Biomedical Engineering Reference
In-Depth Information
Tumor-specific
receptor
Ligand for
targeting
Tumor
cell
Anticancer
drug
Normal
cell
Nanoparticulate
drug carrier
FIGURE 6.2
Schematic representation of ligand-mediated nanoparticulate system for tumor-targeted drug
delivery.
(1) defi ne valid targets as markers of disease-associated cells; (2) develop and validate the necessary
chemistry to conjugate drugs to cell-selective vectors; (3) release drugs from the vectors at the right
place and time; (4) resist hydrostatic, hydrophilic or hydrophobic, and biophysical or biochemical
barriers; (5) overcome cellular resistance to treatment; and (6) resist biotransformation, degrada-
tion, and clearance mechanisms [14-18,20]. Active targeting is expected to lead to higher intratu-
moral accumulation and, in the case of targeting with internalizing ligands, to higher intracellular
concentrations of the drug (Figure 6.2).
Targets that are employed to achieve tumor-selective localization of particulate drug carriers can
be broadly divided into two classes: (1) targets that are overexpressed on tumor cells and (2) targets
that are preferentially expressed on endothelial cells of tumor blood vessels [13]. These targets
include monoclonal antibody (mAb) immunoconjugates and metabolism-based therapies that seek
to exploit increased tumor expression of, for example, proteases, low-density lipoprotein receptors,
hormones, and adhesion molecules [14-21]. This review covers the fundamentals of active targeting
of particulate drug carriers in tumor therapy, as well as the most recent progress in this fi eld.
6.5.3.1 Tumor-Specifi c Targeting
Nanoparticle functionalization with targeting agents that bind to tumor cell membrane receptors
such as ligands or antibodies facilitate specifi c and increased uptake into the target cells through
receptor-medicated endocytosis, increasing
in vivo
drug specifi city [2,14-21] (Figure 6.3). These
systems would ideally be dependent on interactions with cells found specifi cally on the surface of
cancerous cells and not on healthy cells.
6.5.3.1.1 Antibodies
A great amount of work has been done with antibodies to target drugs to specifi c cells, especially
for cancer therapy. Theoretically, targeting with antibodies is ideal because antibody-antigen
interactions are very specifi c [48]. There are basically three types of antigens that can be used
as targeting moieties for antibodies: organotypic antigens, tumor-associated antigens (TAAs),
and tumor-specifi c antigens. Organotypic antigens would restrict the uptake of the drug-antigen
conjugates to one cell type; however, it would not restrict the uptake to the tumor cell. TAAs are
present on the surface of embryonic cells and reappear in the course of malignant transformations
or exist in small amounts on normal cells and in large amounts on tumor cells [48].
