Amphiphilic Block Copolymer Based Nanocarriers for Drug and Gene Delivery - Intracellular Delivery: Fundamentals and Applications - page 274

3 Polymeric Micelles for Delivery of Genetic Therapeutics

3.1 Requirements for Effective Gene/siRNA Transfection

The past several years have witnessed evolution of gene medicine from experimen-
tal technology into new clinic strategies for developing new genetic therapeutics for
a wide range of human disorders such as cancer, AIDS, neurological disorders and
cardiovascular disorders. These include using nucleic acid-based compounds such
as plasmids containing transgenes for gene therapy, oligonucleotides, ribozymes,
DNAzymes, aptamers, and small interfering RNAs (siRNAs). The successful clinical
application of this nucleic acid-based therapeutics in particular for gene and siRNA
greatly relies on an effective delivery system for systemic administration. So far,
various nanomedicine platforms have been developed as viral or non-viral vectors
to meet these challenges for an effective gene or siRNA delivery.
There are several requirements for an effective gene/siRNA delivery system.
Generally, the delivery system needs to able to efficiently encapsulate gene/siRNA,
actively target sites of interest, escape from endosome/lysosomes, and finally
release siRNA intracellularly. In addition to accumulation within desired tissues, it
also requires gene to be delivered to the nucleus and siRNA to be delivered into the
cytoplasm. In particular, it requires the ability of a delivery system to escape endo-
some after cellular endocytosis and effective delivery of nucleic acid based drugs
to their specific targets. Endosomal escape is believed to be achieved through 'pro-
ton sponge effect' ( Fig. 15a ) (Behr 1997 ; Pack et al. 2005 ). It is hypothesized that
polymers with buffering capacities between 7.2 and 5.0, such as PEI and imidazole-
containing polymers, could buffer the endosome and potentially induces its rupture.
Polycations are believed to increase osmotic pressure in the endosome by the
so-called 'proton sponge effect' resulting in endosomal disruption and gene release
(Behr 1997 ; Boussif et al. 1995 ).
Polymeric micelles composed of a hydrophilic and polycationic segments have
attracted attention as non-viral gene/siRNA vectors due to their unique core/shell
structure and highly tunable characteristics. PEO-PLAA based copolymers have been
extensively investigated to develop gene/siRNA delivery. Recently, by introduction
cationic groups on the polyester block, PEO-polyesters have been emerging as impor-
tant polymeric micellar materials. Generally, neutralization of the positive charge on
the polycation by the negatively charged DNA will lead to micellization (Fig. 15b ).

3.2 Development of PIC Micelles from PEO - PLAA

for Gene Delivery

Existence of several functional groups on a PLAA block offers the advantages for
PEO — PLAA to be used for gene/siRNA delivery. PEO-PLAA based gene vectors
can be smartly engineered to meet the challenges for DNA/siRNA delivery due to