Drug Delivery and Translational Research

, Volume 5, Issue 1, pp 38–50 | Cite as

Medicinal facilities to B16F10 melanoma cells for distant metastasis control with a supramolecular complex by DEAE-dextran-MMA copolymer/paclitaxel

Research Article

Abstract

The resistance of cancer cells to chemotherapeutic drugs (MDR) is a major problem to be solved. A supramolecular DEAE-dextran-MMA copolymer (DDMC)/paclitaxel (PTX) complex was obtained by using PTX as the guest and DDMC as the host having 50–300 nm in diameter. The drug resistance of B16F10 melanoma cells to paclitaxel was observed, but there is no drug resistance of melanoma cells to the DDMC/PTX complex in vitro. The cell death rate was determined using Michaelis–Menten kinetics, as the DDMC/PTX complex promoted allosteric supramolecular reaction to tubulin. The DDMC/PTX complex showed a very superior anti-cancer activity to paclitaxel alone in vivo. The median survival time (MST) of the saline, PTX, DDMC/PTX4 (particle size, 50 nm), and DDMC/PTX5 (particle size, 290 nm) groups were 120 h (T/C, 1.0), 176 h (T/C, 1.46), 328 h (T/C, 2.73), and 280 h (T/C, 2.33), respectively. The supramolecular DDMC/PTX complex showed the twofold effectiveness of PTX alone (p < 0.036). Histochemical analysis indicated that the administration of DDMC/PTX complex decreased distant metastasis and increased the survival of mice. A mouse of DDMC/PTX4 group in vivo was almost curing after small dermatorrhagia owing to its anti-angiogenesis, and it will be the hemorrhagic necrotic symptom of tumor by the release of “tumor necrosis factor alpha (TNF-α)” cytokine. As the result, the medicinal action of the DDMC/PTX complex will suppress the tumor-associated action of M2 macrophages and will control the metastasis of cancer cells.

Keywords

DEAE-dextran-MMA copolymer Paclitaxel Melanoma cells Metastatic spread Lymphatic vessel density M2 macrophages 

Abbreviations

PTX

Paclitaxel

DDMC

DEAE-dextran-MMA copolymer

Cd

Cell death

EPR

Enhanced permeation and retention

RES

Reticuloendothelial system

DDS

Drug delivery system

PMMA

Poly(methyl methacrylate)

Notes

Acknowledgments

A portion of this research was carried out with the support of a Japanese Ministry of Health, Labor, and Welfare Scientific Research Grant (H26-Shinko Jitsuyoka-Ippan-007) and the Japan Society for the Promotion of Science Research Grant (Basic B 25300053).

