Abstract
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle in achieving the therapeutic benefits of paclitaxel (PTX) in the treatment of human ovarian carcinoma. This study is aimed to develop an efficient PTX drug delivery approach to overcome MDR. Redox-responsive micelles consisting of amphiphilic polymers containing disulfide linkages, ie, poly (phosphate ester)-SS-D-α-tocopheryl succinate (POPEA-SS-TOS, PSST) were prepared. PTX-loaded PSST micelles (PTX/PSST-M) designed to display synergistic functions, including reversible inhibition of P-gp, intracellular redox-sensitive release and potent anticancer activities. The average size of PTX/PSST-M was 68.1±4.9 nm. The encapsulated PTX was released quickly through redox-triggered dissociation of micelles. The inhibition of P-gp activity and enhanced cellular accumulation of the PSST micelles were validated. PTX/PSST-M showed significantly increased cytotoxicity against PTX-resistant human ovarian cancer A2780/PTX cells: when the cells were treated with PTX/PSST-M for 48 h, the equivalent IC50 value of PTX was reduced from 61.51 to 0.49 μmol/L. The enhanced cytotoxic effects of PTX/PSST-M against A2780/PTX cells were attributed to their synergistic effects on reducing the mitochondrial transmembrane potential, ATP depletion, ROS production, and activation of apoptotic pathways. Furthermore, PTX/PSST-M significantly increased cell apoptosis/necrosis and cell cycle arrest at the G2/M phase in A2780/PTX cells. These results demonstrate that the redox-responsive PSST micelles inhibit P-gp activity and have a good potential to effectively reverse PTX resistance in human ovarian carcinoma cells by activating intrinsic apoptotic pathways.
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References
Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, et al. Phase III randomized trial of docetaxel–carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004; 96: 1682–91.
Amiri-Kordestani L, Basseville A, Kurdziel K, Fojo AT, Bates SE . Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist Updat 2012; 15: 50–61.
Huang IP, Sun SP, Cheng SH, Lee CH, Wu CY, Yang CS, et al. Enhanced chemotherapy of cancer using pH-sensitive mesoporous silica nanoparticles to antagonize P-glycoprotein–mediated drug resistance. Mol Cancer Ther 2011; 10: 761–9.
Yusuf RZ, Duan Z, Lamendola DE, Penson RT, Seiden MV . Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 2003; 3: 1–19.
Gao L, Liu G, Kang J, Niu M, Wang Z, Wang H, et al. Paclitaxel nanosuspensions coated with P-gp inhibitory surfactants: I. Acute toxicity and pharmacokinetics studies. Colloids Surf B Biointerfaces 2013; 111: 277–81.
Kamazawa S, Kigawa J, Kanamori Y, Itamochi H, Sato S, Iba T, et al. Multidrug resistance gene-1 is a useful predictor of Paclitaxel-based chemotherapy for patients with ovarian cancer. Gynecol Oncol 2002; 86: 171–6.
Talekar M, Ouyang Q, Goldberg MS, Amiji MM . Co-silencing of PKM-2 and MDR-1 sensitizes multidrug resistant ovarian cancer cells to paclitaxel in a murine model of ovarian cancer. Mol Cancer Ther 2015; 14: 1521–31.
Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM . Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006; 5: 219–34.
Thomas H, Coley HM . Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein. Cancer Control 2003; 10: 159.
Pusztai L, Wagner P, Ibrahim N, Rivera E, Theriault R, Booser D, et al. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 2005; 104: 682–91.
Collnot EM, Baldes C, Wempe MF, Kappl R, Hüttermann J, Hyatt JA, et al. Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity. Mol Pharm 2007; 4: 465–74.
Collnot EM, Baldes C, Schaefer UF, Edgar KJ, Wempe MF, Lehr CM . Vitamin E TPGS P-glycoprotein inhibition mechanism: influence on conformational flexibility, intracellular ATP levels, and role of time and site of access. Mol Pharm 2010; 7: 642–51.
Duhem N, Danhier F, Préat V . Vitamin E-based nanomedicines for anti-cancer drug delivery. J Control Release 2014; 182: 33–44.
Wang J, Sun J, Chen Q, Gao Y, Li L, Li H, et al. Star-shape copolymer of lysine-linked di-tocopherol polyethylene glycol 2000 succinate for doxorubicin delivery with reversal of multidrug resistance. Biomaterials 2012; 33: 6877–88.
Tang LY, Wang YC, Li Y, Du JZ, Wang J . Shell-detachable micelles based on disulfide-linked block copolymer as potential carrier for intracellular drug delivery. Bioconjug Chem 2009; 20: 1095–9.
