Lipidoids: A Combinatorial Approach to siRNA Delivery - RNA Interference from Biology to Therapeutics - page 154

The application of additional single-step chemistries to the generation of large,
chemically diverse libraries is likely to lead to the discovery of novel delivery mate-
rials. Examples of such synthetic methods include “click” chemistry [ 51 ] and the
Staudinger ligation [ 52 ], though they both require the azide functionality, which
limits the breadth of commercially available reagents. Creative chemists are sure to
play a large role in the progress of the field.
The most significant challenge in the delivery space remains the effective and
selective targeting of specific cells in vivo. Such targeting can decrease dose as well
as side effects. Positively charged nanoparticles often accumulate in the liver,
spleen, and kidneys. To reach distal sites, the particles must avoid clearance by
these natural filtration sites. Such systemically targeted siRNA delivery has been
achieved through the use of aptamer-siRNA chimeras, which have been applied to
address mouse models of prostate cancer [ 53 ] and HIV [ 54, 55 ] . These molecules
are not expected to escape endosomes efficiently, though they seem to be very
efficacious notwithstanding. A second successful approach, which has been vali-
dated in patients, involves nanoparticle surface decoration with a targeting ligand
[ 56 ]. This strategy, in which PEG is employed to enhance circulation time and
amines are incorporated into the carrier to enhance endosomal escape, is likely to
serve as the best means to target lipidoids as well. Additionally, it seems that some
lipidoids inherently confer cell type-specific delivery in the absence of targeting
ligands. The ability to minimize the number of components in a formulation is
desirable because it decreases variability between particles, cost, and likelihood of
immunogenicity (to targeting moieties such as peptides or antibodies). Further stud-
ies are required to elucidate the mechanism underlying the preference of certain
lipidoid structures for certain cells.
Notably, targeted siRNA delivery is different from general targeted drug delivery
(monoclonal antibodies or targeted nanoparticles containing small molecules)
because receptor binding, while necessary, is not sufficient; siRNA delivery requires
internalization of the payload. Interestingly, the modeling of transferrin-mediated
tumor targeting suggested that the efficacy of these targeted nanoparticles was
owing to increased cellular uptake by tumor cells rather than to increased overall
tumor localization relative to nontargeted particles [ 57 ] . Thus, the optimization of
internalization may be the critical step in the development of highly effective, nano-
particle-based targeted RNAi therapeutics.
Advances in understanding the mechanism of particle uptake and subsequent
intracellular transport are thus expected to lead to significant progress in this field.
The bridging of the chemistry and engineering aspects of drug delivery with the
biological and medical aspects of target selection will lead to synergies in the realm
of therapeutics [ 58 ]. Receptor type, density, heterogeneity, shedding, and internal-
ization should all be considered, along with ligand type, density, size, and number.
Particle physicochemical properties are derived from the combination of multiple
constituents, so the contributions of composition, size, charge, shape, and surface
properties to function should also be regarded.
While viruses have evolved over millions of years to deliver nucleic acids into
cells efficiently, nonviral vectors have been developed over the course of the past
20 years. The amount of progress that has been made in this short period of time is