A Novel Nanomedicine System TAR-AuNSs/Dox for the Treatment of Drug-Resistant Lymphoma

Ouyang, Shujuan; Tang, Youqun; Cao, Yanming

doi:https://doi.org/10.1155/2022/5084672

Journal of Nanomaterials

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Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Conflicts of Interest Acknowledgments References Copyright Related Articles

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Nanomaterials for Medical Diagnosis and Treatment

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Research Article | Open Access

Volume 2022 | Article ID 5084672 | https://doi.org/10.1155/2022/5084672

A Novel Nanomedicine System TAR-AuNSs/Dox for the Treatment of Drug-Resistant Lymphoma

Shujuan Ouyang,¹Youqun Tang,²and Yanming Cao²

Academic Editor: Haseeb A. Khan

Received16 Sept 2021

Revised21 Mar 2022

Accepted25 Mar 2022

Published13 Apr 2022

Abstract

Lymphoma is one of the most common malignancies of blood system, and drug resistance is an important cause of treatment failure. Multidrug resistance gene P-glycoprotein (P-gp) plays an important role in lymphoma chemotherapeutic drug resistance. Our previous studies have found that P-gp is highly expressed in doxorubicin-resistant lymphoma cells (Daudi/R). With the development of nanotechnology, a large number of nanomaterials have been applied in various biomedical fields. Therefore, in this study, P-gp inhibitor tariquidar (TAR) and chemotherapy drug doxorubicin were loaded onto gold nanoshells (AuNSs) to construct TAR-AuNSs/Dox nanodrug system. TAR and Dox were slowly released from TAR-AuNSs/Dox in an acidic tumor microenvironment. TAR-AuNSs/Dox increased the uptake of Dox by drug-resistant lymphoma cells and inhibited P-gp expression to reduce Dox pumping. Compared to the free Dox, TAR-AuNSs/Dox had a stronger killing effect on Daudi/R cells, which provided a new therapeutic strategy for the treatment of drug-resistant lymphoma.

1. Introduction

Lymphoma is a group of heterogeneous neoplastic diseases originating from a single mutated lymphocyte [1]. At present, chemotherapy and radiotherapy are the traditional therapeutic strategies for lymphoma [2, 3]. Despite the great progress in diagnosis and treatments for lymphoma, the patients still have a poor prognosis and a short survival [4]. In particular, chemotherapeutic drug resistance is one of the main causes of treatment failure [5, 6]. As a result, it is urgent to search for novel treatment methods to overcome lymphoma resistance.

Numerous studies have focused on the mechanism of tumor drug resistance for decades, and several proteins associated with multiple drug resistance (MDR) were found, including MDR protein, P-glycoprotein (P-gp), and lung cancer resistance-related protein [7, 8]. Especially, P-gp can bind to both drugs and ATPs, and ATPs provide energy to pump intracellular drugs out of the cell, reducing intracellular drug concentration and causing the cell to develop drug resistance [9, 10]. Therefore, inhibition of P-gp expression can resensitize drug-resistant tumor cells by inhibiting drug efflux, which improves the success rate of chemotherapy [11, 12].

Doxorubicin (Dox) is a common tumor chemotherapy drug, which kills cancer cells by inhibiting DNA transcription and replication [13]. However, the clinical application of Dox is limited due to its poor targeting, strong toxic and side effects, and drug resistance [14, 15]. When oxygen supply is insufficient, tumor cells produce a large amount of lactic acid and carbon dioxide through glycolysis, which contributes to the acidic tumor microenvironment, with a pH usually in the range of 6.5-6.8 [16]. Therefore, it is of great significance to design a system that can overcome tumor drug resistance, target tumor site, and effectively release drugs in the acidic tumor microenvironment.

Recently, with the development of nanotechnology, nanodrug carriers have been widely used in tumor treatment research [17]. Compared with other nanoparticles, gold nanoshells have the following advantages: (1) the core is inert and nontoxic; (2) it is easy to prepare, and its particle size can be controlled by adjusting the preparation conditions; and (3) its surface can be modified by a variety of functional groups. By forming N-Au, -COO-Au, and S-Au bonds, drugs can be stably bonded on the surface of gold nanoparticles [18]. Therefore, gold nanoparticle shells are selected as drug carriers under comprehensive consideration. It is worth noting that tariquidar (TAR) is a potent and specific inhibitor of P-glycoprotein (P-gp) with the high affinity [19]. Patil et al. found that TAR improved the therapeutic effect of paclitaxel resistance tumors via inhibiting P-gp expression [20]. Thus, in this study, Dox and TAR were loaded in gold nanoparticle shells to produce TAR-AuNSs/Dox, and then, characterization and antitumor effect of TAR-AuNSs/Dox were explored.

