Targeted Drug Delivery - Nanomaterials for Medical Applications - page 193

can be delivered specifically to the target cell or tissue when a ligand interacts with
its receptor which results in the delivery of large payloads of therapeutic agent
relative to number of ligand-binding sites. This is very advantageous in imaging
tumor through the increase in tumor signal to background ratio. Second, the nano-
carrier is attached to the ligand and the drug is loaded independent of the coupling
of ligands. This avoids compromising the drug activity that may result during for-
mation of the ligand-drug conjugate or inactivated by the potentially aggressive
coupling reaction. Third, a large number of ligand molecules can be attached to the
nanocarrier depending upon the size of the NM and the size of the drug to increase
the probability of binding to target cells especially for those with low binding
affinities. Fourth, active targeting enables efficient distribution of the carriers in
the tumor, thereby reducing the return of drug back to the circulation that may be
caused by high intratumoral pressure. Finally, when ligand is only attached to the
carrier due to the small size of the conjugate, it can only extravasate at the disease
site but not in normal vasculature, and as such, the ligand cannot interact with the
target epitopes of normal tissues avoiding side effects. Sethi et al. 75 exhibited that
VIP receptors of normal cells are not accessible after i.v. injection when VIP was
associated with a nanocarrier. This showed that specific targeting in nanocarriers
can play an important role in reducing toxicities of the drug.
The development of NP delivery systems for targeted drug delivery 10 can be
actively or passively achieved. In active targeting, the therapeutic agent is con-
jugated with the nanocarrier system that has targeting ligands to a tissue or cell-
specific ligand. 83 In passive targeting, the therapeutic agent is incorporated into
a macromolecule or NP that passively reaches the target organ. NP-encapsulated
drugs or drugs coupled to macromolecules can passively target tumors through
the enhanced permeation and retention (EPR) effect. Localized delivery of NPs
bearing drugs to sites of vascular restenosis may provide sustained drug release
at specific sites on the arterial wall. 84,85
5.5.1 Antibodies
Targeting in nano-enabled drug delivery systems is accomplished by labeling the
NP with receptors or biomolecules that specifically attach them to the target cells
or tissues ( Figure 5.4 ). The most common targeting molecules are antibodies ( Fig-
ure 5.5 B) against epithelial growth factor receptors, anti-epidermal growth factor
receptor (EGFR). Because EGFR is expressed in all epithelial cells, this molecule
is a special target when delivering drugs to epithelial cells. Human epithelial recep-
tors (HERs) are commonly overexpressed in a number of different cancer cells
and, therefore, is commonly targeted in nano-enabled targeted drug delivery. 55,56
The HER-2/neu (HER-2) oncogene is another closely related member of
the EGFR family that is known to be upregulated in different types of human
cancers including breast, ovarian, lung, gastric, and oral cancers. Increased
malignancy and poor survival of breast cancer patients have been associated
with upregulation of HER-2 that seems to impart chemoresistance upon the