Cationic Polymers for the Delivery of Therapeutic Nucleotides - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 31

2.3 Major Cationic Polymers Used for Delivery

of Nucleotides

Gene therapy holds great promise for treating a variety of human
diseases and conditions. The field of gene therapy has advanced
rapidly in the last two to three decades. However, a major limiting
factor remains the lack of a suitable gene delivery vector. The
passage of the transgene through the cell to the nucleus is
hampered by many obstacles. The ideal vector must be stable in
the systemic circulation, escape the reticuloendothelial system, be
able to extravasate tissues, enter the target cell, escape lysosomal
degradation, and transport DNA to the nucleus to be transcribed.
With increasing understanding of the physicochemical properties
essential to overcome various barriers, it is possible to apply
rational design to the cationic carriers.

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Thus, various approaches
to maximize gene expression are presently under investigation,

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and
a number of cationic polymers, block co-polymers, dendrimers, etc.,
have been rationally designed to optimize gene delivery.

2.3.1 Polyethylenimine

Polyethylenimine (PEI) is a branched, linear or dendrimer polyamine
polymer (Fig. 2.2), principally applied in gene transfection since
1995. It is simple and easy to prepare and to modify and relatively
safe compared to viral vectors.

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It is composed of 25% primary, 50%
secondary, and 25% tertiary amines with high buffering capacity.
It exhibits proficient endosomal release and contains secondary
and tertiary amines exhibiting pKa values between physiological
and lysosomal pH. PEI has an advantage over other polycations
that it exhibits strong DNA compaction capacity with an intrinsic
endosomolytic activity. It has been termed the “proton sponge”
polymer, and this hypothesis is used to explain endosomal disruption
by cationic polymers with ionizable amine groups. The “proton
sponge” nature of PEI leads to buffering inside endosomes.

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PEI based non-viral vectors have been delivered both
locally or systemically to target gene to tumor, lung, liver, etc.
Although this requires strategies to efficiently shield transfection
polyplexes against non-specific interaction with blood components,
extracellular matrix and untargeted cells and the attachment of
targeting moieties allow for the directed gene delivery to the desired