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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1999 Jan;90(1):122–128. doi: 10.1111/j.1349-7006.1999.tb00675.x

Reduction of the Side Effects of an Antitumor Agent, KRN5500, by Incorporation of the Drug into Polymeric Micelles

Yasuhiro Matsumura 1,✉, Masayuki Yokoyama 2, Kazunori Kataoka 3, Teruo Okano 2, Yasuhisa Sakurai 2, Takanori Kawaguchi 4, Tadao Kakizoe 5
PMCID: PMC5925985  PMID: 10076575

Abstract

For intravenous (i.v.) injection of a water‐insoluble antitumor drug, KRN5500, we have successfully incorporated KRN5500 into polymeric micelles. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines and toxicity in mice of polymeric micelles incorporating KRN5500 (KRN/m) were evaluated in comparison with those of the prototype KRN5500. KRN/m was found to express similar antitumor activity to KRN5500 in the in vitro and in vivo systems. However, the vascular damage and liver focal necrosis observed with KRN5500 i.v. injection were not seen when KRN/m was administered i.v. Therefore, we expect that KRN/m will be superior to KRN5500 for clinical use and that the methodology of polymeric micelle drug carrier systems can be applied to other water‐insoluble drugs.

Keywords: DDS, Micelles, KRN5500

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REFERENCES

  • 1. ) Matsumura , Y. and Maeda , H.A new concept for macro‐molecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs . Cancer Res. , 46 , 6387 – 6392 ( 1986. ). [PubMed] [Google Scholar]
  • 2. ) Dvorak , H. F. , Nagy , J. A. , Dvorak , J. T. and Dvorak , A. M.Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules . Am. J. Pathol. , 133 , 95 – 109 ( 1988. ). [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Maeda , H. and Matsumura , Y.Tumoritropic and lymphotropic principles of macromolecular drugs . Crit. Rev. Ther. Drug Carrier Syst. , 6 , 193 – 210 ( 1989. ). [PubMed] [Google Scholar]
  • 4. ) Matsumura , Y. , Maruo , K. , Kimura , M. , Yamamoto , T. , Konno , T. and Maeda , H.Kinin‐generating cascade in advanced cancer patients and in vitro study . Jpn. J. Cancer Res. , 82 , 732 – 741 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Folkman , J.Angiogenesis in cancer, vascular, rheumatoid and other diseases . Nat. Med. , 1 , 27 – 31 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Kamishohara , M. , Kawai , H. , Sakai , T. , Isoe , T. , Hasegawa , K. , Mochizuki , J. , Uchida , T. , Kataoka , S. , Yamaki , H. , Tsuruo , T. and Otake , N.Antitumor activity of a Spicamycin derivative, KRN5500, and its active metabolite in tumor cells . Oncol. Res. , 6 , 383 – 390 ( 1994. ). [PubMed] [Google Scholar]
  • 7. ) Yokoyama , M. , Satoh , A. , Sakurai , Y. , Okano , T. , Matsumura , Y. , Kakizoe , T. and Kataoka , K.Incorporation of water‐insoluble anticancer drug into polymeric micelles and control of their particle size . J. Controlled Release ( 1998. ), in press . [DOI] [PubMed]
  • 8. ) Yoshimoto , T. , Nishimura , H. , Saito , Y. , Sakurai , K. , Kamisaki , Y. , Wada , H. , Sako , M. , Tsujino , G. and Inada , Y.Characterization of polyethylene glycol‐modified Lasparaginase from Escherichia coli and its application to therapy of leukemia . Jpn. J. Cancer Res. , 77 , 1264 – 1270 ( 1986. ). [PubMed] [Google Scholar]
