Lipidoids: A Combinatorial Approach to siRNA Delivery - RNA Interference from Biology to Therapeutics - page 142

of focused structure-activity relationships. For example, an analogous series of
cationic lipids containing an increasing number of double bonds per alkyl chain was
synthesized to evaluate the correlation between lipid saturation, fusogenicity, and
efficiency of intracellular nucleic acid delivery [ 14 ] . It was shown that increasing
saturation decreases fusogenicity, resulting in lower gene silencing efficiency
despite being more readily internalized by cells. The findings are, however, restricted
to the lipid backbone analyzed because the importance of a functional group for one
lipid should not be extrapolated to other lipids.
Such rational design is very useful in the optimization of effective lead candidate
lipids that have been shown to be effective in vivo; however, because there are few
examples of such validated lipids, this strategy is of limited utility. One notable
example was the use of medicinal chemistry to improve the efficiency of an
efficacious ionizable cationic lipid based on its proposed mechanism of action of
endosomal membrane disruption [ 15 ] . The endeavor was highly focused. Maintaining
a constant hydrocarbon chain—based on the results of the aforementioned study
[ 14 ]—the two other components of the cationic lipid, the linker and headgroup,
were systematically varied.
Though the sample size was modest in this analysis, trends were observed. Lipids
containing alkoxy linkers were consistently more effective than those containing
ester, thioester, or carbamate linkers. While changing the structure of the amine
head group did not greatly influence activity, increasing the distance between the
dimethylamino group and the dioxolane linker by a single methylene group yielded
a surprisingly large improvement in efficacy. This finding highlights the limitation
of the rational approach, which does not allow for the exploration of broad chemical
space: a substantial element of luck is required in selecting the modifications because
it is not obvious which minor changes will confer a major impact. Furthermore, the
yield of these reactions is often poor, and the throughput is low, so the development
of alternative chemistries would be attractive.

7.3 Lipidoids: Synthetic Scheme

The Michael addition reaction allows for the conjugate addition of an amine to
acrylates or acrylamides, enabling the simple and rapid synthesis of large degrad-
able or nondegradable combinatorial libraries, respectively [ 16 ] . This approach has
yielded thousands of structurally diverse lipid-like materials, which have been
dubbed “lipidoids,” from the Greek for “lipid-like” [ 17 ]. The members of the library
chemically resemble lipids and thus protect and enhance the uptake of their siRNA
payload. An inspection of this novel class of materials reveals that these unique
compounds manifest as a hybrid structure between cationic lipids and first-generation
dendrimers [ 18 ] (see Fig. 7.1 ). Notably, unlike traditional cationic lipids, which are
generally comprised of a discrete cationic head group and a hydrophobic tail, lipi-
doids are cationic owing to the presence of reversibly protonatable backbone amines.
Additionally, whereas natural lipids typically possess two tails, lipidoids contain up