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Overcoming multidrug resistance (MDR) in cancer by nanotechnology

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  • Special Topic · Cancer Nanotechnology
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Abstract

The emerging nanotechnology-based drug delivery holds tremendous potential to deliver chemotherapeutic drugs for treatment of multidrug resistance (MDR) cancer. This drug delivery system could improve the pharmacokinetic behavior of antitumor drugs, deliver chemotherapeutic drugs to target sites, control release of drugs, and reduce the systemic toxicity of drugs in MDR cancer. This review addresses the use of nanotechnology to overcome MDR classified on the bases of the fundamental mechanisms of MDR and various approaches to deliver drugs for treatment of MDR cancer.

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References

  1. Boyle P, Levin B. World cancer report: World Health Organization. 2008

  2. Luqmani YA. Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract, 2005, 14: 35–48

    Article  Google Scholar 

  3. Singh R, Lillard Jr JW. Nanoparticle-based targeted drug delivery. Experimental and molecular pathology. Exp Mol Pathol, 2009, 86: 215–223

    Article  CAS  Google Scholar 

  4. Xu Z, Chen L, Gu W, Gao Y, Lin L, Zhang Z, Xi Y, Li Y. The performance of docetaxel-loaded solid lipid nanoparticles targeted to hepatocellular carcinoma. Biomaterials, 2009, 30: 226–232

    Article  Google Scholar 

  5. He Q, Zhang Z, Gao Y, Shi J, Li Y. Intracellular localization and cytotoxicity of mesoporous silica spherical nano-/micro-particles. Small, 2009, 5: 2722–2729

    Article  CAS  Google Scholar 

  6. Gao Y, Chen LL, Gu WW, Xi Y, Lin LP, Li YP. Targeted nanoassembly loaded with docetaxel improves intracellular drug delivery and efficacy in murine breast cancer model. Mol Pharmceutics, 2008, 5: 1044–1054

    Article  CAS  Google Scholar 

  7. Xu Z, Gu W, Huang J, Sui H, Zhou Z, Yang Y, Yan Z, Li Y. In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery. Int J Pharm, 2005, 288: 361–368

    Article  CAS  Google Scholar 

  8. Xu Z, Zhang Z, Chen Y, Chen L, Lin L, Li Y. The characteristics and performance of a multifunctional nanoassembly system for the co-delivery of docetaxel and iSur-pDNA in a mouse hepatocellular carcinoma model. Biomaterials, 2010, 31: 916–922

    Article  CAS  Google Scholar 

  9. Susa M, Iyer AK, Ryu K, Hornicek FJ, Mankin H, Amiji MM, Duan Z. Doxorubicin loaded polymeric nanoparticulate delivery system to overcome drug resistance in osteosarcoma. BMC Cancer, 2009, 9: 399

    Article  Google Scholar 

  10. Matsumura Y, Maeda H. A new concept of macromolecular therapies in cancer chemotherapy: mechanism of tumor tropic accumulation of proteins and the antitumor agent SMANCS. Cancer Res, 1986, 6: 6387–6392

    Google Scholar 

  11. Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ. Sequence-specific knockdown of EWS-FLI1 by targeted, non-viral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic ewing’s sarcoma. Cancer Res, 2005, 65: 8984–8992

    Article  CAS  Google Scholar 

  12. Fletcher JI, Haber M, Henderson MJ, Norris MD. ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer, 2010, 10: 147–156

    Article  CAS  Google Scholar 

  13. Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov, 2006, 5: 219–234

    Article  Google Scholar 

  14. Chinn LW, Kroetz DL. ABCB1 pharmacogenetics: progress, pitfalls, and promise. Clin Pharmacol Ther, 2007, 81: 265–269

    Article  CAS  Google Scholar 

  15. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transpoter. Annu Rev Pharmacol Toxicol, 1999, 39: 361–398

    Article  CAS  Google Scholar 

  16. Pleban K, Ecker GF. Inhibitors of P-glycoprotein lead identification and optimisation. Mini Rev Med Chem, 2005, 5: 153–163

