Biomedical Engineering Reference
In-Depth Information
efficiency decreased when the degree of PEG-RGD grafting onto PEI was further
increased [
127
]. RGD-PEG-PEI conjugates have been successfully used for sys-
temic anti-angiogenic siRNA therapy [
129
]. Repeated intravenous administration
into neuroblastoma-bearing mice resulted in sequence-specific inhibition of tumor
growth. Analogously, RGD-PEG grafting to a defined, oligomerizable lipopolymer
(named EHCO) was applied for systemic targeted delivery of an anti-HIF-1
a
siRNA. The treatment was effective in specific silencing of HIF-1
a
gene expression
and blocking tumor growth in mice [
130
].
The NGR peptide, which shows high affinity for aminopeptidase N (CD13), has
been investigated as a peptide for targeting angiogenic tumor blood vessels. CD13-
targeted PEG-PEI/pDNA polyplexes displayed enhanced transgene expression
at the tumor site. When applied to p53 gene transfer, the polyplexes showed
encouraging antitumoral efficacy, such as significant regressions of lung carcinoma
and improved survival of treated mice [
131
,
132
].
Cell targeting has also been applied in several tissues besides tumors. Hepato-
cyte targeting has been pioneered by Wu and Wu [
133
-
135
], using asialo-
orosomucoid as a liver-specific targeting ligand conjugated with PLL. As the
asialoglycoprotein receptor recognizes trimeric galactoside with high affinity,
many synthetic carbohydrate targeting ligands have been subsequently tested,
with encouraging effects for pDNA and siRNA delivery in vitro and in vivo
[
56
,
136
-
140
].
Both Tf and lactoferrin (Lf) have been evaluated for brain-targeted delivery of
PAMAM-PEG polyplexes [
103
,
141
]. Anti-TfR antibodies had been previously
extensively investigated for liposomal brain targeting. In a direct comparison of
PAMAM-PEG/pDNA polyplex delivery, Lf-targeting was found to be more effec-
tive than Tf-targeting, resulting in more than twofold higher brain accumulation
and gene expression [
141
]. Repeated systemic injections of Lf-modified pDNA
polyplexes delivering the glial cell line-derived neurotropic factor (GDNF) gene
provided effective neuroprotection in a rat brain lesion Parkinson model [
142
].
Various targeting ligands have been tested for pDNA delivery to the lung.
The receptor-mediated endocytosis pathway of airway epithelial polymeric immu-
noglobulin receptor was utilized for in vivo intravenous targeted delivery of
PLL-Fab conjugate/pDNA polyplexes [
143
]. Peptide-PLL conjugates targeting
the serpin-enzyme complex receptor at the apical side of the airway epithelium
was successfully used for topical delivery of CFTR-expressing pDNA [
144
,
145
].
Lf receptors are present at high levels on bronchial epithelial cells but not alveolar
epithelial cells. Consistently, only in this cell type do Lf-PEI conjugates mediate
enhanced gene expression levels as compared to PEI polyplexes [
146
]. Conversely,
insulin receptors are expressed on alveolar but not bronchial epithelial cells. pDNA/
PEI polyplexes coated with insulin increased gene transfer to alveolar epithelial
cells up to 16-fold [
147
].
Also, small chemical drugs such as clenbuterol, an agonist specifically binding
the
b
2-adrenoceptor (
b
2-AR) [
148
], or prostaglandin I2 analogs iloprost and
treprostinil, targeting the prostacyclin receptor IP1 [
149
], have been coupled to
PEI and successfully applied for improved receptor-mediated gene transfer of
