Lipidoids: A Combinatorial Approach to siRNA Delivery - RNA Interference from Biology to Therapeutics - page 143

Fig. 7.1 Synthesis occurs through the conjugate addition of amines to an acrylate or acrylamide.
Depending on the number of addition sites in the amino monomer, lipidoids can be formed with
anywhere from 1 to 7 tails. Amino groups in the lipidoid can be quaternized by treatment with
methyl iodide. For ease of nomenclature, lipidoids are named as follows: (amine number)(acrylate
or acrylamide name)-(number of tails)(“+” if quaternized) (reproduced with permission from [ 18 ] )
to seven tails emanating from the amine backbone. Another interesting chemical
property that renders lipidoids a distinct class of biomaterials is the inversion of its
ester linkage with respect to the aliphatic chain when compared to natural lipids
such as triglycerides. Lipidoids can be quarternized to impart permanent charge
through the addition of alkylating agents such as methyl iodide.
Whereas standard chemistries used to synthesize cationic lipids involve several
onerous steps that include protection, deprotection, solvent exchanges, and serial
puri fi cation [ 19 ], this innovative route enables high-throughput, parallel synthesis
in a single step. To synthesize a lipidoid, one need only add an amine, an acrylate or
acrylamide, and a stir bar. The reaction mixture is then placed in a 90°C oven for
one or six days, respectively. There is tremendous potential for high throughput
because the starting reagents are commercially available and there are no side reac-
tions. As a consequence of this simplicity, the number of lipofection materials syn-
thesized and studied to date was increased by two orders of magnitude.
The first-generation lipidoid library was generated from starting reagents that
provided significant chemical diversity [ 18 ] (see Fig. 7.2 ). The functional groups
included linear and cyclic ethers and diamines; diols; primary, secondary, and ter-
tiary amines; piperidines; pyrrolidines; and imidazoles. These materials were
selected because they imparted good transfection ability upon poly(beta amino)
esters, a class of degradable transfection agents that was previously developed to
deliver plasmid DNA [ 16 ] .
Amines are used because they are thought to promote endosomal escape by
acting as “proton sponges” [ 20, 21 ]. The ability to escape the endosome is of