    CAS  Google Scholar 

  17. Scotto KW. Transcriptional regulation of ABC drug transporters. Oncogene, 2003, 22: 7496–7511

    Article  CAS  Google Scholar 

  18. Raub TJ. P-glycoprotein recognition of substrates and circumvention through rational drug design. Mol Pharm, 2006, 3: 3–25

    Article  CAS  Google Scholar 

  19. Wong HL, Bendayan R, Rauth AM, Xue HY, Babakhanian K, Wu XY. A mechanistic study of enhanced doxorubicin uptake and retention in multidrug resistant breast cancer cells using a polymer-lipid hybrid nanoparticle system. J Pharmacol Exp Ther, 2006, 317: 1372–1381

    Article  CAS  Google Scholar 

  20. Pepin X, Attali L, Domrault C, Gallet S, Metreau JM, Reault Y, Cardot PJ, Imalalen M, Dubernet C, Soma E, Couvreur P. On the use of ion-pair chromatography to elucidate doxorubicin release mechanism from polyalkylcyanoacrylate nanoparticles at the cellular level. J Chromatogr B Biomed Sci Appl, 1997, 702: 181–191

    Article  CAS  Google Scholar 

  21. Vauthier C, Dubernet C, Chauvierre C, Brigger I, Couvreur P. Drug delivery to resistant tumors: the potential of poly(alkyl cyanoacrylate) nanoparticles. J Control Release, 2003, 93: 151–160

    Article  CAS  Google Scholar 

  22. Wang Y, Yu L, Han L, Sha X, Fang X. Di-functional Pluronic copolymer micelles for paclitaxel delivery: Synergistic effect of folate-mediated targeting and Pluronic-mediated overcoming multidrug resistance in tumor cell lines. Int J Pharm, 2007, 337: 63–73

    Article  CAS  Google Scholar 

  23. Lee ES, Na K, Bae YH. Doxorubicin loaded pH-sensitive polymeric micelles for reversal of resistant MCF-7 tumor. J Control Release, 2005, 103: 405–418

    Article  CAS  Google Scholar 

  24. Kim D, Lee ES, Park K, Kwon IC, Bae YH. Doxorubicin loaded pH-sensitive micelle: anti-tumoral efficacy against ovarian A2780/DOXR tumor. Pharm Res, 2008, 25: 2074–2082

    Article  CAS  Google Scholar 

  25. Kim D, Gao ZG, Lee ES, Bae YH. In vivo evaluation of doxorubicin-loaded polymeric micelles targeting folate receptors and early endosomal pH in drug-resistant ovarian cancer. Mol Pharm, 2009, 6: 1353–1362

    Article  CAS  Google Scholar 

  26. Oh KT, Lee ES, Kim D, Bae YH. l-Histidine-based pH-sensitive anticancer drug carrier micelle: Reconstitution and brief evaluation of its systemic toxicity. Int J Pharm, 2008, 358: 177–183

    Article  CAS  Google Scholar 

  27. Kobayashi T, Ishida T, Okada Y, Ise S, Harashima H, Kiwada H. Effect of transferrin receptor-targeted liposomal doxorubicin in P-glycoprotein-mediated drug resistant tumor cells. Int J Pharm, 2007, 329: 94–102

    Article  CAS  Google Scholar 

  28. Mohajer G, Lee ES, Bae YH. Enhanced intercellular retention activity of novel pH-sensitive polymeric micelles in wild and multidrug resistant MCF-7 cells. Pharm Res. 2007, 24: 1618–1627

    Article  CAS  Google Scholar 

  29. Kim D, Lee ES, Oh KT, Gao ZG, Bae YH. Doxorubicin-loaded polymeric micelle overcomes multidrug resistance of cancer by double-targeting folate receptor and early endosomal pH. Small, 2008, 4: 2043–2050

