Biomedical Engineering Reference
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attached to the liposome surface, creating targeting nanoparticles
(Fig. 8.2A). In addition, Huang and King [12] described nanoscale
liposomes coated with the adhesion molecule P-selectin. Another
efficient delivery approach makes use of the peptide transduc-
tion domain-dsRNA-binding domain (PTD-DRBD) fusion protein
(Fig. 8.2B). In this approach, the DRBD binds to the siRNA, thus
masking the negative charge of the molecules, while the PTD
mediates the cellular uptake of the complex [13]. Moreover, siRNAs
can also be delivered into leukocytes via conjugation to RNA
aptamers that bind to specific target molecules, such as glycoprotein
120 [14], without interfering with the binding of the siRNA to Dicer
(Fig. 8.2C). In addition to these strategies, other approaches have
also been demonstrated to deliver siRNAs into leukocytes efficiently
in vivo
and are discussed in the following sections.
8.3
CpG-Conjugated siRNA
Unmethylated CpG oligonucleotides (Fig. 8.2D) internalize
efficiently into dendritic cells, myeloid cells, and B-cells following
binding to TLR9. In a recent study by Kortylewski
[15], CpG
oligonucleotides were conjugated to an siRNA targeting the immune
suppressor gene
et al.
Stat3
. This conjugate was demonstrated to silence
Stat3
leading to the activation of tumor-associated dendritic
cells, macrophages, and B-cells that mediate potent antitumor
immune responses, and resulting in tumor cell apoptosis. However,
the siRNA in this conjugate was unmodified and negatively charged,
reducing its half-life and limiting the therapeutic effect.
in mice,
8.4
Atelocollagen-Complexed siRNA
Atelocollagen is a type I collagen from calf dermis that does not
cause antigenicity or toxicity in animals, as a result of pepsin
digestion of the antigenic telopeptides. The positively charged lysine
and hydroxylysine residues, which are rich in collagen, are thought
to mediate the formation of the atelocollagen-siRNA complex.
Ishimoto
[16] showed that when siRNAs were administrated
intravenously with atelocollagen (Fig. 8.2E), the incorporation of the
siRNAs into murine macrophages, monocytes, and fibroblasts was
et al.
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