  • 9. ) Konno , T. , Maeda , H. , Iwaki , K. , Maki , S. , Tashiro , S. , Uchida , M. and Miyauchi , Y.Selective targeting of anticancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium . Cancer , 54 , 2367 – 2374 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Gill , P. S. , Wernz , J. , Scadden , D. T. , Cohen , P. , Mukwaya , G. M. , von Roenn , J. H. , Jacobs , M. , Kempin , S. , Silverberg , I. , Gonzales , G. , Rarick , Mu. , Myers , A. M. , Shepherd , F. , Sawka , C. , Pike , M. C. and Ross , M. E.Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS‐related Kaposi's sarcoma . J. Clin. Oncol. , 14 , 2353 – 2364 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Northfelt , D. W. , Dezube , B. J. , Thommes , J. A. , Levine , R. , von Roenn , J. H. , Dosik , G. M. , Rios , A. , Krown , S. E. , DuMond , C. and Mamelok , R. D.Efficacy of pegylatedliposomal doxorubicin in the treatment of AIDS‐related Kaposi's sarcoma after failure of standard chemotherapy . J. Clin. Oncol. , 15 , 653 – 659 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Lasic , D. D.Doxorubicin in sterically stabilized liposomes . Nature , 380 , 561 – 562 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Gabizon , A. , Catane , R. , Uziely , B. , Kaufman , B. , Safra , T. , Cohen , R. , Martin , F. , Huang , A. and Barenholz , Y.Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene‐glycol coated liposomes . Cancer Res. , 54 , 987 – 992 ( 1994. ). [PubMed] [Google Scholar]
  • 14. ) Duncan , R. , Hume , I. C. , Kopeckova , P. , Ulbrieh , K. , Strohalm , J. and Kopecek , J.Anticancer agents coupled to N‐(2‐hydroxypropyl)methacrylamide copolymers 3. Evaluation of adriamycin conjugates against mouse leukemia L1210 in vivo . J. Controlled Release , 10 , 51 – 63 ( 1989. ). [Google Scholar]
  • 15. ) Seymour , L. W. , Ulbrich , K. , Steyger , P. S. , Brereton , M. , Subr , V. , Strohalm , J. and Duncan , R.Tumor tropism and anti‐cancer efficacy of polymer‐based doxorubicin prodrugs in the treatment of subcutaneous murine B16 F10 melanoma . Br. J. Cancer , 70 , 636 – 641 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. ) Yokoyama , M. , Miyauchi , M. , Yamada , N. , Okano , T. , Sakurai , Y. , Kataoka , K. and Inoue , S.Polymeric micelle as novel carrier: adriamycin‐conjugated poly(ethyleneglycol)‐poly(aspartic acid) block copolymer . J. Controlled Release , 11 , 269 – 278 ( 1990. ). [Google Scholar]
  • 17. ) Dorn , K. , Hoerpel , G. and Ringsdorf , H.Polymer antitumor agents at a molecular and cellular level . In“Bioactive Polymeric Systems: An Overview ” ed. Gebelein C. G. and Carraher C. E. , pp . 531 – 585 ( 1985. ). Plenum Press; , New York . [Google Scholar]
  • 18. ) Yokoyama , M. , Fukushima , S. , Uehara , R. , Okamoto , K. , Kataoka , K. , Sakurai , Y. and Okano , T.Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor . J. Controlled Release , 50 , 79 – 92 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Kwon , G. S. , Yokoyama , M. , Okano , T. , Sakurai , Y. and Kataoka , K.Biodistribution of micelle forming polymer‐drug conjugate . Pharm. Res. , 10 , 970 – 974 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Katre , N. V. , Knauf , M. J. and Laird , W. J.Chemical modification of recombinant interleukin 2 by polyethylene glycol increases its potency in the murine Meth A sarcoma model . Proc. Natl. Acad. Sci. USA , 84 , 1487 – 1491 ( 1987. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Yokoyama , M. , Okano , T. , Sakurai , Y. , Ekimoto , H. , Shibazaki , C. and Kataoka , K.Toxicity and antitumor activity against solid tumors of micelle‐forming polymeric anticancer drug and its extremely long circulation in blood . Cancer Res. , 51 , 3229 – 3236 ( 1991. ). [PubMed] [Google Scholar]

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