Biomedical Engineering Reference
In-Depth Information
demonstrated the great potential of siRNA in cancer treatment, safe and
efficient
delivery
of
siRNA
into
target
cells
or
organs
still
remains
a
considerable challenge for therapeutic applications.
Nanoparticles are rapidly emerging as siRNA delivery systems both in vitro
and in vivo. A successful siRNA delivery carrier should have several
characteristics, including effective siRNA protection, high transfection efficacy,
improved immune evasion, few off-target effects, and the ability to bypass
intracellular and extracellular barriers. Polymeric micelles in the range of several
tens to hundreds of nanometers can serve as siRNA delivery systems due to their
structure, which can be easily changed and modified. The outer hydrophilic
segments can evade RES recognition to achieve effective extravasation from the
bloodstream to tumors through the EPR effect, resulting in high siRNA
accumulation, and can also be modified with polycations to interact
electrostatically with siRNA and different moieties to target specific cells. The
inner hydrophobic cores improve the stability of particles and allow loading of
hydrophobic drugs. Smart polymeric micelles triggered by intracellular stimuli
can be further developed to improve siRNA efficacy. Several types of polymeric
micelles have already exhibited great therapeutic potential in xenograft cancer
models, and simultaneous delivery of siRNA and drugs into the same cancer
cells by polymeric micellar delivery systems have demonstrated the synergistic
effects of RNA interference and chemotherapy in cancer.
In the future, a significant amount of work will have to be performed to turn
polymeric micelles/siRNA complexes into clinically acceptable therapeutic
drugs. (1) There is still a need for better polymers for micellar formulations and
more highly effective methods of siRNA loading and protection during in vivo
delivery. (2) Methods for preparing polymeric micelles/siRNA complexes on a
larger scale for ongoing production should be developed, and attention must
also be paid to developing more stable polymeric micelles/siRNA complexes
for long-term storage because siRNA is easily degraded under physiological
conditions. (3) siRNA pharmacokinetic and pharmacodynamic parameters
should be clearly defined after systemic administration, which is very
important to provide necessary information for the optimization of an
siRNA dosing regimen. Convenient analysis methods to detect siRNA in
biological samples should also be developed. (4) In vivo safety needs to be
further studied to eliminate unexpected immune stimulation and toxicity of
both polymeric micelle materials and their possible degradation products. (5)
Although enhanced efficacy and specificity of cancer treatment has been found
using a combined approach with siRNA and traditional chemotherapy, the
optimized ratio of the two distinct drugs needs to be further investigated to
obtain the maximum synergistic effect.
d
n
4
y
3
n
g
|
8
7.6 Conclusion
Polymeric micelles as siRNA delivery systems will remain an active area in
future
research
because
the
specific
core-shell
structure
provides
great
