Biomedical Engineering Reference
In-Depth Information
(breast) cell line compared to nontargeting conjugates, while the systemic toxicity of HPMA-HA-
doxorubicin bioconjugates in primary murine fi broblasts was very low [96].
Eliaz et al. developed liposomes containing HA and doxoribicin as a tumor targeting drug
delivery system. They demonstrated that the binding affi n it y of l liposomes is at t r ibuted to t he spe cii c
CD44-HA interaction, and the degree of HA-liposome uptake by murine melanoma B16F10 tumor
cell line was proportional to the loading of HA. The HA-liposomes exhibited almost selective
tumor targeting and cytotoxicity [97].
6.5.3.2
Inhibition of Angiogenesis
Angiogenesis, the formation of new capillaries from pre-existing vessels, is essential for tumor
progression. Antiangiogenic therapy has proven to be a promising concept by eliminating new tumor
vasculature with the destruction of microvasculature. The differentially expressed endothelial cell
surface markers in angiogenic tumor vessels should be excellent targets for site-specifi c therapy
[98]. These molecules regulate the proliferative and invasive activity of the endothelial cells that
line blood vessels. Some examples of therapeutic strategies include limiting endothelial proliferation
and motility, increasing expression of angiogenesis inhibitors, and decreasing the amount of angio-
genesis stimulatory factors at the tumor sites. Some of the most prominent angiogenesis stimulatory
molecules include vascular endothelial growth factor (VEGF), basic fi broblast growth factor, platelet-
derived growth factor, and certain matrix metalloproteinases. Some endogenous angiogenesis
inhibitors are the interferon family (α, β, and γ), thrombospondin-1 and -2, certain tissue inhibitors
of matrix metalloproteinases, and protein fragments such as angiostatin and endostatin [13,98].
For example, streptavidin-coated fl uorescent polystyrene nanoparticles (Fluospheres and Trans-
F fl u o s p h e r e s) we r e u s e d fl in s fl in g fl e c o fl o r fl ow cytometry to detect the epidermal growth receptor (EGFR)
on A431 human epidermoid carcinoma cells. The results showed that the fl uorescent nanoparticles
provided a sensitivity 25-fold greater than the conjugate streptavidin-fl uorescein [28].
Integrin α
V
β
3
is a molecular target for many solid tumors that is highly expressed in angiogenic
endothelial cells. Various α
V
β
3
-targeted therapeutic systems have shown remarkable
in vitro
and
in vivo
success [99]. Gao reported the development of multifunctional polymeric micelles with
cancer-targeting capability via α
V
β
3
integrins. Doxorubicin and a cluster of superparamagnetic
iron oxide (SPIO) nanoparticles were loaded successfully inside the micelle core. The presence
of cRGD on the micelle surface resulted in the cancer-targeted delivery to α
V
β
3
-expressing tumor
cells.
In vitro
MRI and cytotoxicity studies demonstrated the ultrasensitive MRI imaging and
α
V
β
3
-specii c cytotoxicity response of these multifunctional polymeric micelles [34].
6.5.3.3 Vascular Targeting
Unlike the inhibition of angiogenesis, which aims at preventing the growth of new blood vessels,
vascular targeting aims at the rapid and selective shutdown and/or damage of the established tumor
vasculature, leading to secondary tumor cell death. This strategy shows potential advantages
compared with the direct attack of tumor cells [100-102]. It has been known that the endothelium
and surrounding stroma in tumors differ from normal tissues. The blood fl ow through the tumor
capillaries is often sluggish due to the disorganized and tortuous tumor vasculature compared
with the vasculature in normal organs [103]. The endothelial cell has been shown to respond
transcriptionally to all these stimuli, giving rise to the production of new proteins on its surface
or surrounding extracellular matrix. Some of these specifi c markers found either directly on the
endothelial cells or secreted into the stroma surrounding the blood vessels could be used as targets
for vascular targeting approaches [100].
The fi rst vascular targeting was approved by the FDA in 1999 for the treatment of age-related
macular degeneration. In 2003, clinical trials with antiangiogenesis drug Avastin (Genentech)
showed prolonged survival of patients with metastatic colorectal cancer. Hood et al. investigated
