Manipulation of Leukocytes Using Therapeutic RNAi Delivered by Targeted and Stabilized Nanoparticles - Nanotechnology for the Delivery of Therapeutic Nucleic Acids - page 185

facilitated, without causing adverse effects such as the induction of
interferon, or liver and renal damage.

8.5 Cationic Nona-d-Arginine Peptide-

Complexed siRNA

Kumar [17] described a single-chain variable fragment (scFV)

form of anti-CD7 that was modified with cysteine at its C-terminus,
in order to enable its conjugation to the cationic nona-d-arginine
(9R) peptide for the targeted delivery of a negatively charged
siRNA payload into mouse T-cells

et al.

(Fig. 8.2F). This study
demonstrated the ability of an siRNA-based treatment to control
and suppress HIV replication, without inducing toxicity in target
cells. In another study [18], the 9R peptide fused to a dendritic cell-
targeting 12-mer peptide delivered siRNA targeting TNFa effectively

in vivo

in vivo , in order to suppress the production of TNFa by dendritic cells

upon induction in mice. Kim et al. [19] reported that TNFa-targeted

siRNAs, delivered to macrophages using a 9R peptide fused

to the ACh receptor-binding peptide, reduced LPS-induced TNFa
levels in the blood and brains of injected mice and led to a significant
reduction in neuronal apoptosis.
Despite the promising results obtained from such siRNA delivery
approaches, the whole spectrum of hematopoietic cells has not
been addressed. In addition, the low payload delivered with these
strategies might undermine their clinical efficacy. To overcome these
obstacles, a leukocyte cell-specific integrin-based approach using
I-tsNPs has been developed by Peer and colleagues (Fig. 8.2G) [8].

in vivo

8.6 I-tsNP as RNAi Delivery Vehicle for

Leukocyte-Associated Diseases

Integrins comprise the largest family of cell adhesion molecules,
mediating cell-to-cell and cell-to-extracellular matrix attachment.
These molecules are

α β

/ heterodimeric proteins and form at least

24 different heterodimers. Leukocyte integrins mediate the

adhesive interaction that is crucial for the migration of cells to sites
of inflammation. Antibodies targeting leukocyte integrins have been
used for the treatment of inflammatory disorders and function by

α

/

β