Biomedical Engineering Reference
In-Depth Information
(A)
(B)
(a)
(b)
2.5
µ
m
5.0
µ
m
(c)
(d)
7.5
µ
m
10.0
µ
m
(a)
(e)
(f)
12.5
µ
m
15.0
µ
m
(b)
FIGURE 6.5
(A) Confocal fl uorescence microscopy images of MCF-7 cells after 15 h
in vitro
exposure to
(a) fl uorescent paclitaxel-loaded PEG/PCL copolymeric nanoparticles and (b) fl uorescent paclitaxel-loaded
folate-conjugated PEG/PCL nanoparticles (
×
1000). (B) A series of representative lateral (
x-y
) confocal fl uo-
rescence microscopy images of MCF-7 cells incubated with fl uorescent paclitaxel-loaded folate-conjugated
PEG/PCL nanoparticles as a function of cell depth. (From Park, E.K., Kim, S.Y., Lee, S.B., and Lee, Y.M.
Journal of Controlled Release
109, 158-168, 2005.)
FR-overexpressing cancer cells. PLL-PEG-FOL coated PLGA nanoparticles demonstrated far
greater extent of cellular uptake to KB cells (A human epidermal carcinoma cell line; folate recep-
tor overexpressing cell line), suggesting that they were mainly taken up by FR-mediated endo-
cytosis. The enhanced cellular uptake was also observed even in the presence of serum proteins,
possibly due to the dense-seeded PEG chains [93]. Lee et al. developed folate ligand-coupled DSPE
using a PEG linker (folate-PE
2000
-DSPE) to deliver liposome-encapsulated doxorubicin epithelial
cancer cells that resulted in a 45-fold increased uptake of encapsulated doxorubicin compared with
nontargeted vesicles [42,94,95].
6.5.3.1.4
Hyaluronic Acid
Hyaluronic acid (HA), a negative polysaccharide containing two alternating units of d-glucuronic
acid and
N
-acetyl-d-glucosamine with a molecular weight of 10
5
-10
7
Da, is one of the major compo-
nents of extracellular matrix. HA is responsible for various functions within the extracellular matrix,
such as cell growth, differentiation, and migration. Various HA-binding receptors are known, such
as cell surface glycoprotein CD44, receptor for HA-mediated motility (RHAMM), HA receptor for
endocytosis (HARE), lymphatic vessel endocytic receptor (LYVE-1), and intracellular HA-binding
proteins including CDC37, RHAMM/IHABP, P-32, and IHABP4. HA levels are elevated in various
cancer cells (epithelial, ovarian, colon, stomach, and acute leukemia), resulting in enhanced binding
and internalization of HA [19].
Luo et al. used HA as a tumor-targeting moiety in a drug delivery system with
N
-(2-hydroxy-
propyl)methacrylamide (HPMA) polymer. HPMA-HA-doxorubicin bioconjugates with lysosome-
degradable peptide linkage showed enhanced internalization and cytotoxicity for the HBL-100
