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Docetaxel-loaded D-α-tocopheryl polyethylene glycol-1000 succinate liposomes improve lung cancer chemotherapy and reverse multidrug resistance

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In this study, D-alpha-tocopheryl polyethylene glycol-1000 succinate (TPGS)–coated docetaxel-loaded liposomes were developed to reverse multidrug resistance (MDR) and enhance lung cancer therapy. Evaluations were performed using human lung cancer A549 and resistant A549/DDP cells. The reversal multidrug resistant effect was assessed by P-gp inhibition assay, cytotoxicity, cellular uptake, and apoptosis assay. The tumor xenograft model was built by subcutaneous injection of A549/DDP cells in the right dorsal area of nude mice. The tumor volumes and body weights were measured every other day. The TPGS-coated liposomes showed a concentration- and time-dependent cytotoxicity and significantly enhanced the cytotoxicity of docetaxel in A549/DDP cells. Confocal laser scanning images indicated that higher concentrations of coumarin-6 were successfully delivered into the cytoplasm, and the TPGS-coated liposomes enhanced intracellular drug accumulation by inhibiting overexpressed P-glycoprotein. The TPGS-coated liposomes were shown to induce apoptosis. Furthermore, in vivo anti-tumor studies revealed that TPGS-coated docetaxel-loaded liposomes had outstanding anti-tumor efficacy in an A549/DDP xenograft model. The TPGS-coated liposomes, compared with PEG-coated liposomes, showed significant advantages in vitro and in vivo. The TPGS-coated liposomes were able to reverse MDR and enhance lung cancer therapy.


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  1. 1.

    Assanhou AG, Li W, Zhang L, Xue L, Kong L, Sun H, et al. Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment. Biomaterials. 2015;73:284–95.

  2. 2.

    Bajelan E, Haeri A, Vali AM, Ostad SN, Dadashzadeh S. Co-delivery of doxorubicin and PSC 833 (Valspodar) by stealth nanoliposomes for efficient overcoming of multidrug resistance. J Pharm Pharm Sci. 2012;15(4):568–82.

  3. 3.

    Kato Y, Okuma Y, Watanabe K, Yomota M, Kawai S, Hosomi Y, et al. A single-arm phase II trial of weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) monotherapy after standard of chemotherapy for previously treated advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2019;84(2):351–8.

  4. 4.

    Chang M, Lu S, Zhang F, Zuo T, Guan Y, Wei T, et al. RGD-modified pH-sensitive liposomes for docetaxel tumor targeting. Colloids Surf B Biointerfaces. 2015;129:175–82.

  5. 5.

    Cohen K, Emmanuel R, Kisin-Finfer E, Doron S, Dan P. Modulation of drug resistance in ovarian adenocarcinoma using chemotherapy entrapped in hyaluronan-grafted nanoparticle clusters. ACS Nano. 2014;8(3):2183–95.

  6. 6.

    Dian L-H, Hu Y-J, Lin J-Y, Zhang J-Y, Yan Y, Cui Y-N, et al. Fabrication of paclitaxel hybrid nanomicelles to treatresistant breast cancer via oral administration. Int J Nanomedicine. 2018;13:719–31.

  7. 7.

    Füredi A, Szebényi K, Tóth S, Mihály C, Hámori L, Nagy V, et al. Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer. J Control Release. 2017;261:287–96.

  8. 8.

    Gao W, Ye G, Duan X, Yang X, Yang VC. Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer. Int J Nanomedicine. 2017;12:1047–64.

  9. 9.

    Guan G, Sun J, Sun F, Lou B, Zhang D, Mashayekhi V, et al. Hypoxia-induced tumor cell resistance is overcome by synergistic GAPDH-siRNA and chemotherapy co-delivered by long-circulating and cationic-interior liposomes. Nanoscale. 2017;9:9190–01.

  10. 10.

