Lipoplexes and Polyplexes: From Gene Delivery to Gene Expression - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 10

protamine, prior to the addition of a cationic lipid or polymer. The
gold standard lipopolyamine RPR-120535 from the first approach
has been co-formulated with a histone H1-derived peptide. The
peptide-DNA-lipid particles displayed enhanced transfection

efficiency over that observed with classical DNA/lipid complexes
and in particular conferred transfection capacity in the presence
of serum. This serum resistance is cell-type independent and was
observed with a variety of lipopolyamines. Pre-compacting DNA
with a histone H1-derived peptide enhances gene transfer in an

in vitro

in

vivo model of Lewis lung carcinoma [32].

1. Lipopolyaminoguanidines

Further, we have introduced amidinium moieties into cationic
lipids by introducing amidino-moieties through the linker or taking
advantage of a similar combinatorial approach to that applied
for obtaining polyamine-building blocks. In the first series of
molecules, we introduced guanidinium groups in the position of the
linker between the lipid and the polyamine [20-23, 25]. Product
#8 (Fig. 1.9) displayed enhanced transfection activity compared
to Lipofectamine on NIH3T3, Rabbit SMC, 3LL Lewis lung, and
CaCo2 colon carcinoma cell lines. Product RPR120531 displays
high level of transgene expression that is not inhibited by the
presence of serum [27].

N H

2

O

O

O

N

N

N

N H N

O O

N H

O

O N

N

N H

N N

N N

H N

H

H N N

RPR120531

RPR115335

2

N H

2

Figure 1. Lipopolyamines bearing a guanidinium function as side chain.

We then extended the family of poly(guanidinium)amine-
lipids exploiting combinatorial chemistry technology. A second-
generation library of mono-functionalized poly(guanidinium)amines