2. Materials and Methods

2.1. Preparation and Characterization of TAR-AuNSs/Dox

TAR (5 mg, Selleck, China) was dissolved in 0.5 ml DMSO (Solarbio, China) and slowly added to 5 ml AuNSs (nanoComposix, USA, 1 mg/ml, including EDC/NHS 0.4 mg/0.6 mg), followed by stirring slowly in the dark for 4 h. TAR-AuNSs were obtained by centrifugation and washing. DOX (5 mg/ml, Aladdin, China) was dissolved in 0.5 ml DMSO, added to 5 ml TAR-AuNSs (1 mg/ml) drop by drop, and stirred slowly in darkness for 24 h. TAR-AuNSs/DOX were obtained by centrifugation and washing. Morphological characteristics and dimensions of TAR-AuNSs/Dox were observed by TEM (HT7800, Hitachi, Japan). Zeta potential and hydrodynamic dimensions of TAR-AuNSs/Dox were detected by Zetasizer Nano Z (Malvern, UK).

2.2. Drug Loading Capacity (LC) and Encapsulation Efficiency (EE)

The concentration of Dox and TAR in TAR-AuNSs/Dox was determined by an ultraviolet-visible spectrophotometer. The characteristic absorption peak of Dox and TAR was 480 nm and 264 nm. The formulas for LC and EE of TAR-AuNSs/Dox are as follows:

2.3. Drug Release Experiment In Vitro

Dox and TAR released from AuNSs/Dox and TAR-AuNSs/Dox were tested at different pH values. In short, 0.5 ml AuNSs/Dox and TAR-AuNSs/Dox were added into dialysis bags (10 kDa), immersed in PBS buffers (50 ml, pH 7.4 and 6.5), and stirred at 37°C away from light. After 0.5 h, 1 h, 2 h, 4 h, 6 h, 9 h, 12 h, and 24 h, 0.5 ml dialysate was taken and measured by a UV-vis spectrophotometer. Considering the limited solubility of Dox and TAR in water, the buffer was replaced at 2 h, 6 h, and 12 h, respectively.

2.4. CCK8 Assay

Human lymphoma cell lines Daudi and drug-resistant cell lines Daudi/R were obtained from Beinuo (Shanghai, China) and cultured in DMEM (Gibco, USA) culture containing 10% fetal bovine serum (Gibco, USA) at 37°C and 5% CO₂. To assess the toxicity of AuNSs, Daudi and Daudi/R cells were cultured in 96-well plates with AuNSs (10 to 500 μg/ml) for 24 h. After that, each well was added with 10 μl CCK8 solution for further incubation for 4 h, and the absorbance of each well at 450 nm was measured with a micrometer, and the survival rate of cells was calculated. In addition, different concentrations of Dox, AuNSs/Dox, and TAR-AuNSs/Dox were incubated for 24 h, and cell activity was determined via CCK8 assay.

2.5. The Uptake of TAR-AuNSs/Dox In Vitro

Daudi/R cells were cultured in 6-well plates for 24 h. Dox, AuNSs/Dox, and TAR-AuNSs/Dox (Dox, 10 g/ml) were added and incubated for 30 min and 1 h, respectively. After washing with PBS, the intensity of Dox red fluorescence in cells was observed by a fluorescence microscope (Nikon, Japan).

2.6. TUNEL Assay

Apoptotic cells were detected with an in situ cell death detection kit (Roche, Germany). Daudi/R cells were first cultured in a 12-well plate for 24 h, followed by PBS, Dox, AuNSs/Dox, and TAR-AuNSs/Dox for 24 h, fixed with 4% paraformaldehyde and 0.1% Triton X-100 for permeable culture. Finally, the cells were incubated with a TUNEL reaction mixture (terminal deoxynucleotide transferase and TMR red-labeled nucleotide) and imaged by a fluorescence microscope (Nikon, Japan).

