Varying the Unsaturation in N4,N9-Dioctadecanoyl Spermines: Nonviral Lipopolyamine Vectors for More Efficient Plasmid DNA Formulation

Ahmed, Osama A. A.; Pourzand, Charareh; Blagbrough, Ian S.

doi:10.1007/s11095-005-8717-3

Cited by 33 publications

(69 citation statements)

References 60 publications

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“…NH 3 200:10:1 to 100:10:1 to 50:10:1; v/v/v). N 4 ,N 9 -Dioleoyl-1,12-diamino-4,9-diazadodecane 1 Prepared via N 1 ,N 12 -ditrifluoroacetyl-N 4 ,N 9 -dioleoyl-1,12-diamino-4,9-diazadodecane (36), the target lipopolyamine displayed HRMS: found (m/z [M+H] + ) 731.7115, C 46 H 91 N 4 O 2 requires 731.7142 (Δ ppm 3.7), consistent with the data previously reported (2,3).…”

Section: General Detailssupporting

confidence: 88%

“…Our NVGT focus is on lipopolyamines composed of two long-carbon chains (or a steroid) covalently bound to a polyamine e.g. spermine (1,12-diamino-4,9-diazadodecane) (2,3). Other research groups are investigating a variety of alternative approaches, including: naked polynucleotides, gene gun (bound to gold particles), electroporation, and the use of a wide variety of cationic lipids (lipoplexes) (4)(5)(6)(7)(8) and cationic polymers (polyplexes), for reviews see: (9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…Our aims are to design and develop efficient, non-toxic, non-viral vectors for in vitro and possible in vivo applications, using our novel spermine conjugates, based on change to the type, length, position, and number of the hydrophobic anchors (2,3). These cationic lipids (lipospermines) probably assist in the self-assembling of polycationic scaffolds, as well as facilitating absorptive endocytosis and/or fusion with cell membranes.…”

Section: Introductionmentioning

confidence: 99%

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Very Long Chain N 4 ,N 9 -Diacyl Spermines: Non-Viral Lipopolyamine Vectors for Efficient Plasmid DNA and siRNA Delivery

Ghonaim

Blagbrough

2008

Pharm Res

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Section: General Detailssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Very Long Chain N 4 ,N 9 -Diacyl Spermines: Non-Viral Lipopolyamine Vectors for Efficient Plasmid DNA and siRNA Delivery

Ghonaim

Blagbrough

2008

Pharm Res

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“…Different saturation levels are shown to influence DNA formulation. 21 Comparing all the unsaturated derivatives, DNA retardation is observed at lower concentrations with complexes formulated with linolylspermine. The DNase I protection assay, on the other hand, is not very conclusive, as bands do not seem to follow any trend.…”

Section: Resultsmentioning

confidence: 99%

“…Polyamines have been extensively used for the development of nonviral vectors and this includes studies in which lipospermines typically either contain double or have longer hydrocarbon chains. 18,21,[28][29][30][31] It has previously been suggested that DNA-binding affinity is a function of both charge and hydrophobicity. 19,32 However, to what degree this affinity is beneficial for gene delivery is not clear.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid–spermine conjugates as DNA carriers for nonviral in vivo gene delivery

et al. 2009

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The lack of efficient in vivo gene delivery is a well-known shortcoming of nonviral delivery vectors, in particular of chemical vectors. We developed a series of novel nonviral carriers for plasmid-based in vivo gene delivery. This new transport device is based on the assembly of DNA plasmids with synthetic derivatives of naturally occurring moleculesfatty acid-spermine conjugates (or lipospermines). We tested the ability of these fatty acid conjugates to interact with plasmid DNA (pDNA) and found that they formed DNA nanocomplexes, which are protected from DNase I degradation. This protection was shown to directly correlate with the length of the aliphatic component. However, this increase in the length of the hydrocarbon chain resulted in increased toxicity. The cationic lipids used for transfection typically have a C 16 and C 18 hydrocarbon chain. Interestingly, toxicity studies, together with further characterization studies, suggested that the two most suitable candidates for in vivo delivery are those with the shortest hydrocarbon chain, butanoyl-and decanoylspermine. Morphological characterization of DNA nanocomplexes resulting from these lipospermines showed the formation of a homogenous population, with the diameter ranging approximately from 40 to 200 nm. Butanoylspermine was found to be the most promising carrier from this series, resulting in a significantly increased gene expression, in relation to naked plasmid, in both tissues herein targeted (dermis and M. tibialis anterior). Thus, we established a correlation between the in vitro properties of the ensuing DNA nanocarriers and their efficient in vivo gene expression.

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Practical Synthesis of Polyamine Succinamides and Branched Polyamines

et al. 2022

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Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram‐positive and Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4‐Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo‐ and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram‐negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo‐ and hetero‐dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram‐positive or Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16–32 μg mL−1.

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Varying the Unsaturation in N4,N9-Dioctadecanoyl Spermines: Nonviral Lipopolyamine Vectors for More Efficient Plasmid DNA Formulation

Abstract: The dienoic fatty acyl spermine conjugate N4,N9-dilinoleoyl spermine efficiently condenses DNA and achieves the highest transfection levels among the studied lipopolyamines in cultured cells.

Cited by 33 publications

References 60 publications

Very Long Chain N 4 ,N 9 -Diacyl Spermines: Non-Viral Lipopolyamine Vectors for Efficient Plasmid DNA and siRNA Delivery

Very Long Chain N 4 ,N 9 -Diacyl Spermines: Non-Viral Lipopolyamine Vectors for Efficient Plasmid DNA and siRNA Delivery

Fatty acid–spermine conjugates as DNA carriers for nonviral in vivo gene delivery

Practical Synthesis of Polyamine Succinamides and Branched Polyamines

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