Biomedical Engineering Reference
In-Depth Information
4 Therapeutic Strategies ........................................................................ 14
4.1 Ex Vivo and Localized Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.2 Systemic Therapies ..................................................................... 15
5 Conclusions ................................................................................... 17
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1
Introduction
Polymers can be designed in non-immunogenic and biocompatible form, incor-
porating different physicochemical properties and attachment sites for (covalent or
noncovalent) modification. In theory, they are an excellent drug carrier platform for
targeted, repeated drug applications resulting in long-lasting therapeutic effects [
1
].
Medicinal nucleic acids present a novel class of drugs with exciting possibilities.
From the functional perspective, at least three subcategories can be defined. The
first category induces gene expression in a sequence-derived way; plasmid DNA
(pDNA) expression vectors [
2
-
8
], natural or chemically modified messenger RNA
(mRNA) [
9
,
10
], exon-skipping oligonucleotides [
11
], and microRNA antagonists
(antagomirs) [
12
,
13
] belong to this category. The second category triggers shut-
down of gene expression and includes antisense oligonucleotides [
14
,
15
], synthetic
short interfering RNA (siRNA) [
16
-
23
] and microRNA [
24
], ribozymes [
25
], and
DNA decoys [
26
]. In the third category, medicinal nucleic acids may act by direct
interaction with proteins in form of RNA or DNA aptamers [
27
,
28
], or immune-
stimulating and apoptosis-inducing RNA [
29
-
31
]. Targeted delivery is the major
bottleneck in the further development of such medicinal nucleic acids.
In the field of polymer-enhanced nucleic acid therapy, the road towards wide-
spread clinical use is still filled with many obstacles and challenges, despite signi-
ficant improvements in polymer-based carriers over the last three decades [
32
-
35
].
The major challenges include the following:
1. Precise chemical synthesis and analysis of polymers, which are macromolecular
structures more complex than small chemical molecules
2. Controlled supramolecular assembly of polymeric carriers with the nucleic acid
into uniform nanoparticles
3. Better understanding of the mechanisms and alternative pathways required for
further optimization of extracellular and intracellular targeted delivery of medic-
inal nucleic acids.
This chapter reviews the main delivery barriers for medicinal nucleic acids and the
strategies to overcome these barriers by using functionalized polymer conjugates
(Sect.
2
). Chemical strategies will be presented to illustrate how polymers can be
designed to be bioresponsive (Sect.
3
). The advantages of such dynamic polymer
systems responding to the biological microenvironment of the various delivery steps
will be discussed. Current therapeutic strategies using medicinal nucleic acids in
preclinical and clinical setting will be presented (Sect.
4
).
