Biomedical Engineering Reference
In-Depth Information
7.2
Motivation: Need for Novel siRNA
Carriers
in vivo
Originally reported in 2008, lipidoids were designed to deliver
siRNA efficiently to hepatocytes. Cholesterol-conjugated siRNA
was used to enable the first illustration of therapeutic silencing of
an endogenous gene by systemic siRNA administration.
4
Lipids can
facilitate siRNA transfection not only through direct conjugation
to the payload but also through physical entrapment.
5, 6
Though
these early successes hinted at what types of materials might
effectively deliver siRNA, the investigation of new materials was
limited by difficult chemical syntheses, requiring multiple steps and
purifications. The engineering community had faced similar issues
related to the delivery of DNA, which shares many of the physical
properties of RNA.
7.3
Approach: Efficient Chemistry Allows for
High-Throughput Combinatorial Library
Synthesis and Screening
To overcome these difficulties, a simple hypothesis — that
biodegradable, cationic compounds might facilitate safe delivery
— was used as rationale for the synthesis of a structurally diverse
library of poly(β-amino esters).
7
To produce a large library without
time-consuming protection and purification steps, diacrylates were
reacted with amines via the Michael addition. This efficient scheme
produced more than 2,000 distinct compounds, enough to justify
relationships between chemical structure, particle size, and gene
transfection efficiency.
7
The structure-function relationships from
this library were used to design a second library,
8
which in turn led
to the identification of a potent compound that was fine-tuned to
optimize delivery.
9
These studies illustrated that a broad structural
class of molecules could be screened to enable the isolation of a
specific, robust compound through iterative libraries derived from
efficient chemistry.
7-9
These large polymers, which were designed
to bind long nucleic acids through electrostatic interactions, did not
efficiently condense small RNAs, so an alternative structure was
required.
Search WWH ::
Custom Search