2.7. PCR Assay

Trizol (Invitrogen) was used to extract total RNA from Daudi and Daudi/R cells, and cDNA was obtained by reverse transcription using SuperScript IV Kit (ThermoFisher, USA). PCR was performed by Invitrogen Platinum II (ThermoFisher, USA). The PCR products were electrophoresed by agarose gel, added fluorescent dyes, and imaged under UV light.

2.8. Western Blotting

The cells were lysed with RIPA lysate (Beyotime, China); total protein was extracted and quantified with BCA kit (Beyotime, China). After SDS-PAGE electrophoresis, the protein was transferred to PVDF membrane by electricity and then added into 5% skim milk for 2 h. P-gp (Abcam, USA) and β-actin antibody (Beyotime, China) were incubated overnight. After washing, it was then incubated with secondary antibody for 2 h, and imaging was performed with enhanced chemiluminescence (ECL, Beyotime, USA).

2.9. The Antitumor Effect of TAR-AuNSs/Dox In Vivo

BALB/C nude mice were obtained from SJA laboratory animal Co., Ltd (Hunan, China). Animal experiments have been approved by the Animal Ethics Committee of Central South University. Daudi/R cells were cultured and transplanted subcutaneously in nude mice, and subsequent experiments were conducted when the tumor volume reached 100 mm³. PBS, Dox, AuNSs/Dox, and TAR-AuNSs/Dox (Dox, 10 mg/kg,) were injected through the tail vein. Body weight and tumor volume were measured for 18 days. On the 18th day, the mice were anesthetized and sacrificed; the blood was collected for hematological indexes, liver function indexes, and kidney function index detection; and the tumor weight was measured. The tumor, kidney, lung, liver, spleen, and heart were fixed with 4% paraformaldehyde and embedded in paraffin. Ultrathin sections were used for HE and P-gp immunohistochemical staining.

2.10. Statistical Analysis

The quantitative data are expressed as . SPSS 13 was used to analyze the data, and multiple comparisons (Tukey’s post hoc test) were performed after one-way ANOVA. was considered as statistically significant.

3. Results

3.1. Characterization of TAR-AuNSs/Dox

As shown in the TEM image (Figure 1(a)), TAR-AuNSs/Dox have a spherical shell structure and a size of ~100 nm. Furthermore, the mean hydrodynamic diameter of TAR-AuNSs/Dox was about 135 nm, and the zeta potential was mV (Figure 1(b)). As shown in the UV-vis image (Figure 1(c)), TAR-AuNSs/Dox had absorption peaks at 264 nm, 480 nm, and 696 nm, consistent with the absorption peaks of TAR, Dox, and AuNSs, respectively, which confirmed the successful preparation of TAR-AuNSs/Dox. As shown in Figure 1(d), the Dox loading capacity (LC) and encapsulation efficiency (EE) in TAR-AuNSs/Dox were 34.1% and 96.3%, and the TAR loading capacity (LC) and encapsulation efficiency (EE) in TAR-AuNSs/Dox were 30.5% and 86%, respectively. And then, Dox release from AuNSs/Dox and TAR-AuNSs/Dox and TAR release from TAR-AuNSs/Dox were tested. As shown in Figures 1(e) and 1(f), Dox and TAR present pH-responsive release. Dox released from both AuNSs/Dox and TAR-AuNSs/Dox within 24 h at pH 6.5 (75% and 76%) was much higher than that at pH 7.4 (35% and 37%). Meanwhile, TAR released from TAR-AuNSs/Dox within 24 h at pH 6.5 (73%) was also much higher than that at pH 7.4 (33%). These results confirmed that TAR-AuNSs/Dox were suitable for tumor acidic microenvironment.

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3.2. P-gp Expression in Daudi-Resistant Cells

P-gp mRNA and protein were determined by qRT-PCR, western blot, and immunofluorescence in Daudi and Daudi/R cells. In the results of qRT-PCR (Figure 2(a)), compared with Daudi cells, the P-gp mRNA was highly expressed in Daudi/R cells. Consistently, P-gp protein was much higher in Daudi/R cells than that in Daudi cells by western blotting (Figure 2(b)) and immunofluorescence staining (Figure 2(c)).