    Article  CAS  Google Scholar 

  30. Lee ES, Gao Z, Kim D, Park K, Kwon IC, Bae YH. Super pH-sensitive multifunctional polymeric micelle for tumor pHe specific TAT exposure and multidrug resistance. J Control Release, 2008, 129: 228–236

    Article  CAS  Google Scholar 

  31. Song XR, Cai Z, Zheng Y, He G, Cui FY, Gong DQ, Hou SX, Xiong SJ, Lei XJ, Wei YQ. Reversion of multidrug resistance by co-encapsulation of vincristine and verapamil in PLGA nanoparticles. Eur J Pharm Sci, 2009, 37: 300–305

    Article  CAS  Google Scholar 

  32. Wong HL, Bendayan R, Rauth AM, Wu XY. Simultaneous delivery of doxorubicin and GG918 (Elacridar) by new polymer-lipid hybrid nanoparticles (PLN) for enhanced treatment of multidrug-resistant breast cancer. J Control Release, 2006, 116: 275–284

    Article  CAS  Google Scholar 

  33. Patil Y, Sadhukha T, Ma L, Panyam J. Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. J Control Release, 2009, 136: 21–29

    Article  CAS  Google Scholar 

  34. Fire A Z. Gene silencing by double-stranded RNA. Cell Death Differ, 2007, 14: 1998–2012

    Article  CAS  Google Scholar 

  35. Mello CC, Conte D Jr. Revealing the world of RNA interference. Nature, 2004, 431: 338–342

    Article  CAS  Google Scholar 

  36. Faltus T, Yuan J, Zimmer B, Krämer A, Loibl S, Kaufmann M, Strebhardt K. Silencing of the HER2/neu gene by siRNA inhibits proliferation and induces apoptosis in HER2/neu-overexpressing breast cancer cells. Neoplasia, 2004, 6: 786–795

    Article  CAS  Google Scholar 

  37. Oliveira S, Fretz MM, Høgset A, Storm G, Schiffelers RM. Photochemical internalization enhances silencing of epidermal growth factor receptor through improved endosomal escape of siRNA. Biochim Biophys Acta, 2007, 1768: 1211–1217

    Article  CAS  Google Scholar 

  38. Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, Molema G, Lu PY, Scaria PV, Woodle MC. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res, 2004, 32: 149

    Article  Google Scholar 

  39. Hua J, Mutch DG, Herzog TJ. Stable suppression of MDR- 1 gene using siRNA expression vector to reverse drug resistance in a human uterine sarcoma cell line. Gynecol Oncol, 2005, 98: 31–38

    Article  CAS  Google Scholar 

  40. Logashenko EB, Vladimirova AV, Repkova MN, Venyaminova AG, Chernolovskaya EL, Vlassov VV. Silencing of MDR 1 gene in cancer cells by siRNA. Nucleosides Nucleotides Nucleic Acids, 2004, 23: 861–866

    Article  CAS  Google Scholar 

  41. Xiong XB, Uludağ H, Lavasanifar A. Biodegradable amphiphilic poly(ethylene oxide)-block-polyesters with grafted polyamines as supramolecular nanocarriers for efficient siRNA delivery. Biomaterials, 2009, 30: 242–253

    Article  CAS  Google Scholar 

  42. Yadav S, van Vlerken LE, Little SR, Amiji MM. Evaluations of combination MDR-1 gene silencing and paclitaxel administration in biodegradable polymeric nanoparticle formulations to overcome multidrug resistance in cancer cells. Cancer Chemother Pharmacol, 2009, 63: 711–722

    Article  CAS  Google Scholar 

  43. Cheng J, Wu W, Chen BA, Gao F, Xu W, Gao C, Ding J, Sun Y, Song H, Bao W, Sun X, Xu C, Chen W, Chen N, Liu L, Xia G, Li X, Wang X. Effect of magnetic nanoparticles of Fe3O4 and 5-bromotetrandrine on reversal of multidrug resistance in K562/A02 leukemic cells. Int J Nanomedicine, 2009, 4: 209–216

