Biomedical Engineering Reference
In-Depth Information
2 Functions Required Within Polyplexes for Overcoming
Delivery Barriers
Medicinal nucleic acids are too polar and too large to passively enter the intracel-
lular target tissue compartments where they should exert their therapeutic function.
In addition, they are rapidly recognized by the host defense system and easily
enzymatically degraded by nucleases. Cationic polymers can package nucleic
acids into polyplexes [ 36 ] and protect them against degradation. Cationic polymers
primarily bind nucleic acids via electrostatic interactions with the negatively
charged phosphate backbone. Nucleic acid binding depends on charge density,
size, flexibility, and topology of polymers. For example, linear polymers such
as poly( L -lysine) (PLL) [ 37 , 38 ], linear polyethylenimine (LPEI) [ 39 ], and many
others linear structures [ 40 , 41 ]; branched polymers such as branched PEI (brPEI)
[ 42 ]; and dendrimers including polyamidoamines (PAMAMs) [ 43 - 46 ] have been
used. In addition to electrostatic interaction, hydrogen bonding [ 47 ] and hydropho-
bic polymer interactions [ 48 , 49 ] can increase the stability of polyplexes. Also,
caging [ 50 - 52 ] or covalent coupling to the nucleic acid [ 53 - 57 ] has been pursued.
Polymers can directly or indirectly (via targeting ligands) attach the cargo to cells
and trigger intracellular uptake. They can participate in intracellular delivery steps
including endosomal escape and cytosolic transport, nuclear uptake, and cytosolic
or nuclear presentation of the nucleic acid in bioactive form.
2.1 Extracellular Transport
Locoregional administration of gene vectors and other therapeutic nucleic acids,
such as aerosol delivery into the lung, various injections into muscle [ 2 , 5 , 58 ], brain
[ 59 ], the eye [ 60 ], or into isolated tumors [ 4 , 8 , 61 ] can be quite useful for the
treatment of some diseases. For many therapeutic applications, intravenous sys-
temic treatment would be preferred. However, vascular barriers and numerous
unintended interactions with biological surfaces including blood proteins, extracel-
lular matrix, and immune cells and other non-target cells mean that only a tiny
fraction (in the low percentage range or even less) reaches the actual target tissue.
Cationic polymers used for polyplex formation activate the alternative pathway of
the complement system, which is part of the innate immune system [ 62 ], and sys-
temically administered positively charged polyplexes are rapidly cleared by the
reticuloendothelial system [ 63 , 64 ]. Also, dissociation of polyplexes by serum
proteins or extracellular matrix presents a significant problem [ 65 - 67 ].
Several of these problems can be solved by polyplex modification with polyeth-
ylene glycol (PEG). PEGylation has been broadly explored for surface shielding
(“stealthing”) of many liposomal and nanoparticulate carriers. In the case of
cationic polymers, Plank et al. [ 62 ] demonstrated that complement activation can
be reduced when the polymers are PEGylated. Such a modification can be
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