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3.3. Cellular Uptake of TAR-AuNSs/Dox

As shown in Figure 3, there were no significant differences of Dox fluorescence intensity in Daudi cells treated with Dox, AuNSs/Dox, and TAR-AuNSs/Dox at both 0.5 h and 1 h. However, the Dox fluorescence intensity in Daudi/R cells treated with AuNSs/Dox and TAR-AuNSs/Dox was much high than that with free Dox. Obviously, the strongest red fluorescence was detected in cells with TAR-AuNSs/Dox at both 0.5 h and 1 h. The above results showed that TAR promotes cell uptake of TAR-AuNSs/Dox and inhibited the efflux of Dox.

3.4. The Anticancer Effect of TAR-AuNSs/Dox In Vitro

The antitumor effect of AuNSs/Dox and TAR-AuNSs/Dox was evaluated by CCK8 assay. As shown in Figures 4(a) and 4(b), different concentrations of AuNSs or TAR-AuNSs treatments showed no significant toxicity to both Daudi and Daudi/R cells. The cytotoxicity induced by AuNSs/Dox and TAR-AuNSs/Dox presents a dose-dependent effect. Compared with free Dox, cell viability was obviously decreased with AuNSs/Dox and TAR-AuNSs/Dox treatment. What is more, there were no significant differences in Daudi cells treated with AuNSs/Dox and TAR-AuNSs/Dox (Figure 4(c)), while in Daudi/R cells, because of the existence of TAR, TAR-AuNSs/Dox showed lower cell viability than AuNSs/Dox (Figure 4(d)).

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3.5. The P-gp Expression in Daudi/R Cells with TAR-AuNSs/Dox In Vitro

After being treated with PBS, AuNSs, TAR-AuNSs, Dox, AuNSs/Dox, and TAR-AuNSs/Dox, respectively, Daudi/R cells were used to determine the mRNA and protein of P-gp. As shown in Figure 5(a), the P-gp mRNA showed no obvious difference in Daudi/R cells treated with AuNSs, free Dox, and AuNSs/Dox. However, P-gp mRNA was obviously reduced after treatment with TAR-AuNSs and TAR-AuNSs/Dox (Figure 5(a)). In agreement with the above result, similar expression trend of P-gp protein was observed by western blotting (Figure 5(b)).

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3.6. Effect of TAR-AuNSs/Dox on Apoptosis In Vitro

Apoptotic cells were stained with red fluorescence by TUNEL staining and flow cytometry. As shown in Figure 6(a), compared with PBS, the number of apoptotic cells was obviously increased in free Dox treatment. Notably, compared with free Dox, AuNSs/Dox induced more apoptotic cells, and TAR-AuNSs/Dox induced the most apoptotic cells. In addition, cell apoptosis rate was quantified by FACS (Figure 6(b)). The results of FACS were consistent with TUNEL staining.

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3.7. The Anticancer Effect and Biocompatibility of TAR-AuNSs/Dox In Vivo

In vivo experiments indicated that after treatment with PBS, Dox, AuNSs/Dox, and TAR-AuNSs/Dox, there was no significant difference in body weight of tumor-bearing mice (Figure 7(a)). Furthermore, as shown in Figures 7(b) and 7(c), compared with the control group, tumor volume was declined in a time-dependent manner after Dox, AuNSs/Dox, and TAR-AuNSs/Dox application, and the TAR-AuNSs/Dox group had the lowest tumor volume (). Consistently, as shown in Figure 7(d), the AuNSs/Dox group had the lowest tumor weight, followed by the AuNSs/Dox and Dox groups. The Dox accumulation in vivo was demonstrated by fluorescence microscopy of cryosectioned tumors. As shown in Figure 7(e), the red fluorescence of Dox in TAR-AuNSs/Dox-treated tumors was much stronger than that in Dox and AuNSs/Dox-treated tumors, which confirmed that TAR-AuNSs/Dox could promote Dox uptake by tumor cells. Next, the expression of P-gp in mice tumors was determined by western blot (Figure 7(f)) and immunohistochemical staining (Figure 7(g)). Compared with Dox and AuNSs/Dox, TAR-AuNSs/Dox significantly inhibited the expression of P-gp.

