetrical and biodegradable cationic lipid. Synthesis and application for efficient gene transfection

Obika, Satoshi; Yu, Wei; Shimoyama, Atsuko; Uneda, Takeshi; Miyashita, Kazuyuki; Doi, Takefumi; Imanishi, Takeshi

doi:10.1016/s0960-894x(97)00317-x

Cited by 17 publications

(8 citation statements)

References 21 publications

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“…The structure of cationic lipids generally comprises a cationic head group attached via a linker to a large hydrophobic domain. The head group often consists of primary, secondary or tertiary amines, but quaternary ammonium salts, guanidino and imidazole groups have also been investigated [16][17][18][19][20][21][22][23]. The most common linkers used are ethers and esters, although amides and carbamates are also employed [24][25][26].…”

Section: Cationic Lipids and Liposomes (A) -Lipidsmentioning

confidence: 99%

Structure-Activity Relationship in Cationic Lipid Mediated Gene Transfection

Niculescu‐Duvaz¹,

Heyes²,

Springer³

2003

CMC

141

112

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Non-viral synthetic vectors for gene delivery represent a safer alternative to viral vectors. Their main drawback is the low transfection efficiency, especially in vivo. Among the non-viral vectors currently in use, the cationic liposomes composed of cationic lipids are the most common. This review discusses the physicochemical properties of cationic lipids, the formation, macrostructure and specific parameters of the corresponding formulated liposomes, and the effect of all these parameters on transfection efficiency. The optimisation of liposomal vectors requires both the understanding of the biological variables involved in the transfection process, and the effect of the structural elements of the cationic lipids on these biological variables. The biological barriers relevant for in vitro and in vivo transfection are identified, and solutions to overcome them based on rational design of the cationic lipids are discussed. The review focuses on the relationship between the structure of the cationic lipid and the transfection activity. The structure is analysed in a modular manner. The hydrophobic domain, the cationic head group, the backbone that acts as a scaffold for the other domains, the linkers between backbone, hydrophobic domain and cationic head group, the polyethyleneglycol chains and the targeting moiety are identified as distinct elements of the cationic lipids used in gene therapy. The main chemical functionalities used to built these domains, as well as overall molecular features such as architecture and geometry, are presented. Studies of structure-activity relationships of each cationic lipid domain, including the authors', and the trends identified by these studies, help furthering the understanding of the mechanism governing the formation and behaviour of cationic liposomes in gene delivery, and therefore the rational design of new improved cationic lipids vectors capable of achieving clinical significance.

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Section: Cationic Lipids and Liposomes (A) -Lipidsmentioning

confidence: 99%

Structure-Activity Relationship in Cationic Lipid Mediated Gene Transfection

Niculescu‐Duvaz¹,

Heyes²,

Springer³

2003

CMC

141

112

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“…2–4 Recently, environmentally responsive materials capable of condensing DNA have received increasing attention due to their potential to improve controlled release 5–10 and reduce cell toxicity in biological environments. 11–13 In particular, materials containing reducible disulfide bonds have attracted strong interest.…”

Section: Introductionmentioning

confidence: 99%

“…Environmentally responsive materials are designed to switch functional properties (e.g., triggerable and controlled release of entrapped molecules and sensing nanoprobes) in response to environmental stimuli (e.g., change in pH, UV irradiation, or change in redox potential). − Recently, environmentally responsive materials capable of condensing DNA have received increasing amounts of attention because of their potential to improve controlled release − and reduce cell toxicity in biological environments. − In particular, materials containing reducible disulfide bonds have attracted strong interest. Disulfide bonds can be reductively cleaved into the constituting thiols (e.g., in the reducing environment of the intracellular matrix whereas they are stable in the extracellular space).…”

Section: Introductionmentioning

confidence: 99%

Structural Evolution of Environmentally Responsive Cationic Liposome–DNA Complexes with a Reducible Lipid Linker

Shirazi¹,

Ewert²,

Silva

et al. 2012

Langmuir

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Environmentally responsive materials, i.e., materials that respond to changes in their environment with a change in their properties or structure, are attracting an increasing amount of interest. We recently designed and synthesized a series of cleavable multivalent lipids (CMVLn, with n = 2 to 5 the number of positive headgroup charges at full protonation) with a disulfide bond in the linker between cationic headgroup and hydrophobic tails. The self-assembled complexes of the CMVLs and DNA are a prototypical environmentally responsive material, undergoing extensive structural rearrangement when exposed to reducing agents. We investigated the structural evolution of CMVL–DNA complexes at varied complex composition, temperature and incubation time using small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS). A related lipid with a stable linker, TMVL4, was used as a control. In a nonreducing environment CMVL–DNA complexes form the lamellar (LαC) phase, with DNA rods sandwiched between lipid bilayers. However, new self-assembled phases form when the disulfide linker is cleaved by dithiothreitol or the biologically relevant reducing agent glutathione. The released DNA and cleaved CMVL headgroups form a “loosely organized” phase, giving rise to a characteristic broad SAXS correlation profile. CMVLs of high headgroup charge also form condensed DNA bundles. Intriguingly, the cleaved hydrophobic tails of the CMVLs reassemble into tilted chain-ordered Lβ′ phases upon incubation at physiological temperature (37 °C), as indicated by characteristic WAXS peaks. X-ray scattering further reveals that two of the three phases (LβF, LβL, and LβI) comprised by the Lβ′ phase coexist in these samples. The described system may have applications in lipid-based nanotechnologies.

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“…28 -30 The presence of the double bond has a similar effect as acyl chain shortening and gives rise to a less rigid bilayer. 31 Obika and coworkers 32,33 have attempted the synthesis and utilization of cationic triglycerides for lipofection, and it was found that the transfection activity of symmetrical cationic triglycerides is comparable with asymmetrical cationic triglycerides. The cholesterol -derived cationic lipids generally cannot form stable bilayers on their own.…”

Section: Hydrophobic Chainmentioning

confidence: 99%

“…26 The use of ester linkage enables fast hydrolysis after transfection, which reduces cytotoxicity of cationic lipid amphiphiles. 32 Generally, cationic lipid amphiphiles that are composed of ether linkages are more toxic compared with those that are composed of biodegradable linkages, such as ester, amide, and carbamoyl bonds. The use of a linker segment with a length of 3 -6 atoms can optimize transfection activity 34 as well as lower cytotoxicity, given that the linkage is degradable.…”

Section: Linkermentioning

confidence: 99%