Tri-peptide cationic lipids for gene delivery

Abstract

Several novel tri-peptide cationic lipids were designed and synthesized for delivering DNA and siRNA. They have tri-lysine and tri-ornithine as head groups, carbamate group as linker and 12 and 14 carbon atom alkyl groups as tails. These tri-peptide cationic lipids were prepared into cationic liposomes for the study of the physicochemical properties and gene delivery. Their particle size, Zeta potential and DNA-binding were characterized to show that they were suitable for gene transfection. The further results indicate that these lipids can transfer DNA and siRNA very efficiently into NCI-H460 and Hep-2 tumor cells. The selected lipid, CDO14, was able to deliver combined siRNAs against c-Myc and VEGF for silencing distinct oncogenic pathways in lung tumors of mice, with little in vitro and in vivo toxicity.

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

“…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]. Most of these studies have confirmed that: i) the effective positive charge of the GCL or the MVCL is a certain percentage lower than its nominal one; and ii) the electrostatic interaction between the cationic gene vector and the negative nucleic acid is moderate-to-strong.…”

“…Authors conclude that the greater siRNA complexation efficacy displayed by 10k CDPR + (comparable to those of bPEI and Lipo2000) together with its 100−200-fold lower toxicity, suggest that this polyrotaxane derivative may be suitable for in vivo studies. Gene silencing studies have been also carried out in the literature with: (a) lipoplexes with gemini-like amphiphilic peptides [122,150], nucleolipids [194], aminoacid-based lipids [195], alginate scaffold [196] or dendritic multivalent [72,139] lipids; and (b) polyplexes with…”

“…In general, biological activity (as silencing vectors) reported by lipoplexes (with GCLs or MVCLs) is higher than that reported by polyplexes. polymers [201], polycation derivatives from cyclodextrin [193]; and (b) gene silencing/knockdown efficacy (KE) of lipoplexes formed by siRNA with tetraethylenpentamine or tripeptide MVCLs [202] [122], and polyplexes with PEI derivatives [187] or POEAA [144] cationic polymers.…”

“…(ii) multivalent cationic lipids [67,78,139,178,181], derivated oligoamines [182] and tripeptide multivalent lipids [122]; (iii) cationic polymers derivatives from PEI [124,127,183,184], PAMAM [132,140], PDMAEMA [123,133,185], PAA [103,131,186,187], chitosan [188], polyphosphoramidates [189], polyhydroxyalkanoate [92], polyamines [107], polyaminoacids [127,190] or diblock copolymers [191]; (iv) polycations from calixarene [40,136,165,192] or cyclodextrin [134,135,142,164,193] derivatives; (v) lipopolymers from lysine derivatives [170]; (vi) pendant polymercationic cyclodextrins [129,130,163]; and (vii) cationic polymer-cyclodextrin polyrotaxanes [89]. The picture that results from these transfection studies is that many of the polyplexes show efficacies comparable to that reported by the Lipo2000 positive control and also by most of the commercial or synthezised univalent CLs, but its efficacy as transfecting agents of DNA is still below than that reported by most of t...…”

“…The results confirm that all these optimized formulations did not report any toxicity to the cell lines studied, the cell viability after transfection being considerably better than the commercial control Lipo2000. The cell viability/cytotoxicity of several complexes between nucleic acids and a wide variety of recent synthesized MVCVs has been analyzed: (i) GCLs as cholesterol-based with alkyl or oligo-oxyethylene spacers [118,119,121,206,207], aromatic-based with alkyl or oligo-oxyethylene spacers [46], ammonium derivatives [54,71,93] imidazolium derivatives [45,75,99] and pyridinium derivatives [57] with alkyl type spacers, aminoacid-based [64,208], SS14 linkers [66], gemini-like amphiphilic peptides [150] or cyclen-based CLs [120,180]; (ii) several MVCLs [67,72,122,181,182]; (iii) cationic polymer-derivatives from PEI [124,127,183,209], PAMAM [140], PDMAEMA [123,133], chitosan [188], polyphosphoramidates [189], polyhydroxyalkanoates [92], polyamines [107,187] or polyaminoacids [127,190]; (iv)…”