Biomedical Engineering Reference
In-Depth Information
132
(P-gp).
Since drug resistance is a key obstacle in the successful-
ness of chemotherapy, the main efforts in cancer research have
been devoted to find a proper strategy to tackle the P-gp function
by either down-regulating its expression or inhibiting its function.
One approach to overcoming multi-drug resistance (MDR) is to
utilize NPs to entrap the free drug and deliver it into the cytoplasm
or lysosome so that the drug cannot be effluxed out of the cancer
cell in a process mediated by P-gp. In order to overcome MDR,
N,N-distearyl-N-methyl-N-2-(N
-arginyl) aminoethyl ammonium
chloride (DSAA) has been used instead of DOTAP in LPD NPs.
DSAA is a cationic lipid, with both guanidinium and lysine residue
in its head group, that can inhibit P-gp activity and ultimately
increase drug accumulation. This mechanism has been confirmed
by incubating doxorubicin with either DSAA or other cationic
lipids with no guanidinium group. The lipids without guanidinium
moiety only slightly increase doxorubicin uptake, while DSAA
significantly enhances doxorubicin accumulation. The guanidinium
group of DSAA induces reactive oxygen species (ROS) by donating
an electron and also by down-regulating mitogen-activated protein
kinase (MAPK) signaling pathways, which results in the down-
regulation of the MDR transporter expression.
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In addition to its intrinsic therapeutic effect, DSAA can also
be utilized as a component of LPD NPs to co-deliver therapeutic
siRNA and small molecule drug. One may expect a synergistic
therapeutic effect from both drugs. Targeted LPD with DSAA, loaded
with both doxorubicin and VEGF siRNA, increases tumor uptake
and also suppresses tumor growth by overcoming P-gp mediated
drug resistance. However, non-targeted NPs containing DSAA or
targeted NPs with DOTAP have shown a reduced therapeutic effect,
compared to that of the targeted LPD containing DSAA with both
doxorubicin and VEGF siRNA. This suggests that the efficiency of the
therapeutic effects of the particles depends on both the lipid and the
ligand.
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Although DSAA showed a preeminent potential both as a
formulation component of a delivery carrier and as a therapeutic
agent that inhibited MDR expression, it still showed a limitation
in its use. The competent interaction of doxorubicin and cationic
lipid with therapeutic DNA caused a poor entrapment efficiency of
doxorubicin (only ~10%) in NPs. Low entrapment of doxorubicin
in NPs could be resolved by replacing the cationic lipid with the
anionic lipid, which allowed DNA to interact only with protamine
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