Biomedical Engineering Reference
In-Depth Information
For example, although some of upregulated targeting receptors such as folate
and transferrin receptors correlate with metabolic rates and are overexpressed
in various tumors, they are also expressed in fast-growing healthy cells such as
some fibroblasts and epithelial cells.
50,51
This can lead to nonspecific targeting
and increase toxicity in healthy tissues. More specifically, folate receptor-
targeted liposomes have been extensively studied in cancer therapy.
52
While in
vitro studies showed encouraging results, demonstrating that drugs delivered
via folate receptor-targeted liposomes were rapidly internalized in cancer cells,
the in vivo performance of these agents did not show much improved
therapeutic efficacy in terms of prolonged survival.
53
In another example, PK2
is a polyHPMA-Gly-Phe-Leu-Gly-doxorubicin conjugate that contains the
sugar galactosamine and which was used to target the asialoglycoprotein
receptor (ASGPR) expressed on hepatomas. However, since ASGPR is also
expressed on healthy hepatocytes, the targeted nanomedicines also nonspeci-
fically accumulated in normal liver cells.
54
In addition to receptor expression levels, the density of the receptors and the
strength of the noncovalent interactions between targeting ligands and
receptors are also important in achieving specific cell targeting. Park et al.
found that a receptor density of 10
5
ERBB2 receptors per cell was necessary
for an improved therapeutic effect of anti-ERBB2-targeted liposomal
doxorubicin over nontargeted liposomal doxorubicin in a metastatic breast
cancer model.
55
The targeting ligands on the nanomedicine surface need to
engage in molecular interactions with receptors at a strength of 50-300
piconewtons (pN) and a density of y500 cm
22
.
19,56,57
Once attached on the
cell surface, the target molecules are rapidly saturated, and their turnover time
is typically about 20 minutes. To enhance binding avidity, multivalent binding
provides an effective strategy to increase nanoparticle targeting to the cancer
cells. The cooperative binding from multivalent interactions is much stronger
than monovalent interactions. For example, dendrimer nanocarriers con-
jugated with an average of five folate molecules showed a 2,500- to 170,000-
fold enhancement in dissociation constants (K
d
) over free folate when
attaching to folate-binding proteins immobilized on a surface.
19
Despite the
increased binding avidity, it should be cautioned that polyvalent interactions
from ligands on the nanoparticle surface may affect the receptor recycling
efficiency during endocytosis. In some cases, nanoparticle binding will change
receptors from recycling to the cell surface to lysosomal degradation, which
will limit their availability for further cargo internalization.
47
For solid tumors,
though higher binding affinity can increase targeting efficacy, this can also
reduce penetration of nanocarriers due to a ''binding-site barrier'', where the
nanocarrier binds to its target so strongly that penetration into the tissue is
hampered.
58
In several cancer-targeting nanomedicine formulations, the linkers between
targeting ligands and drug carriers employ peptidase cleavable or acid labile
bonds.
59
Nonspecific cleavage of the linkers may lead to the loss of the
targeting moiety and thus influence the performance of the active targeting
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