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Figure 7

The killing effect of TAR-AuNSs/Dox on drug-resistant tumor-bearing mice. Body weights (a), tumor images (b), tumor volumes (c), and tumor weights (d) of mice with PBS, Dox, AuNSs/Dox, and TAR-AuNSs/Dox, respectively. (e) Fluorescence images of cryosectioned tumors after application of Dox, AuNSs/Dox, and TAR-AuNSs/Dox at 48 h. Blue represents nuclei; red represents Dox. The expression of P-gp in drug-resistant tumor was detected by western blot (f) and immunohistochemical staining (g) after application of Dox, AuNSs/Dox, and TAR-AuNSs/Dox. P-gp-positive cells are stained in brown. .

In addition, biocompatibility of TAR-AuNSs/Dox in mice was investigated, as shown in Figure 8(a); there were no significant alterations of hematological indexes (RBC, Hb, WBC, and PLT), liver function indexes (ALT and AST), and kidney function indexes (CREA and BUN) after Dox, AuNSs/Dox, and TAR-AuNSs/Dox application. Next, HE staining (Figure 8(b)) showed no obvious pathological changes in the main organs (including lung, liver, spleen, kidney, and heart). These results proved that TAR-AuNSs/Dox has good biocompatibility and significant antitumor effects.

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4. Discussion

In this research, AuNSs/Dox and TAR-AuNSs/Dox were successfully prepared with high Dox loading rate and acid response release. TAR modification obviously elevated AuNSs uptake by tumor cells and inhibited the expression of drug-resistant-related protein P-gp. In addition, compared with free Dox, AuNSs/Dox and TAR-AuNSs/Dox obviously reduced Daudi/R cell activity and induced apoptosis. Furthermore, after treatment with Dox, AuNSs/Dox, and TAR-AuNSs/Dox for 18 days, there were no obvious pathological changes in hematological indexes (RBC, Hb, WBC, and PLT), liver function indexes (ALT, AST), renal function indexes (CREA, BUN), and HE staining of major organs (including the lung, liver, spleen, kidney, and heart). This was mainly because AuNSs concentrated in tumor sites under enhanced permeability and retention effect and had no significant toxicity. AuNSs is a promising drug delivery system for hydrophobic drugs with high loading rate and good biocompatibility.

Doxorubicin is a cyclically nonspecific drug and has a wide antitumor spectrum and can kill a variety of tumors [21]. In this research, free Dox obviously reduced the activity of Daudi cells but not Daudi/R cells and increased the apoptosis rate, which was consistent with the in vivo animal study. However, Dox and other anticancer drugs are poorly water-soluble, and their clinical application in cancer treatment is limited [22]. It was reported that AuNSs is a promising drug delivery system for hydrophobic drugs with high loading rate [23]. Srivastava et al. [24] found that harmine-loaded mesoporous silica can induced apoptosis of lymphoma cells via an anti-inflammatory mechanism in vitro. Because of the increase of drug aggregation in the tumor site, the growth of tumor was significantly inhibited in the Daudi xenograft mouse model. In this study, Dox was successfully loaded into AuNSs with good loading rate. AuNSs/Dox and TAR-AuNSs/Dox obviously inhibited Daudi/R cell proliferation by inducing apoptosis compared with free Dox. Notably, Dox released from AuNSs/Dox and TAR-AuNSs/Dox in acidic tumor microenvironment (pH 6.5) were obviously higher than those in plasma (pH 7.4) within 24 h, further confirming that AuNSs/Dox and TAR-AuNSs/Dox were superior to free Dox. In addition, the issue of chemotherapeutic drug resistance is prominent, and this study focused on whether TAR-modified AuNSs/Dox can improve tumor resistance and antitumor effect. P-gp is widely expressed in drug-resistant tumor cells as a drug transporter, mediating the efflux of intracellular drugs and causing drug resistance of chemotherapy drugs. TAR is an effective, selective, noncompetitive P-gp inhibitor [25]. It was reported that TAR and elacridar-loaded liposomes can regulate the expression of P-gp to enhance the entry of elacridar into the brain [26]. In this study, it was found that the expression of P-gp was upregulated in drug-resistant Daudi/R cells compared with wild-type Daudi cells. Furthermore, both TAR-AuNSs and TAR-AuNSs/Dox can inhibit P-gp expression. TAR-AuNSs/Dox could further inhibit Daudi/R cell proliferation compared with AuNSs/Dox. The above results showed that TAR-AuNSs/Dox inhibited the expression of P-gp and external excretion of Dox, and its antitumor effect was significantly stronger than that of AuNSs/Dox and free Dox.