    Article  CAS  Google Scholar 

  44. Li R, Wu R, Zhao L, Wu M, Yang L, Zou H. P-glycoprotein antibody functionalized carbon nanotube overcomes the multidrug resistance of human leukemia cells. ACS Nano, 2010, 4: 1399–1408

    Article  CAS  Google Scholar 

  45. Sargent RG, Brenneman MA, Wilson JH. Repair of site-specific double-strand breaks in a mammalian chromosome by homologous and illegitimate recombination. Mol. Cell Biol, 1997, 17: 267–277

    CAS  Google Scholar 

  46. Arnaudeau C, Lundin C, Helleday T. DNA doublestrand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J Mol Biol, 2001, 307: 1235–1245

    Article  CAS  Google Scholar 

  47. Lindahl T, Demple B, Robins P. Suicide inactivation of the E. coli O6-methylguanine-DNA methyltransferase. EMBO J, 1982, 1: 1359–1363

    CAS  Google Scholar 

  48. Gao JM, Ming J, He B, Gu ZW, Zhang XD. Controlled release of 9-nitro-20(S)-camptothecin from methoxy poly(ethylene glycol)-poly (D,L-lactide) micelles. Biomed Mater, 2008, 3, 15–13

    Article  Google Scholar 

  49. Khan O, Middleton MR. The therapeutic potential of O6-alkylguanine DNA alkyltransferase inhibitors. Expert Opin Investig Drugs, 2007, 16: 1573–1584

    Article  CAS  Google Scholar 

  50. Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer, 2008, 8: 193–204

    Article  CAS  Google Scholar 

  51. Bhabra G, Sood A, Fisher B, Cartwright L, Saunders M, Evans WH, Surprenant A, Lopez-Castejon G, Mann S, Davis SA, Hails LA, Ingham E, Verkade P, Lane J, Heesom K, Newson R, Case CP. Nanoparticles can cause DNA damage across a cellular barrier. Nat Nanotechnol, 2009, 4: 876–883

    Article  CAS  Google Scholar 

  52. Kang B, Mackey MA, El-Sayed MA. Nuclear targeting of gold nanoparticles in cancer cells induces DNA damage, causing cytokinesis arrest and apoptosis. J Am Chem Soc, 2010, 132: 1517–1519

    Article  CAS  Google Scholar 

  53. Porcel E, Liehn S, Remita H, Usami N, Kobayashi K, Furusawa Y, Le Sech C, Lacombe S. Platinum nanoparticles: A promising material for future cancer therapy? Nanotechnology, 2010, 21: 85103

    Article  Google Scholar 

  54. Asharani PV, Xinyi N, Hande MP, Valiyaveettil S. DNA damage and p53-mediated growth arrest in human cells treated with platinum nanoparticles. Nanomedicine (Lond), 2010, 5: 51–64

    Article  CAS  Google Scholar 

  55. Foldbjerg R, Dang DA, Autrup H. Cytotoxicity and genotoxicity of silver nanoparticles in the human lung cancer cell line, A549. Arch Toxicol, 2010, DOI 10.1007/s00204-010-0545-5

  56. Trouiller B, Reliene R, Westbrook A, Solaimani P, Schiestl RH. Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Res, 2009, 69: 8784–8789

    Article  CAS  Google Scholar 

  57. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene, 2003, 22: 8543–8567

    Article  CAS  Google Scholar 

  58. Ziegler DS, Kung AL, Kieran MW. Anti-apoptosis mechanisms in malignant gliomas. J Clin Oncol, 2008, 26: 493–500

    Article  CAS  Google Scholar 

  59. Debatin KM. The role of the CD95 system in chemotherapy. Drug Resist Updat, 1999, 2: 85–90

    Article  CAS  Google Scholar 

  60. Herr I, Debatin KM. Cellular stress response and apoptosis in cancer therapy. Blood, 2001, 98: 2603–2614

    Article  CAS  Google Scholar 

  61. Debatin KM. Anticancer drugs, programmed cell death and the immune system: defining new roles in an old play. J Natl Cancer Inst, 1997, 89: 750–753

