Biomedical Engineering Reference
In-Depth Information
Extracellular space
(pH 7.4)
Cancer cell surface
Internalization
Ferrous iron transporter
(DMT1)
Clathrin-
coated pit
Membrane fusion
H+
H+
Early endosomes
Recycling endosomes
H+
H+
H+
H+
H+
H+
H+
Transferrin receptor
Fe
2
-transferrin
Linker
Intracelluar active agents
Acidified endosomes
(pH 5.5)
Endosomal release
Fe
3+
Fe
3+
FIGURE 6.4
The cellular uptake pathway of Tf-conjugated nanoparticles through TfR-mediated
endocytosis.
6.5.3.1.3
Folate
Folic acid (folate) has become an attractive candidate molecule for targeting cancer cells because it is
an essential vitamin for the biosynthesis of nucleotide bases and is consumed in elevated quantities
by proliferating cells [89-92]. The folate receptor (FR) is overexpressed in many human cancers,
including ovary, brain, kidney, breast, myeloid cells, and lung malignancies. The attractiveness of
folate has been further enhanced by the high binding affi nity (
K
d
≈
10
−
10
M), low immunogenicity,
441.4), storage stability, compatibility with a variety of
organic and aqueous solvents, and low cost [19,89-92]. Although the precise mechanism of FR
transport into the cells remains unresolved, it is clear that nondestructive folate uptake by mam-
malian cells occurs via receptor-mediated endocytosis [89].
Lee et al. developed the folate-conjugated, block copolymer nanoparticles composed of PEG and
PCL and demonstrated that paclitaxel-loaded, folate-conjugated PEG/PCL nanoparticles exhibited
much higher cytotoxicity for cancer cells, such as MCF-7 and HeLa cells, than nanoparticles without
the folate group [91,92]. Moreover, Figure 6.5 shows confocal microscopy measurements revealing
that as a consequence of FR-mediated endocytosis, folate-conjugated nanoparticles were selectively
taken up by MCF-7 cells [92]. FR-mediated uptake of PEG disastearoyl phosphatidylethanolamine
(DSPE) liposomes (70-100 nm) loaded with doxorubicin resulted in increased cytosol uptake
and release of doxorubicin into the cytoplasm. The drug was released within 2 h
in vivo
in M109-
HiFR multidrug-resistant cancer cells. Folate-targeted liposome drug uptake was increased 10-fold
compared with free doxorubicin and was more toxic
in vivo
than free doxorubicin [2].
Park et al. investigated that poly(d,l-lactide-
co
-glycolic acid) (PLGA) nanoparticles with
anionic surface charge were surface coated with cationic diblock copolymer (poly[l-lysine]-PEG-
folate [PLL-PEG-FOL]) conjugate, for enhancing their site-specifi c intracellular delivery against
ease of modifi cation, small size (
M
w
=