Conflicts of interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    DeVita VT. Principles of cancer management: chemotherapy. In: DeVita VT, editor. Cancer principles and practice of oncology. New York: Lippincott-Raven; 1977. p. p333–347.Google Scholar
  2. 2.
    Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986;46(12 Pt 1):6387–92.PubMedGoogle Scholar
  3. 3.
    Allen TM, Chonn A. Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Lett. 1987;223:42–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Oku N, Namba Y, Okada S. Tumor accumulation of novel RES-avoiding liposomes. Biochim Biophys Acta. 1992;1126:255–60.PubMedCrossRefGoogle Scholar
  5. 5.
    Savic R, Luo L, Eisenberg A, Maysinger D. Micellar nanocontainers distribute to defined cytoplasmic organelles. Science. 2003;300:615–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Hamblin MR, Miller JL, Rizvi I, Ortel B, Maytin EV, Hasan T. Polymer conjugate increases tumor targeting of photosensitizer. Cancer Res. 2001;61:7155–62.PubMedGoogle Scholar
  7. 7.
    Nishiyama N, Nori A, Malugin A, Kasuya Y, Kopeckova P, Kopecek J. Free and N-(2-hydroxypropyl) methacrylamide copolymer-bound geldanamycin derivative induce different stress responses in A2780 human ovarian carcinoma cells. Cancer Res. 2003;63:7876–82.PubMedGoogle Scholar
  8. 8.
    Lehn J-M. Supramolecular chemistry—scope and perspectives: molecules, supermolecules and molecular devices. Angew Chem. 1988;100:91–116.CrossRefGoogle Scholar
  9. 9.
    Tagaki W. Selective micellar reactions—micellar artificial enzymes. Kobunshi. 1986;35:938–41.CrossRefGoogle Scholar
  10. 10.
    Willstatter R, Pfannenstiel AI. Über succinyldiessigsäureester. Justus Liebigs Ann Chem. 1920;422:1–15.CrossRefGoogle Scholar
  11. 11.
    Onishi Y, Maruno S, Kamiya S, Hokkoku S, Hasegawa M. Preparation and characteristics of dextran-methyl methacrylate graft copolymer. Polymer. 1978;19:1325–8.CrossRefGoogle Scholar
  12. 12.
    Onishi Y, Maruno S, Hokkoku S. Graft copolymerization of methyl methacrylate onto dextran and some properties of copolymer. Kobunshi Ronbunshu. 1979;36:535–41.CrossRefGoogle Scholar
  13. 13.
    Onishi Y. Effects of dextran molecular weight on graft copolymerization of dextran-methyl methacrylate. Polymer. 1980;21:819–24.CrossRefGoogle Scholar
  14. 14.
    Onishi Y, Eshita Y, Mizuno M. Dextrans-g-copolymers: synthesis, properties and applications. In: Kalia S, Sabaa MW, editors. Polysaccharide based graft copolymers. Berlin Heidelberg: Springer-Verlag; 2013. p. 205–69.CrossRefGoogle Scholar
  15. 15.
    Onishi Y, Eshita Y, Murashita A, Mizuno M, Yoshida J. Synthesis and characterization of 2-diethylaminoethyl(DEAE)-dextran-MMA graft copolymer for non-viral gene delivery vector. J Appl Polym Sci. 2005;98:9–14.CrossRefGoogle Scholar
  16. 16.
    Onishi Y, Eshita Y, Murashita A, Mizuno M, Yoshida J. Characteristics of 2-diethylaminoethyl(DEAE)-dextran-MMA graft copolymer as a non-viral gene carrier. Nanomedicine: Nanotech Biol Med. 2007;3:184–91.CrossRefGoogle Scholar
  17. 17.
    Eshita Y, Onishi M, Mizuno M, Yoshida J, Kubota N, Onishi Y. Mechanism of introducing exogenous genes into cultured cells using DEAE-dextran- MMA graft copolymer as non-viral gene carrier. Molecules. 2009;14:2669–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Onishi Y, Eshita Y, Murashita A, Mizuno M, Yoshida J. A novel vector of 2-diethyl aminoethyl (DEAE)-dextran-mma graft copolymer for non-viral gene delivery. J Gene Med. 2008;10:472.Google Scholar
  19. 19.
    Onishi Y, Eshita Y, Mizuno M. DEAE-dextran and DEAE-dextran-MMA graft copolymer for nonviral delivery of nucleic acids. In: Bartul Z, Trenor J, editors. Advances in nanotechnology, volume 3. New York: Nova Science Publishers; 2009. p. 409–47.Google Scholar
  20. 20.
    Onishi Y, Eshita Y, Mizuno M. DEAE-dextran-MMA graft copolymer matrices for nonviral delivery of DNA. In: Jorgenson L, Nielson HM, editors. Delivery technologies for biopharmaceuticals. New York: Wiley; 2009. p. 339–55.CrossRefGoogle Scholar
  21. 21.
    Onishi Y, Eshita Y, Mizuno M. DEAE-dextran and DEAE-dextran-MMA graft copolymer for nanomedicine. Polym Res J. 2010;3:415–53.Google Scholar
  22. 22.
    Eshita Y, Onishi M, Mizuno M, Yoshida J, Kubota N, Onishi Y. Mechanism of the introduction of exogenous genes into cultured cells using DEAE-dextran-MMA graft copolymer as a non-viral gene carrier. II. Its thixotropy property. J Nanomedic Nanotechnol. 2011;2:1–8. doi: 10.4172/2157-7439.1000105.CrossRefGoogle Scholar
  23. 23.
    Zarogoulidis P, Hohenforst-Schmidt W, Darwiche K, Krauss L, Sparopoulou D, Sakkas L, et al. 2-diethylaminoethyl-dextran methyl methacrylate copolymer nonviral vector: still a long way toward the safety of aerosol gene therapy. Gene Ther. 2013;20:1022–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Baliaka A, Zarogoulidis P, Domvri K, Hohenforst-Schmidt W, Sakkas A, Huang H, et al. Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-diethylaminoethyl-dextran methyl methacrylate copolymer non-viral vector-p53. Gene Ther. 2014;21:158–67.PubMedCrossRefGoogle Scholar
  25. 25.
    Eshita Y, Ji RC, Onishi M, Mizuno M, Yoshida J, Kubota N, et al. Supramolecular facilities to melanoma cells B16F10 with nanoparticles of a DEAE-dextran-MMA copolymer-paclitaxel complex. J Nanomed Nanotechol. 2012;S5:002. doi: 10.4172/2157-7439.S5-002.Google Scholar