5. Conclusion

Based on TAR-regulated P-gp-mediated drug excretion, TAR-AuNSs/Dox was successfully designed and prepared. TAR-AuNSs/Dox showed better antitumor activity than AuNSs/Dox in Daudi/R cells by reversing drug resistance. In summary, TAR-AuNSs/Dox offers a promising nanoplatform for the treatment of drug-resistant tumors.

Data Availability

The data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors report no conflicts of interest in this work.

Acknowledgments

This study was supported by Scientific Research Project of Hunan Provincial Health Commission (B2019100).

References

K. Li, F. Wang, Z. Yang et al., “TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation,” Nature Communications, vol. 11, no. 1, p. 6316, 2020.
View at: Publisher Site | Google Scholar
Y. Liu, N. Azizian, Y. Dou, L. Pham, and Y. Li, “Simultaneous targeting of XPO1 and BCL2 as an effective treatment strategy for double-hit lymphoma,” Journal of Hematology & Oncology, vol. 12, no. 1, p. 119, 2019.
View at: Publisher Site | Google Scholar
R. Chen, P. Zinzani, H. Lee et al., “Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087,” Blood, vol. 134, no. 14, pp. 1144–1153, 2019.
View at: Publisher Site | Google Scholar
P. Armand, Y. Chen, R. Redd et al., “PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation,” Blood, vol. 134, no. 1, pp. 22–29, 2019.
View at: Publisher Site | Google Scholar
J. Chen, Y. Zhou, X. Dong et al., “Discovery of CJ-2360 as a potent and orally active inhibitor of anaplastic lymphoma kinase capable of achieving complete tumor regression,” Journal of Medicinal Chemistry, vol. 63, no. 22, pp. 13994–14016, 2020.
View at: Publisher Site | Google Scholar
L. Carrassa, I. Colombo, G. Damia, and F. Bertoni, “Targeting the DNA damage response for patients with lymphoma: preclinical and clinical evidences,” Cancer Treatment Reviews, vol. 90, p. 102090, 2020.
View at: Publisher Site | Google Scholar
J. Chen, H. Li, Q. Wu et al., “A multidrug-resistant P-glycoprotein assembly revealed by tariquidar-probe's super-resolution imaging,” Nanoscale, vol. 13, no. 40, pp. 16995–17002, 2021.
View at: Publisher Site | Google Scholar
P. Liu-Kreyche, H. Shen, A. Marino, R. A. Iyer, W. G. Humphreys, and Y. Lai, “Lysosomal P-gp-MDR1 confers drug resistance of brentuximab vedotin and its cytotoxic payload monomethyl auristatin E in tumor cells,” Frontiers in Pharmacology, vol. 10, p. 749, 2019.
View at: Publisher Site | Google Scholar
Y. Mu, Y. Fu, J. Li et al., “Multifunctional quercetin conjugated chitosan nano-micelles with P-gp inhibition and permeation enhancement of anticancer drug,” Carbohydrate Polymers, vol. 203, pp. 10–18, 2019.
View at: Publisher Site | Google Scholar
P. Joshi, R. Vishwakarma, and S. Bharate, “Natural alkaloids as P-gp inhibitors for multidrug resistance reversal in cancer,” European Journal of Medicinal Chemistry, vol. 138, pp. 273–292, 2017.
View at: Publisher Site | Google Scholar
R. Tuguntaev, S. Chen, A. Eltahan et al., “P-gp inhibition and mitochondrial impairment by dual-functional nanostructure based on vitamin E derivatives to overcome multidrug resistance,” ACS Applied Materials & Interfaces, vol. 9, no. 20, pp. 16900–16912, 2017.
View at: Publisher Site | Google Scholar
L. Zhang, Y. Li, Q. Wang et al., “The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer,” Molecular Cancer, vol. 19, no. 1, p. 10, 2020.
View at: Publisher Site | Google Scholar
X. Zhao, H. Cho, S. Lee et al., “BAY60-2770 attenuates doxorubicin-induced cardiotoxicity by decreased oxidative stress and enhanced autophagy,” Chemico-Biological Interactions, vol. 328, p. 109190, 2020.
View at: Publisher Site | Google Scholar
