Biomedical Engineering Reference
In-Depth Information
The introduction of reducible disulfide bond in lipopolyamines has contributed sig-
nificantly to the research of cationic lipid. This approach was supposed to increase traf-
ficking of pDNA to the nucleus by modulating the degradation of lipid in the cell by
a naturally occurring reduction system. A series of lipopolyamines having a disulfide
bridge in different positions on the backbone were synthesized and evaluated in vitro
against HepG2 and Hela cells [231] . An extensive structure activity relationship (SAR)
study has been carried out to achieve the highest transfection efficiency. The effect of
physiochemical characteristics of the complex formed by this compound, either alone
or in combination with helper lipid, on transfection efficiency was evaluated [232] .
4.3.3 Cationic Lipids Containing Both Quaternary Ammonium Salt
and Lipoamines
The first cationic lipid of this class containing both quaternary ammonium salt and
polyamines in one lipid was 2,3-dioleoyloxy- N -(2-spermine carboxamido)ethyl- N , N -
dimethyl-1-propanaminium trifluroacetate (DOSPA) ( Fig. 4.15 ) coformulated with
DOPE to give Lipofectamine TM [233,234] . Although Lipofectamine TM is a highly effi-
cient transfecting agent, relatively high cytotoxicity in vitro and in vivo has prevented
further clinical development. Later, GAP-DLRIE containing one amine and one qua-
ternary ammonium salt ( Fig. 4.15 ) was introduced, which displayed a high level of
transfection with low cytotoxicity [195] . Life Technologies has proposed DOSPA-
DLRIE and GAP-DLRIE and compounds D and E containing carbamate linker bonds,
with the objective of improving bioavailability and reducing toxicity ( Fig. 4.15 ) [235] .
These compounds displayed low toxicity when tested in vitro and in vivo .
The use of piperazine backbone to synthesize mixed polar head cytofections, F,
G, and H, was proposed by Vical Inc. ( Fig. 4.16 ) [236,237] . This compound, when
coformulated with DOPE, demonstrated comparable or higher transfection efficiency
against C2C12 and COS-7 cells as compared to the DMRIE-DOPE system. Following
in vivo administration, compound F displayed higher transfection activity than GAP-
DLRIE in mouse tumor assay and intralung transfection assay. Also, transfection
assay after IP administration in C57/B16 mice displayed a modest result in some cases
but was lower than those obtained for GAP-DLRIE. Haes introduced spermine scaf-
fold-based diamino-bis-quarternary ammonium salt lipid, I ( Fig. 4.16 ) [238] . These
compounds, when coformulated with DOPE, demonstrated 2 to 2.4 folds transfection
efficiency against HepG2 and Hela cells as compared to N , N , N , N -tetraethyl palmityl
spermine (TMTPS). In addition, the transfection efficiency was more than fivefold
higher than Lipofectin TM when tested in primary human tracheobronchial cells. The
same compound was also effective in transfecting primary human epidermal keratino-
cytes [239] .
4.3.4 Amidinium Salt Lipids and Miscellaneous Cationic Entities
Ruysschaert et al. demonstrated the use of amidine-based moieties as efficient trans-
fection vectors [240] . Megabios Corp. revealed the first gene delivery system based
on amidinium lipids [241] . Following IV administration of compounds ADPDE and
ADODE, coformulated cholesterol demonstrated comparable transfection efficiency,
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