  26. 26.
    Eshita Y, Ji RC, Onishi M, Runtuwene LR, Noguchi K, Kobayashi T, et al. Supramolecular targeting of B16F10 melanoma cells with nanoparticles consisting of a DEAE-dextran-MMA copolymer-paclitaxel complex in vivo and in vitro. J Nanomed Biotherapeut Discov. 2012;2:109. doi: 10.4172/2155-983X.1000109.CrossRefGoogle Scholar
  27. 27.
    Onishi Y, Eshita Y, Ji RC, Onishi M, Mizuno M, Yoshida J, et al. Anti-cancer facility by nano-particle using supramolecular complex by DEAE-dextran-MMA graft copolymer/paclitxel as an artificial enzyme. Proc Reports Facul Eng Oita Univ. 2014;61:17–30.Google Scholar
  28. 28.
    Nakano T, Takewaki K, Yade T, Okamoto Y. Dibenzofulvene, a 1,1-diphenylethylene analogue, gives a π-stacked polymer by anionic, free-radical, and cationic catalysts. J Am Chem Soc. 2001;123(37):9182–3.PubMedCrossRefGoogle Scholar
  29. 29.
    Leffler JE. The enthalpy-entropy relationship and its implications for organic chemistry. J Org Chem. 1955;20:1202–31.CrossRefGoogle Scholar
  30. 30.
    Okumura Y, Ito K, Hayakawa R. Theory on inclusion behavior between cyclodextrin molecules and linear polymer chains in solutions. Polym Adv Technol. 2000;11:815–9.CrossRefGoogle Scholar
  31. 31.
    Miyano S. Cancer and supercomputer. CICSJ Bulletin. 2011;29:42–8.Google Scholar
  32. 32.
    Cheng Y, Prusoff WH. Relationship between the inhibition constant (KI) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973;22:3099–108.PubMedCrossRefGoogle Scholar
  33. 33.
    Hill AV. The possible effects of the aggregation of the molecules of haemoblobin on its dissociation curve. J Physiol. 1910;40:iv–vii. Retrieved 2009-03-18.Google Scholar
  34. 34.
    Yu J, Zhang X, Kuzontkoski PM, Jiang S, Zhu W, Li DY, et al. Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway. Cell Commun Signal. 2014. doi: 10.1186/1478-811X-12-25.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Shields JD, Borsetti M, Rigby H, Harper SJ, Mortimer PS, Levick JR. Lymphatic density and metastatic spread in human malignant melanoma. Br J Cancer. 2004;90:693–700.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Graff JW, Dickson AM, Clay G, McCaffrey AP, Wilson ME. Identifying functional microRNAs in macrophages with polarized phenotypes. J Biol Chem. 2012;287:21816–25.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Evangelista AM, Deschamps AM, Liu D, Raghavachari N, Murphycor E. miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1. Physiol Genomics. 2013;45(12):493–8.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Shime H, Matsumoto M, Oshiumi H, Tanaka S, Nakane A, Iwakura Y, et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. PNAS. 2012;109:2066–71.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Lanni JS, Lowe SW, Licitra EJ, Liu JO, Jacks T. p53-independent apoptosis induced by paclitaxel through an indirect mechanism. PNAS. 1997;94:9679–83.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Horlad H, Fujiwara Y, Takemura K, Ohnishi K, Ikeda T, Tsukamoto H, et al. Corosolic acid impairs tumor development and lung metastasis by inhibiting the immunosuppressive activity of myeloid-derived suppressor cells. Mol Nutr Food Res. 2013;57:1046–54.PubMedCrossRefGoogle Scholar
  41. 41.
    Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 2010;11:936–44.PubMedCrossRefGoogle Scholar
  42. 42.
    Ji RC. Macrophages are important mediators of either tumor-orinflammation-induced lymphangiogenesis. Cell Mol Life Sci. 2012;69(6):897–914.PubMedCrossRefGoogle Scholar
  43. 43.
    Xiao H, Verdier-Pinard P, Fernandez-Fuentes N, Burd B, Angeletti R, Fiser A, et al. Insights into the mechanism of microtubule stabilization by Taxol. PNAS. 2006;103:10166–73.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Wadsworth P, Khodjakov A. E pluribus unum: towards a universal mechanism for spindle assembly. Trends Cell Biol. 2004;14:413–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Minoura I, Muto E. Dielectric measurement of individual microtubules using the electroorientation method. Biophys J. 2006;90:3739–48.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Onishi, Y. Allosteric facilities as artificial enzymes to cancer cell of supramolecular complex by polymer/anti-cancer agents. J Nanomed Biotherapeut Discov. 2014; 4:e127. doi: 10.4172/2155-983X.1000e127
  47. 47.
    Onishi Y, Eshita Y, Ji RC, Onishi M, Mizuno M, Yoshida J, et al. Anticancer efficacy of a nanoparticle using a supramolecular complex by 2-diethylaminoethyl(DEAE)-dextran-MMA graft copolymer/paclitaxel as an artificial enzyme. Beilstein J Nanotechnol. 2014;5:2293–307.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Controlled Release Society 2014

Authors and Affiliations

  1. 1.Department of Infectious Disease Control, Faculty of MedicineOita UniversityYufuJapan
  2. 2.Department of Human Anatomy, Faculty of MedicineOita UniversityYufuJapan
  3. 3.The Center for Advanced Medicine and Clinical ResearchNagoya University HospitalNagoyaJapan
  4. 4.Japan Labour Health and Welfare OrganizationChubu Rosai HospitalNagoyaJapan
  5. 5.Department of Chemistry, Faculty of MedicineOita UniversityYufuJapan
  6. 6.Ryujyu Science CorporationSetoJapan

Personalised recommendations