Structure–delivery relationships of lysine-based gemini surfactants and their lipoplexes

Abstract

The synthesis and properties of gemini surfactants of the type (R(1)(CO)-Lys(H)-NH)2(CH2)n are reported. For a spacer length of n = 6, the hydrophobic acyl tail was varied in length (R(1) = C8, C10, C12, C14, C16, and C18) and, for R(1) = C18, the degree of unsaturation. For R(1)(CO) = oleoyl (C18:1 Z) the spacer length (n = 2-8) and the stereochemistry of the lysine building block were varied; a 'half-gemini' derivative with a single oleoyl tail and head group was also prepared. The potential of the gemini surfactants to transfer polynucleotides across a cell membrane was investigated by transfection of HeLa cells with beta-galactosidase, both in the presence and absence of the helper lipid DOPE. Oleoyl was found to be by far the best hydrophobic tail for this biological activity, whereas the effect of the lysine stereochemistry was less pronounced. The effect of an optimum spacer length (n = 6) was observed only in the absence of helper lipid. The most active surfactant, i.e. the one with oleoyl chains and n = 6, formed liposomes with sizes in the range of 60-350 nm, and its lipoplex underwent a transition from a lamellar to a hexagonal morphology upon lowering the pH from 7 to 3.

Recent progress in gene therapy to deliver nucleic acids with multivalent cationic vectors

“…3), the size sharply reach a maximum followed by a decrease at higher positive charge ratios which has been attributed to the re-entrant condensation effect [146]. [45,54,60,62,75,93,113] or multivalent cationic lipids [63,65,67,147]; (b) polyplexes formed by pDNA with cationic polymers [148,149] or polycations [141]; (c) lipoplexes formed by siRNA with GCLs [114,150,151] or MVCLs [72,152] mediated by a helper lipid as DOPE, MOG or DOPC; and (d) polyplexes formed by siRNA with cationic polymers [153]. Fig.…”

“…Other groups have reported the electrostatic interaction when the GCL contains an oligo-oxyethylene spacer [93,115], and/or other headgroups as imidazolium or pyridinium [45, 57-59, 75, 99, 116]. Looking for more biocompatible vectors, GCLs that incorporate aminoacid rests, such as GCL-lysine 12 based and GCL-arginine based [60,62,64], GCL-cholesterol based [117][118][119], and GCL-cyclen-based [120] have been also investigated. Lipoplexes containing a MVCL with dendritic-type headgroup have been also analyzed [67,121,122].…”

“…TEM and/or cryo-TEM studies have reported many micrographs to characterize the size, shape, and morphology of a wide variety of lipoplexes as: (a) pDNA with GCLs [45,54,57,62,64,75,93,115,117,118,120], MVCLs [63], cationic polymers [107,133,[169][170][171] or polycations [40,84,100,136]; and (b) siRNA with cationic polymers [90,104]. Fig.…”

“…As a result of that, the transfection capability [75]. Recent studies reporting TE of lipoplexes and polyplexes have been investigated: (i) divalent GCLs, as cholesterol-based with alkyl or oligooxyethylene spacers [118,119,121], aromatic-based with alkyl or oligo-oxyethylene spacers [46,93], SS14 linkers [66], ammonium with alkyl or oligo-oxyethylene spacers [54,71,93,179], imidazolium or pyridinium derivatives with alkyl-or oligooxyethylene spacers [45,59,75], aminoacid-based [62,64] or gemini-like amphiphilic peptides [150], cyclen-based CLs [120,180], and archael tetraether-based lipids [138];…”

“…The cationic groups commonly used are ammonium [53,54], imidazolium [55][56][57], pyridinium [58,59], lysine or arginine [60][61][62], and/or amine/polyamines [63][64][65][66][67].…”