    Hu Q, Li W, Hu X, Hu Q, Shen J, Jin X, et al. Synergistic treatment of ovarian cancer by co-delivery of survivin shRNA and paclitaxel via supramolecular micellar assembly. Biomaterials. 2012;33(27):6580–91.

  11. 11.

    Juang V, Lee H-P, Lin AM-Y, Lo Y-L. Cationic PEGylated liposomes incorporating an antimicrobial peptide tilapia hepcidin 2–3: an adjuvant of epirubicin to overcome multidrug resistance in cervical cancer cells. Int J Nanomedicine. 2016;11:6047–64.

  12. 12.

    Kievit FM, Wang FY, Fang C, Mok H, Wang K, Silbe JS, et al. Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. J Control Release. 2011;152(1):76–83.

  13. 13.

    Li Y, Li R, Liu Q, Li W, Zhang T, Zou M, et al. One-step self-assembling nanomicelles for pirarubicin delivery to overcome multidrug resistance in breast cancer. Mol Pharm. 2016:3934–44.

  14. 14.

    Liu B-Y, Wu C, He X-Y, Zhuo R-X, Cheng S-X. Multi-drug loaded vitamin E-TPGS nanoparticles for synergistic drug delivery to overcome drug resistance in tumor treatment. Sci Bull. 2016;61(7):552–60.

  15. 15.

    Liu T, Liu X, Xiong H, Xu C, Yao J, Zhu X, et al. Mechanisms of TPGS and its derivatives inhibiting Pglycoprotein efflux pump and application for reversing multidrug resistancein hepatocellular carcinoma. Polym Chem. 2018:1827–39.

  16. 16.

    Mu L-M, Ju R-J, Liu R, Bu Y-Z, Zhang J-Y, Li X-Q, et al. Dual-functional drug liposomes in treatment of resistant cancers. Adv Drug Deliv Rev. 2017:46–56.

  17. 17.

    Muthu MS, Kulkarni SA, Xiong J, Feng S-H. Vitamin E TPGS coated liposomes enhanced cellular uptake and cytotoxicity of docetaxel in brain cancer cells. Int J Pharm. 2011;421(2):332–40.

  18. 18.

    Niwa T, Kasuya Y, Suzuki Y, Ichikawa K, Yoshida H, Kurimoto A, et al. Novel immunoliposome technology for enhancing the activity of the agonistic antibody against the tumor necrosis factor receptor superfamily. Mol Pharm. 2018;15(9):3729–40.

  19. 19.

    Peng Y, Nie J, Cheng W, Liu G, Zhu D, Zhang L, et al. A multifunctional nanoplatform for cancer chemo-photothermal synergistic therapy and overcoming multidrug resistance. Biomater Sci. 2018;6(5):1084–98.

  20. 20.

    Ruiz-Moreno C, Velez-Pardo C, Jimenez-Del-Rio M. Vitamin E D-α-tocopheryl polyethylene glycol succinate (TPGS) provokes cell death in human neuroblastoma SK-N-SH cells via a pro-oxidant signaling mechanism. Chem Res Toxicol. 2018;31(9):945–53.

  21. 21.

    Ruttala HB, Ramasamy T, Gupta B, Gupta B, Choi HG, Yong CS, et al. Multiple polysaccharide–drug complex-loaded liposomes: a unique strategy in drug loading and cancer targeting. Carbohydr Polym. 2017;173:57–66.

  22. 22.

    Shen J, Kim H-C, Wolfram J, Mu C, Zhang W, Liu H, et al. A liposome encapsulated ruthenium polypyridine complex as a theranostic platform for triple-negative breast cancer. Nano Lett. 2017;17:2913–20.

  23. 23.

    Shi C, Zhang Z, Shi J, Wang F, Luan Y. Co-delivery of docetaxel and chloroquine via PEO–PPO–PCLTPGS micelles for overcoming multidrug resistance. Int J Pharm. 2015;495(2):932–9.