Sun TM, Du JZ, Yan LF, Mao HQ, Wang J . Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery. Biomaterials 2008; 29: 4348–55.
Wang YC, Wang F, Sun TM, Wang J . Redox-responsive nanoparticles from the single disulfide bond-bridged block copolymer as drug carriers for overcoming multidrug resistance in cancer cells. Bioconjug Chem 2011; 22: 1939–45.
Shao H, Zhang M, He J, Ni P . Synthesis and characterization of amphiphilic poly (ɛ-caprolactone)-b-polyphosphoester diblock copolymers bearing multifunctional pendant groups. Polymer 2012; 53: 2854–63.
Cheng R, Meng F, Deng C, Klok HA, Zhong Z . Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 2013; 34: 3647–57.
Mura S, Nicolas J, Couvreur P . Stimuli-responsive nanocarriers for drug delivery. Nat Mater 2013; 12: 991–1003.
Yin Q, Shen J, Zhang Z, Yu H, Li Y . Reversal of multidrug resistance by stimuli-responsive drug delivery systems for therapy of tumor. Adv Drug Deliv Rev 2013; 65: 1699–715.
Li J, Huo M, Wang J, Zhou J, Mohammad JM, Zhang Y, et al. Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel. Biomaterials 2012; 33: 2310–20.
Chen W, Zhong P, Meng F, Cheng R, Deng C, Feijen J, et al. Redox and pH-responsive degradable micelles for dually activated intracellular anticancer drug release. J Control Release 2013; 169: 171–9.
Zhang Q, Vakili MR, Li XF, Lavasanifar A, Le XC . Polymeric micelles for GSH-triggered delivery of arsenic species to cancer cells. Biomaterials 2014; 35: 7088–100.
Yu ZQ, Yan JJ, You YZ, Zhou QH . Bioreducible and acid-labile poly (amido amine) s for efficient gene delivery. Int J Nanomedicine 2012; 7: 5819–32.
Guo Q, Luo P, Luo Y, Du F, Lu W, Liu S, et al. Fabrication of biodegradable micelles with sheddable poly (ethylene glycol) shells as the carrier of 7-ethyl-10-hydroxy-camptothecin. Colloids Surf B Biointerfaces 2012; 100: 138–45.
Steinbach T, Alexandrino EM, Wurm FR . Unsaturated poly(phosphoester)s via ring-opening metathesis polymerization. Polym Chem 2013; 4: 3800–6.
Zhang P, Hu L, Wang Y, Wang J, Feng L, Li Y . Poly (ɛ-caprolactone)-block-poly (ethyl ethylene phosphate) micelles for brain-targeting drug delivery: in vitro and in vivo valuation. Pharm Res 2010; 27: 2657–69.
Wang YC, Yuan YY, Du JZ, Yang XZ, Wang J . Recent progress in polyphosphoesters: from controlled synthesis to biomedical applications. Macromol Biosci 2009; 9: 1154–64.
Zhang J, Chen R, Fang X, Chen F, Wang Y, Chen M . Nucleolin targeting AS1411 aptamer modified pH-sensitive micelles for enhanced delivery and antitumor efficacy of paclitaxel. Nano Res 2015; 8: 201–18.
Zhang Z, Tan S, Feng SS . Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomaterials 2012; 33: 4889–906.
Yu H, Xu Z, Wang D, Chen X, Zhang Z, Yin Q, et al. Intracellular pH-activated PEG-b-PDPA wormlike micelles for hydrophobic drug delivery. Polym Chem 2013; 4: 5052–5.
Yu P, Yu H, Guo C, Cui Z, Chen X, Yin Q, et al. Reversal of doxorubicin resistance in breast cancer by mitochondria-targeted pH-responsive micelles. Acta Biomater 2015; 14: 115–24.
Stuart MC, van de Pas JC, Engberts J . The use of Nile Red to monitor the aggregation behavior in ternary surfactant-water-organic solvent systems. J Phys Org Chem 2005; 18: 929–34.
Wang J, Yang G, Guo X, Tang Z, Zhong Z, Zhou S . Redox-responsive polyanhydride micelles for cancer therapy. Biomaterials 2014; 35: 3080–90.
O'Connor R, Ooi MG, Meiller J, Jakubikova J, Klippel S, Delmore J, et al. The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias. Cancer Chemother Pharmacol 2013; 71: 1357–68.
Fung KL, Pan J, Ohnuma S, Lund PE, Pixley JN, Kimchi-Sarfaty C, et al. MDR1 synonymous polymorphisms alter transporter specificity and protein stability in a stable epithelial monolayer. Cancer Res 2014; 74: 598–608.
