Biomedical Engineering Reference
In-Depth Information
Functional Polymer Conjugates for Medicinal
Nucleic Acid Delivery
Ernst Wagner
Abstract Medicinal nucleic acids like antisense oligonucleotides, antagomirs,
gene vectors, mRNA, or siRNA are exciting novel drugs for manipulating gene
expression in a controlled, therapeutically useful way. Because of their physico-
chemical nature, medicinal nucleic acids cannot freely diffuse to the intracellular
target sites to exert their therapeutic function. Polymers have been developed as
carriers, which package nucleic acids and protect them against degradation. These
carriers specifically attach their nucleic acid cargo to cells via targeting ligands and
trigger intracellular uptake. They participate in intracellular delivery steps includ-
ing endosomal escape. Depending on the intracellular site of action, they may play
an important role in cytosolic migration, nuclear import, and subsequent presenta-
tion of the nucleic acid in active form. Ideally, polymers act in a bioresponsive way
to overcome the different delivery steps. Therapeutic developments with medicinal
nucleic acid polyplexes, including recent clinical trials, are discussed.
Keywords Gene transfer
Plasmid DNA
Polyplex
siRNA
Targeting
Contents
1 Introduction ................................................................................... 2
2 Functions Required Within Polyplexes for Overcoming Delivery Barriers . . ............. 3
2.1 Extracellular Transport ................................................................. 3
2.2 Cell Targeting and Intracellular Uptake . .............................................. 4
2.3 Intracellular Transport . . . . . . . . ......................................................... 7
3 Polymer Design for Bioresponsive Activity ................................................. 9
3.1 Bioresponsive Polyplex Shielding . . . .................................................. 10
3.2 Bioresponsive Lipid Bilayer Interaction .............................................. 12
3.3 Bioresponsive Polyplex Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
E. Wagner
Pharmaceutical Biotechnology, Center for System-based Drug Research, and Center for
Nanoscience, LMU University of Munich, Butenandtstrasse 5-13, 81377 Munich, Germany
e-mail:
ernst.wagner@cup.uni-muenchen.de