  24. 24.

    Shi C, Zhang Z, Wang F, Luan Y. Docetaxel-loaded PEO–PPO–PCL/TPGS mixed micelles for overcoming multidrug resistance and enhancing antitumor efficacy. J Mater Chem B Mater Biol Med. 2015:4259–71.

  25. 25.

    Song X, Zhu J, Wen Y. Thermoresponsive supramolecular micellar drug delivery system based on star-linear pseudo-block polymer consisting of b-cyclodextrin-poly(N-isopropylacrylamide) and adamantyl-poly(ethylene glycol). J Colloid Interface Sci. 2017;490:372–9.

  26. 26.

    Song J, Huang H, Xia Z, Wei Y, Yao N, Zhang L, et al. TPGS/phospholipids mixed micelles for delivery of icariside II to multidrug-resistant breast cancer. Integr Cancer Ther. 2016;15(3):390–9.

  27. 27.

    Tan S, Zou C, Zhang W, Lin M, Gao X, Tang Q, et al. Recent developments in d-alpha-tocopheryl polyethylene glycol-succinate-based nanomedicine for cancer therapy. Drug Deliv. 2017;24(1):1831–42.

  28. 28.

    Tang J, Zhang L, Gao H, Liu Y, Zhang Q, Ran R, et al. Co-delivery of doxorubicin and P-gp inhibitor by a reduction-sensitive liposome to overcome multidrug resistance, enhance anti-tumor efficiency and reduce toxicity. Drug Deliv. 2015:1–14.

  29. 29.

    Chen G, Sheng L, Du X. Efficacy and safety of liposome-paclitaxel and carboplatin based concurrent chemoradiotherapy for locally advanced lung squamous cell carcinoma. Cancer Chemother Pharmacol. 2018.

  30. 30.

    Tang S, Yin Q, Zhang Z, Gu W, Chen L, Yu H, et al. Co-delivery of doxorubicin and RNA using pH-sensitive poly (b-aminoester) nanoparticles for reversal of multidrug resistance of breast cancer. Biomaterials. 2014;35(27):6047–59.

  31. 31.

    Vahed SZ, Salehi R, Davaran S, Simin S. Liposome-based drug co-delivery systems in cancer cells. Mater Sci Eng C. 2017;71:1327–41.

  32. 32.

    Chen L, Han X, Hu Z, Chen L. The PVT1/miR-216b/Beclin-1 regulates cisplatin sensitivity of NSCLC cells via modulating autophagy and apoptosis. Cancer Chemother Pharmacol. 2019;83(5):921–31.

  33. 33.

    Li N, Tingting F, Fei W, Han T, Xiangshuai G, Hou Y, et al. Vitamin E D-alpha-tocopheryl polyethylene glycol 1000 succinate-conjugated liposomal docetaxel reverses multidrug resistance in breast cancer cells. J Pharm Pharmacol. 2019;71(8):1243–54.

  34. 34.

    Wang Y, Feng L, Yang X, Wang F, Lu W. Folic acid-conjugated liposomal vincristine for multidrug resistant cancer therapy. Asian J Pharm Sci. 2013;8(2):118–27.

  35. 35.

    Wu C, Gong M-Q, Liu B-Y, Zhuo R-X, Cheng S-X. Co-delivery of multiple drug resistance inhibitors by polymer/inorganic hybrid nanoparticles to effectively reverse cancer drug resistance. Colloids Surf B Biointerfaces. 2016;19:250–9.

  36. 36.

    Xia Y, Wang X, Cheng H, Fang M, Ning P, Zhou Y, et al. A polycation coated liposome as efficient siRNA carrier to overcome multidrug resistance. Colloids Surf B Biointerfaces. 2017;159:427–36.

  37. 37.

    Yang C, Wu T, Qi Y, Zhang Z. Recent advances in the application of vitamin E TPGS for drug delivery. Theranostics. 2018;8(2):464–85.