Zubris KAV, Liu R, Colby A, Schulz MD, Colson YL, Grinstaff MW . In vitro activity of paclitaxel-loaded polymeric expansile nanoparticles in breast cancer cells. Biomacromolecules 2013; 14: 2074–82.
Jain S, Spandana G, Agrawal AK, Kushwah V, Thanki K . Enhanced antitumor efficacy and reduced toxicity of docetaxel loaded estradiol functionalized stealth polymeric nanoparticles. Mol Pharm 2015; 12: 3871–84.
Bao Y, Guo Y, Zhuang X, Li D, Cheng B, Tan S, et al. D-α-Tocopherol polyethylene glycol succinate-based redox-sensitive paclitaxel prodrug for overcoming multidrug resistance in cancer cells. Mol Pharm 2014; 11: 3196–209.
He Q, Gao Y, Zhang L, Zhang Z, Gao F, Ji X, et al. A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multi-drug resistance. Biomaterials 2011; 32: 7711–20.
Zhou Y, Yu Q, Qin X, Bhavsar D, Yang L, Chen Q, et al. Improving the anticancer efficacy of laminin receptor-specific therapeutic ruthenium nanoparticles (RuBB-loaded EGCG-RuNPs) via ROS-dependent apoptosis in SMMC-7721 cells. ACS Appl Mater Inter 2016; 8: 15000–12.
Liang D, Wang A, Yang Z, Liu Y, Qi X . Enhance cancer cell recognition and overcome drug resistance using hyaluronic acid and α-tocopheryl succinate based multifunctional nanoparticles. Mol Pharm 2015; 12: 2189–202.
Lv S, Tang Z, Zhang D, Song W, Li M, Lin J, et al. Well-defined polymer-drug conjugate engineered with redox and pH-sensitive release mechanism for efficient delivery of paclitaxel. J Control Release 2014; 194: 220–7.
Dintaman JM, Silverman JA . Inhibition of P-glycoprotein by D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharm Res 1999; 16: 1550–6.
Tang L, Yang X, Yin Q, Cai K, Wang H, Chaudhury I, et al. Investigating the optimal size of anticancer nanomedicine. Proc Natl Acad Sci U S A 2014; 111: 15344–9.
Prabhakar U, Maeda H, Jain RK, Sevick-Muraca EM, Zamboni W, Farokhzad OC, et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res 2013; 73: 2412–7.
Niko Y, Arntz Y, Mely Y, Konishi Gi, Klymchenko AS . Disassembly-driven fluorescence turn-on of polymerized micelles by reductive stimuli in living cells. Chemistry 2014; 20: 16473–7.
Jess TJ, Belham CM, Thomson FJ, Scott PH, Plevin RJ, Gould GW . Phosphatidylinositol 3′-kinase, but not p70 ribosomal S6 kinase, is involved in membrane protein recycling: wortmannin inhibits glucose transport and downregulates cell-surface transferrin receptor numbers independently of any effect on fluid-phase endocytosis in fibroblasts. Cell Signal 1996; 8: 297–304.
Ly JD, Grubb DR, Lawen A . The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 2003; 8: 115–28.
Hrycyna CA, Ramachandra M, Ambudkar SV, Ko YH, Pedersen PL, Pastan I, et al. Mechanism of action of human P-glycoprotein ATPase activity photochemical cleavage during a catalytic transition state using orthovanadate reveals cross-talk between the two ATP sites. J Biol Chem 1998; 273: 16631–4.
Bansal T, Akhtar N, Jaggi M, Khar RK, Talegaonkar S . Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation. Drug Discov Today 2009; 14: 1067–74.
Choi SU, Lee CO, Kim KH, Choi EJ, Park SH, Shin HS, et al. Reversal of multidrug resistance by novel verapamil analogs in cancer cells. Anticancer Drugs 1998; 9: 157–65.
Acknowledgements
This study was supported by the Macao Science and Technology Development Fund (096/2015/A3), the Research Fund of the University of Macau (MYRG2014-00033-ICMS-QRCM, MYRG2014-00051-ICMS-QRCM, MYRG2015-00171-ICMS-QRCM and MYRG2016-00130-ICMS-QRCM), and the National Natural Science Foundation of China (81403120).
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Chen, Fq., Zhang, Jm., Fang, Xf. et al. Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of α-tocopheryl succinate-based polyphosphoester copolymers. Acta Pharmacol Sin 38, 859–873 (2017). https://doi.org/10.1038/aps.2016.150
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DOI: https://doi.org/10.1038/aps.2016.150
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