Lipidoids: A Combinatorial Approach to siRNA Delivery - RNA Interference from Biology to Therapeutics - page 151

the DNA repair enzyme Parp1 was used to generate a synthetic lethal phenotype in
the context of Brca1 deficiency [ 45 ], which is a hallmark of the familial forms of
ovarian and breast cancer [ 47 ]. The treatment of mice harboring disseminated
tumors derived from genetically defined Brca1-deficient cells resulted in survival
extension, with a marked increase in apoptotic cells relative to treatment with con-
trol siRNA or to tumors derived from Brca1 wild-type cells.
Lipidoids can also transfect lung epithelia upon intranasal administration.
Lipidoid-formulated siRNA targeting the respiratory syncytial virus (RSV) pro-
vided greater than two log reduction in viral plaques relative to saline and mismatch
siRNA controls in a mouse model of RSV [ 18 ] . Together, these data demonstrate
that lipidoids are relevant to nonsystemic applications of RNAi and can deliver
siRNA to nonhepatic cell types.
Notably, lipidoids can also be used to deliver other classes of nucleic acid thera-
peutics. Specifically, lipidoids were used to transfect hepatocytes with single-
stranded oligoribonucleotides targeting miRNAs (anti-miRs) in vivo [ 18 ] . The
successful delivery of anti-miR122 resulted in silencing of this miRNA and con-
comitant derepression of its target genes. The lipidoid formulation was found to
confer greater repression than a 16-fold higher dose of cholesterol-conjugated oli-
gonucleotide, highlighting the efficiency of its delivery capacity. The successful
delivery of anti-miRs suggests that lipidoids can be used to deliver nucleic acid
therapeutics that not only silence genes but also upregulate them, enabling the
manipulation of targeted pathways at multiple nodes. Clearly, the ability of lipidoids
to deliver multiple payloads to multiple cell types in vitro and in vivo represents a
robust platform.

7.7 Evolution of a Platform

Several approaches have been adopted to improve the lipidoid system. Because lipi-
doids possess multiple tails, it is possible to fix the structure of some of the tails
while varying the structure of others. This approach also allows for the determina-
tion of functional group effects in a combinatorial manner [ 48 ] . The top amine back-
bones from the first-generation library, amine 98 (triethylenetetramine) and amine
100 (diaminopropane), were reacted with N 12 to yield precursors with n − 2 tails.
A final tail was added in a combinatorial manner with acrylate- or acrylamide-
derived tails that contained hydroxyl, carbamate, ether, or amine functional groups
as well as variations in alkyl chain length and branching. Such heterofunctional
materials bear differential capacities for hydrogen bonding, hydrophobic interac-
tions, and protonation states. The results of the study supported previous findings
that suggested that the most-active lipidoids contain three or four secondary or ter-
tiary amines [ 18, 49 ]. Lipidoids featuring final tails containing ethylene or propyl-
ene glycol units were observed to confer silencing in vivo, though none of the
members of this new library was as effective as the parent molecules that contained
the N 12 aliphatic final tail. While valuable for extending the structure-activity