  38. 38.

    Ranson MR, Cheeseman S, White S, Margison J. Caelyx (stealth liposomal doxorubicin) in the treatment of advanced breast cancer. Crit Rev Oncol Hematol. 2001;37(2):115–20.

  39. 39.

    Stebbing J, Gaya A. Pegylated liposomal doxorubicin (Caelyx?) in recurrent ovarian cancer. Cancer Treat Rev. 2002;28:121–5.

  40. 40.

    Huang C. Studies on phosphatidylcholine vesicles, formation and physical characteristics. Biochemistry. 1969;8:344–52.

  41. 41.

    Samad A, Sultana Y, Aqil M. Liposomal drug delivery systems: an update review. Curr Drug Deliv. 2007;4:297–305.

  42. 42.

    Qu M-H, Zeng R-F, Fang S, Dai Q-S, Li H-P, Long J-T. Liposome-based co-delivery of siRNA and docetaxel for the synergistic treatment of lung cancer. Int J Pharm. 2014;474:112–22.

  43. 43.

    Yu L, Dong A, Guo R, Yang M, Deng L, Zhang J. DOX/ICG coencapsulated liposome-coated thermosensitive nanogels for NIR-triggered simultaneous drug release and photothermal effect. ACS Biomater Sci Eng. 2018:2424–34.

  44. 44.

    Zhou J, Dong F, Cui F, Xu R, Tang X. The role of circulating tumor cells in evaluation of prognosis and treatment response in advanced non-small-cell lung cancer. Cancer Chemother Pharmacol. 2017:825–33.

  45. 45.

    Zhang X, Guo S, Fan R, Yu M, Li F, Zhu C, et al. Dual-functional liposome for tumor targeting and overcoming multidrug resistance in hepatocellular carcinoma cells. Biomaterials. 2012;33(29):7103–14.

  46. 46.

    Zhang X, He F, He K, Zhang J, Xu M, Long P, et al. CD44-targeted facile enzymatic activatable chitosan nanoparticles for efficient antitumor therapy and reversal of multidrug resistance. Biomacromolecules. 2018:883–95.

  47. 47.

    Zhao P, Li L, Zhou S, Qiu L, Qian Z, Liu X, et al. TPGS functionalized mesoporous silica nanoparticles for anticancer drug delivery to overcome multidrug resistance. Mater Sci Eng C. 2018;84:108–17.

  48. 48.

    Zhao Y-Z, Dai D-D, Lu C-T, Chen L-J, Lin M, Shen X-T, et al. Epirubicin loaded with propylene glycol liposomes significantly overcomes multidrug resistance in breast cancer. Cancer Lett. 2013;30(1):74–83.

  49. 49.

    Lian D, Chen Y, Xu G, Zeng X, Li Z, Li Z, et al. Delivery of siRNA targeting HIF-1a loaded chitosan modified D-a-tocopheryl polyethylene glycol 1000 succinate-b-poly(3-caprolactone-ran-glycolide) nanoparticles into nasopharyngeal carcinoma cell to improve the therapeutic efficacy of cisplatin. RSC Adv. 2016;6(44):37740–9.

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Correspondence to Jianhong Yang.

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All animal studies were performed in compliance with the guidelines outlined in the Guide for the Care and Use of Laboratory Animals. All animal experiments were reviewed and approved by the Animal Experiment Ethics Committee of Ningxia Medical University.

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Li, N., Mai, Y., Liu, Q. et al. Docetaxel-loaded D-α-tocopheryl polyethylene glycol-1000 succinate liposomes improve lung cancer chemotherapy and reverse multidrug resistance. Drug Deliv. and Transl. Res. (2020). https://doi.org/10.1007/s13346-020-00720-9

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  • Liposomes
  • Docetaxel
  • TPGS
  • Multidrug resistance
  • Lung cancer