Folic Acid-Modified Nanoerythrocyte for Codelivery of Paclitaxel and Tariquidar to Overcome Breast Cancer Multidrug Resistance.
2020
The efflux of anticancer
agents mediated by P-glycoprotein (P-gp)
is one of the main causes of multidrug resistance (MDR) and eventually
leads to chemotherapy failure. To overcome this problem, the delivery
of anticancer agents in combination with a P-gp inhibitor using nanocarrier
systems is considered an effective strategy. On the basis of the physiological
compatibility and excellent drug loading ability of erythrocytes,
we hypothesized that nanoerythrocytes could be used for the codelivery
of an anticancer agent and a P-gp inhibitor to overcome MDR in breast
cancer. Herein, a folic acid-modified nanoerythrocyte system (PTX/TQR
NPs@NanoRBC-PEG/FA) was prepared to simultaneously transport paclitaxel
and tariquidar, and the in vitro and in vivo characteristics of this
delivery system were evaluated through several experiments. The results
indicated that the average diameter and surface potential of this
nanocarrier system were 159.8 ± 1.4 nm and −10.98 mV,
respectively. Within 120 h, sustained release of paclitaxel was observed
in both pH 6.5 media and pH 7.4 media. Tariquidar release from this
nanocarrier suppressed the P-gp function of MCF-7/Taxol cells and
significantly increased the intracellular paclitaxel level (p < 0.01 versus the PTX group). The results of the MTT
assay indicated that the simultaneous transportation of paclitaxel
and tariquidar could significantly inhibit the growth of MCF-7 cells
or MCF-7/Taxol cells. After 48 h of incubation with PTX/TQR NPs@NanoRBC-PEG/FA,
the viability of MCF-7 cells and MCF-7/Taxol cells decreased to 7.37%
and 30.2%, respectively, and the IC50 values were 2.49
μM and 6.30 μM. Pharmacokinetic results illustrated that,
compared with free paclitaxel, all test paclitaxel nanoformulations
prolonged the drug release time and showed similar plasma concentration–time
profiles. The peak concentration (Cmax), area under the curve (AUC0–∞), and half-life
(t1/2) of PTX/TQR NPs@NanoRBC-PEG/FA were
3.33 mg/L, 6.02 mg/L·h, and 5.84 h, respectively. Moreover, this
active targeting nanocarrier dramatically increased the paclitaxel
level in tumor tissues. Furthermore, compared with those of the other
paclitaxel formulations, the cellular reactive oxygen species (ROS)
and malondialdehyde (MDA) levels of the PTX/TQR NPs@NanoRBC-PEG/FA
group increased by 1.38-fold (p < 0.01) and 1.36-fold
(p < 0.01), respectively, and the activities of
superoxide dismutase (SOD) and catalase (CAT) decreased to 67.8% (p < 0.01) and 65.4% (p < 0.001),
respectively. More importantly, in vivo antitumor efficacy results
proved that the PTX/TQR NPs@NanoRBC-PEG/FA group exerted an outstanding
tumor inhibition effect with no marked body weight loss and fewer
adverse effects. In conclusion, by utilizing the inherent and advantageous
properties of erythrocytes and surface modification strategies, this
biomimetic targeted drug delivery system provides a promising platform
for the codelivery of an anticancer agent and a P-gp inhibitor to
treat MDR in breast cancer.
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