Polymeric Micelles for siRNA Delivery - RNA Interference from Biology to Therapeutics - page 176

multiple functions at an appropriate timing during the delivery process. In this
regard, a great advantage for synthetic polymers is the possibility of preparing dif-
ferent structures and blocks of polymers capable to perform specific functions.
These block copolymers have been utilized to form nanoscale polymeric micelles
for siRNA delivery based on previous knowledge obtained for drug and gene deliv-
ery systems.
The rational design of novel stimuli-responsive block copolymers for the forma-
tion of new polymeric micelles has been shown to be a promising strategy toward
effective RNAi. Future directions on polymer synthesis will couple biological infor-
mation on tissue microenvironment changes and the available library of responsive
chemical groups and moieties for the preparation of novel stimuli-responsive block
copolymers. Biodegradable functional polymers as well as biocompatible materials
may play an important role for the approval in toxicological tests. New options of
hydrophilic polymers are also desirable as alternatives for PEG, such as poly( N -[2-
hydroxypropyl]methacrylamide). Furthermore, although non-targeting system are
exploiting the leaky vasculature of tissue for passive accumulation by the EPR
effect, targeting systems holds the promise to sharply regulate the biodistribution by
active targeting in vivo. Finally, polymeric micelles composed of multifunctional
polymers rationally designed to overcome extracellular and intracellular barriers
offer the potential to be translated into therapeutics.
The possibility to incorporate siRNA and imaging agents in the same nanocarrier
provides new paths for future research. This exciting approach is the design of ther-
anostics, the union of therapeutics and diagnostics to be realized in the future. The
strategy will require convenient methods to prepare multifunctional versatile nano-
carriers with tunable structure and properties, and synthetic polymer chemistry may
play an important role to achieve this.
The feasibility for the clinical translation of polymeric micelles will depend on
several factors which include the efficient performance in preclinical tests allied to
its safety. A complete preclinical evaluation of nanocarriers can provide robust vali-
dation for consistent introduction into clinical tests. Rigorous toxicological assess-
ment and effective pharmacokinetics and biodistribution data are essential.
Much effort has been made to translate RNAi biology into RNAi therapeutics.
The following years promise to be crucial for the demonstration of efficacy and
safety of polymeric micelles to enable the clinical use of RNAi. With only few years
since initial characterization of RNAi, there is still a completely open field for new
ideas, approaches, targets, diseases, and nanocarriers systems.
References
1. Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discov
2(5):347-360
2. Kataoka K, Kwon GS, Yokoyama M, Okano T, Sakurai Y (1993) Block-copolymer micelles as
vehicles for drug delivery. J Control Release 24:119-132