The Potential and Current Progress of Internalizing Molecules in Targeted Drug Delivery - Intracellular Delivery: Fundamentals and Applications - page 105

therapeutic efficacy of the drugs in tumor cells (Heidel et al. 2007 ; Davis 2009 ).
One group developed a Tf-conjugated cyclodextrin-containing polycation delivery
system for siRNAs, which resulted in 50% greater gene silencing in the tumor versus
a non-targeted delivery system in an immunodeficient mouse model (Bartlett et al.
2007 ). Most recently, the same group conducted the first in-human phase
I clinical trial using a Tf-targeted nanoparticle delivery system and their work pro-
vided direct evidence of intercellular delivery of the siRNA which triggered the
RNA interference mechanism (Davis et al. 2010 ).
Since the brain capillaries are specifically known to express TfR, Tf-conjugated
nanocarriers were also successfully applied for brain targeting (Chang et al. 2009 ).
For example, Tf chemically conjugated to polyamidoamine (PAMAM) dendrimers
resulted in an increase in the brain uptake of the therapeutic DNA (Huang et al.
2007 ). In a similar study, Tf-coated PEG nanoparticles delivered an antiretroviral
agent (azidothymidine, AZT) across the blood-brain barrier to the central nervous
system (Mishra et al. 2006 ). Additionally, another glycoprotein lactoferrin, a globular
iron-binding protein, also could function as a lung and brain targeting molecule
(Elfinger et al. 2007 ). It is known that lactoferrin receptors are predominantly
expressed in brain capillaries and bronchial epithelial cells, thereby suggesting a
new target for brain delivery as well (Huang et al. 2008a ).

3.2.2 Epidermal Growth Factor (EGF)

The epidermal growth factor receptor (EGFR), the cell-surface receptor for members
of the EGF-family of extracellular protein ligands, is over-expressed in the majority
of human cancers (Muslimov 2008 ). EGF acts by high affinity binding to EGFR on
the cell surface thereby stimulating the intrinsic protein-tyrosine kinase activity of
the receptor (Agarwal et al. 2008 ). Through the formation of dimers EGF is endo-
cytosed into the cells after receptor-binding. Moreover, because EGF only has 53
amino acids and a molecular weight of ~6 kDa, it has been widely employed as an
internalizing ligand for tumor targeting. A number of such examples have been
reported in the literatures (Lee et al. 2003 ; Lee and Park 2002 ). For example, biotin-
modified EGF molecules were installed onto a Streptavidin-modified PEI com-
plexed plasmid DNA via the interaction of biotin-Streptavidin (Lee et al. 2002 ).
The resulting EGF-targeted PEI delivery system resulted in a significantly higher
transfection efficiency than non-targeted system in a human epidermal carcinoma
cell line. Recently, EGF was attached to single-wall carbon nanotubes (SWNTs)
loaded with cisplatin or quantum dots (QDs) and used for targeted therapy and
tumor imaging (Bhirde et al. 2009 ).

3.2.3 Apolipoprotein A-I

Apolipoprotein A-I (apo A-I) is a protein component of the high-density lipoprotein
(HDL) (von Eckardstein et al. 2001 ). It has been demonstrated that apo A-I can
predominantly be internalized to the liver via the cell-surface receptor scavenger