    Article  CAS  Google Scholar 

  62. Kaufmann SH, Earnshaw WC. Induction of apoptosis by cancer chemotherapy. Exp Cell Res, 2000, 256: 42–49

    Article  CAS  Google Scholar 

  63. Solary E, Droin N, Bettaieb A, Corcos L, Dimanche-Boitrel MT, Garrido C. Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies. Leukemia, 2000, 14: 1833–1849

    Article  CAS  Google Scholar 

  64. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis, 2000, 21: 485–495

    Article  CAS  Google Scholar 

  65. Kaufmann SH, Gores GJ. Apoptosis in cancer: cause and cure. Bioessays, 2000, 22: 1007–1017

    Article  CAS  Google Scholar 

  66. Debatin KM. Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother, 2004, 53: 153–159

    Article  Google Scholar 

  67. Kuijlen JM, Mooij JJ, Platteel I, Hoving EW, van der Graaf WT, Span MM, Hollema H, den Dunnen WF. TRAIL-receptor expression is an independent prognostic factor for survival in patients with a primary glioblastoma multiforme. J Neurooncol, 2006, 78: 161–171

    Article  CAS  Google Scholar 

  68. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. Tilman O, Elmore SW, Shoemaker AR, Armstrong RC. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature, 2005, 435: 677–681

    Article  CAS  Google Scholar 

  69. Chen AM, Zhang M, Wei D, Stueber D, Taratula O, Minko T, He H. Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug resistant cancer cells. Small, 2009, 5: 2673–2677

    Article  CAS  Google Scholar 

  70. Wang Y, Gao S, Ye WH, Yoon HS, Yang YY. Co-delivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nat Mater, 2006, 5: 791–796

    Article  CAS  Google Scholar 

  71. Minko T, Batrakova EV, Li S, Li Y, Pakunlu RI, Alakhov VY, Kabanov AV. Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells. J Control Release, 2005, 105: 269–278

    Article  CAS  Google Scholar 

  72. Guo DD, Moon HS, Arote R, Seo JH, Quan JS, Choi YJ, Cho CS. Enhanced anticancer effect of conjugated linoleic acid by conjugation with Pluronic F127 on MCF-7 breast cancer cells. Cancer Lett, 2007, 254: 244–254

    Article  CAS  Google Scholar 

  73. Chen BA, Lai BB, Cheng J, Xia GH, Gao F, Xu WL, Ding JH, Gao C, Sun XC, Xu CR, Chen WJ, Chen NN, Liu LJ, Li XM, Wang XM. Daunorubicin-loaded magnetic nanoparticles of Fe3O4 overcome multidrug resistance and induce apoptosis of K562-n/VCR cells in vivo. Int J Nanomedicine, 2009, 4: 201–208

    Article  CAS  Google Scholar 

  74. Van Vlerken LE, Duan Z, Seiden MV, Amiji MM. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res, 2007, 67: 4843–4850

    Article  Google Scholar 

  75. Yang X, Deng W, Fu L, Blanco E, Gao J, Quan D, Shuai X. Folate-functionalized polymeric micelles for tumor targeted delivery of a potent multidrug-resistance modulator FG020326. J Biomed Mater Res A, 2008, 86: 48–60

    Google Scholar 

  76. Pakunlu RI, Wang Y, Saad M, Khandare JJ, Starovoytov V, Minko T. In vitro and in vivo intracellular liposomal delivery of antisense oligonucleotides and anticancer drug. J Control Release, 2006, 114: 153–162

    Article  CAS  Google Scholar 

  77. Saad M, Garbuzenko OB, Minko T. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine (Lond), 2008, 3: 761–776

    Article  CAS  Google Scholar 

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  1. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    HuiHui Bu, Yu Gao & YaPing Li

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Bu, H., Gao, Y. & Li, Y. Overcoming multidrug resistance (MDR) in cancer by nanotechnology. Sci. China Chem. 53, 2226–2232 (2010). https://doi.org/10.1007/s11426-010-4142-5

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