The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 106

receptor BI (SR-BI) (Kim et al. 2007 ). As a typical serum protein, apo A-I
functions as a beneficial factor to decrease cholesterol levels and therefore should
not trigger immunological side effects in clinical applications. Thus, apo A-I can be
used as an internalizing moiety for liver targeting. A proof-of-concept study has
shown the potential of apo A-I for the systemic delivery of nucleic acids to the liver
using real-time in vivo imaging (Kim et al. 2007 ). Apo A-I was formulated onto the
surface of the lipid bilayer of a representative cationic liposome and facilitated the
hepatocyte-specific siRNA delivery via receptor-mediated endocytosis. The Apo
A-I-coating liposome carrying an anti-hepatitis B virus (HBV) siRNA showed a
prolonged inhibition of the target protein expression at low doses in a mouse model.
A subsequent study further evaluated the efficacy of an apo A-I - mediated liver-
specific delivery of an siRNA against hepatitis C virus (HCV) in a transient HCV
model (Kim et al. 2009b ). The results of this study showed Apo-liposome nanopar-
ticles systemically delivered an siRNA into mouse hepatocytes expressing HCV
resulting in siRNA mediated inhibition of the targeted HCV protein expression.

3.3 Peptide-Mediated Drug Delivery

3.3.1 RGD Peptide

Peptides based on the three-amino-acid sequence arginine-glycine-aspartate, known
as RGD peptides have been used extensively as tumor cell-recognizable ligands in
tumor diagnostics and therapeutics (Ruoslahti 2003 ). The RGD sequence, originally
identified as a cell binding site in the extracellular matrix (ECM) protein (fibronectin
and vitronectin), can bind to the integrin receptor a n b 3 with high affinity (Cheresh
1987 ). Since the integrins are specifically over-expressed at the surface of tumor
cells and angiogenic endothelial cells at the tumor site, RDG-mediated drug delivery
generally leads to high levels of accumulation in tumor tissues compared with free
drug or non-targeted drug delivery systems. Both linear RGD and cyclic RGD have
been popularly applied for targeted delivery of traditional drugs, genes and polymers.
For example, a dimeric RGD peptide was conjugated to an oligonucleotide (ON),
thereby increasing cellular uptake and the biological function of the ON (Alam et al.
2010 ; Alam et al. 2008 ). Additionally, Dai et al. chemically conjugated a cyclic
RGD peptide to the terminal group in a phospholipid - single-walled carbon nano-
tube (PL-SWNT), which resulted in enhanced and specific delivery of doxorubicin
(Dox) to RGD positive U87 cancer cells (Liu et al. 2007a ).
Recently, Ruoslahti and colleagues identified a cyclic peptide iRGD
(CRGDKGPDC and its related variants), which can target tumor cells by binding
a n integrins that are specifically expressed in the tumor vessel endothelium
(Sugahara et al. 2009 ). They combined the tumor-homing RGD sequence with
another peptide ligand (the CendR motif) for neuropilin-1 (NRP1, a transmembrane
receptor) that mediates penetration into tissue and cells. The resulting peptide-
mediated delivery system (iRGD) was first recruited to tumor tissue through the