Z. Li, H. Li, B. Liu et al., “Inhibition of miR-25 attenuates doxorubicin-induced apoptosis, reactive oxygen species production and DNA damage by targeting PTEN,” International Journal of Medical Sciences, vol. 17, no. 10, pp. 1415–1427, 2020.
View at: Publisher Site | Google Scholar
M. Morsy, A. El-Sheikh, A. Ibrahim, K. Venugopala, and M. Kandeel, “In silico and in vitro identification of secoisolariciresinol as a re-sensitizer of P-glycoprotein-dependent doxorubicin-resistance NCI/ADR-RES cancer cells,” Peer J, vol. 8, article e9163, 2020.
View at: Publisher Site | Google Scholar
S. Qing, C. Lyu, L. Zhu et al., “Biomineralized bacterial outer membrane vesicles potentiate safe and efficient tumor microenvironment reprogramming for anticancer therapy,” Advanced Materials, vol. 32, no. 47, article e2002085, 2020.
View at: Publisher Site | Google Scholar
T. Chen, T. Gu, L. Cheng, X. Li, G. Han, and Z. Liu, “Porous Pt nanoparticles loaded with doxorubicin to enable synergistic chemo-/electrodynamic therapy,” Biomaterials, vol. 255, p. 120202, 2020.
View at: Publisher Site | Google Scholar
K. Exner and A. Ivanova, “Identifying a gold nanoparticle as a proactive carrier for transport of a doxorubicin-peptide complex,” B, Biointerfaces, vol. 194, p. 111155, 2020.
View at: Publisher Site | Google Scholar
W. Zhang, M. Liu, L. Yang et al., “P-glycoprotein inhibitor tariquidar potentiates efficacy of astragaloside IV in experimental autoimmune encephalomyelitis mice,” Molecules, vol. 24, no. 3, p. 561, 2019.
View at: Publisher Site | Google Scholar
Y. Patil, T. Sadhukha, L. Ma, and J. Panyam, “Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance,” Journal of Controlled Release, vol. 136, no. 1, pp. 21–29, 2009.
View at: Publisher Site | Google Scholar
M. Norouzi, V. Yathindranath, J. Thliveris, B. M. Kopec, T. J. Siahaan, and D. W. Miller, “Doxorubicin-loaded iron oxide nanoparticles for glioblastoma therapy: a combinational approach for enhanced delivery of nanoparticles,” Scientific Reports, vol. 10, no. 1, p. 11292, 2020.
View at: Publisher Site | Google Scholar
J. Jiménez-López, L. García-Hevia, C. Melguizo, J. Prados, M. Bañobre-López, and J. Gallo, “Evaluation of novel doxorubicin-loaded magnetic wax nanocomposite vehicles as cancer combinatorial therapy agents,” Pharmaceutics, vol. 12, no. 7, p. 637, 2020.
View at: Publisher Site | Google Scholar
S. Lee, D. Kumar, Y. Li et al., “PEGylated crushed gold shell-radiolabeled core nanoballs for in vivo tumor imaging with dual positron emission tomography and Cerenkov luminescent imaging,” Journal of Nanobiotechnology, vol. 16, no. 1, p. 41, 2018.
View at: Publisher Site | Google Scholar
P. Srivastava, S. Hira, D. Srivastava et al., “ATP-decorated mesoporous silica for biomineralization of calcium carbonate and P 2 purinergic receptor-mediated antitumor activity against aggressive lymphoma,” ACS Applied Materials & Interfaces, vol. 10, no. 8, pp. 6917–6929, 2018.
View at: Publisher Site | Google Scholar
Y. Xia, M. Fang, J. Dong et al., “pH sensitive liposomes delivering tariquidar and doxorubicin to overcome multidrug resistance of resistant ovarian cancer cells,” B, Biointerfaces, vol. 170, pp. 514–520, 2018.
View at: Publisher Site | Google Scholar
R. Nieto Montesinos, A. Béduneau, A. Lamprecht, and Y. Pellequer, “Liposomes coloaded with elacridar and tariquidar to modulate the P-glycoprotein at the blood-brain barrier,” Molecular Pharmaceutics, vol. 12, no. 11, pp. 3829–3838, 2015.
View at: Publisher Site | Google Scholar

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Copyright © 2022 Shujuan Ouyang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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