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. 2001 Mar;92(3):328–336. doi: 10.1111/j.1349-7006.2001.tb01099.x

Cisplatin‐incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

Yasuo Mizumura 1, Yasuhiro Matsumura 1,✉, Tetsuya Hamaguchi 1, Nobuhiro Nishiyama 2, Kazunori Kataoka 2, Takanori Kawaguchi 3, William J M Hrushesky 4, Fuminori Moriyasu 5, Tadao Kakizoe 6
PMCID: PMC5926709  PMID: 11267944

Abstract

cis‐Diamminedichloroplatinum (II) (cisplatin, CDDP), a potent anticancer agent, was bound to the aspartic acid residues of poly(ethylene glycol)‐poly(aspartic acid) (PEG‐P(ASP)) block copolymer by ligand substitution reaction at the platinum atom of CDDP. The polymeric drug thus obtained was observed to form a micelle structure in aqueous medium, showing excellent water solubility. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines, toxicity and pharmacokinetic characteristics in rodents of CDDP‐incorporated polymeric micelles (CDDP/m) were evaluated in comparison with those of CDDP. In vitro, CDDP/m exhibited 10‐17% of the cytotoxicity of CDDP against human tumor cell lines. CDDP/m given by intravenous (i.v.) injection yielded higher and more sustained serum levels than CDDP. In vivo CDDP/m treatment resulted in higher and more sustained levels in tumor tissue than CDDP, and showed similar antitumor activity to CDDP against MKN 45 human gastric cancer xenograft. CDDP/m treatment caused much less renal damage than CDDP. These results indicate that CDDP/m treatment can reduce CDDP‐induced nephrotoxicity without compromising the anticancer cytotoxicity of CDDP.

Keywords: Polymeric micelles, Cisplatin, Nephrotoxicity, EPR effect, DDS

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References

  • 1.Rozencwing , M. , von Hoff , D. D. . and Slovik , M.Cis‐diamminedichloroplatinum (II), a new anticancer drug . Ann. Intern. Med. , 86 , 803 – 812 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 2.van der Veer , J. L. . and Reedijk , J.Investigating antitumor drug mechanisms . Chem. Br. , 24 , 775 – 780 ( 1988. ). [Google Scholar]
  • 3.Zwelling , L. A. . and Kohn , K. W.Mechanism of action of cis‐dichlorodiammineplatinum (II) . Cancer Treat. Rep. , 63 , 1439 – 1444 ( 1979. ). [PubMed] [Google Scholar]
  • 4.Bruckner , H. W. , Cohen , C. J. , Wallach , R. C. , Kabakow , B. , Deppe , G. , Greenspan , E. M. , Gusberg , S. B. . and Holland , J. F.Treatment of advanced ovarian cancer with cis‐dichlorodi‐ammineplatinum (II): poor‐risk patients with intensive prior therapy . Cancer Treat. Rep. , 62 , 555 – 558 ( 1978. ). [PubMed] [Google Scholar]
  • 5.von Hoff , D. D. , Schilisky , R. , Reichert , C. M. , Reddick , R. L. , Rozencweig , M. , Young , R. C. and Muggia , F. M . Toxic effect of cis‐dichlorodiammineplatinum (II) in man . Cancer Treat. Rep. , 63 , 1527 – 1534 ( 1979. ). [PubMed] [Google Scholar]
  • 6.Prestayko , A. W. , D'Aoust , J. C. , Issel , B. F. . and Crooke , S. T.Cisplatin (cis‐diamminedichloroplatinum (II)) . Cancer Treat. Rev. , 6 , 17 – 39 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 7.Madias , N. E. . and Harrington , J. T.Platinum nephrotoxicity . Am. J. Med , 65 , 307 – 314 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 8.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]
  • 9.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]
  • 10.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]
  • 11.Folkman , J.Angiogenesis in cancer, vascular, rheumatoid and other diseases . Nat. Med. , 1 , 27 – 31 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 12.Dvorak , H. R , 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]
  • 13.Yokoyama , M. , Miyauchi , M. , Yamada , N. , Okano , T. , Sakurai , Y. , Kataoka , K. . and Inoue , S.Characterization and anticancer activity of micelle‐forming polymeric antitumor drug adriamicin‐conjugated poly(ethylene glycol)‐poly(aspartic acid) block copolymer . Cancer Res. , 50 , 1693 – 1700 ( 1990. ). [PubMed] [Google Scholar]
  • 14.Yokoyama , M. , Okano , T. , Sakurai , Y. , Ekimoto , H. , Shibazaki , C. . and Kataoka , K.Toxicity and antitumor activity against solid tumors of micelle‐forming polymeric antitumor drug and its extremely long circulation in blood . Cancer Res. , 51 , 3229 – 3236 ( 1991. ). [PubMed] [Google Scholar]
  • 15.Yokoyama , M. , Inoue , S. , Kataoka , K. , Yui , N. , Okano , T. . and Sakurai , Y.Molecular design for missile drug: synthesis of adriamycin conjugated with immunoglobulin G using poly(ethylene glycol)‐block‐poly(aspartic acid) as intermediate carrier . Makromol. Chem. , 190 , 2041 – 2054 ( 1989. ). [Google Scholar]
  • 16.Yokoyama , M. , Miyauchi , M. , Yamada , N. , Okano , T. , Sakurai , Y. , Kataoka , K. . and Inoue , S.Polymeric micelles as novel drug carrier: adriamycin‐conjugated poly(ethylene glycol)‐poly(aspartic acid) block copolymer . J. Controlled Release , 11 , 269 – 278 ( 1990. ). [PubMed] [Google Scholar]
  • 17.Yokoyama , M. , Okano , T. , Sakurai , Y. , Suwa , S. . and Kataoka , K.Introduction of cisplatin into micelle . J. Controlled Release , 39 , 351 – 356 ( 1996. ). [Google Scholar]
  • 18.Nishiyama , N. , Yokoyama , M. , Aoyagi , T. , Okano , T. , Sakurai , Y. . and Kataoka , K.Preparation and characterization of self‐assembled polymer‐metal complex micelle from cis‐dichlorodiammineplatinum (II) and poly(ethylene glycol)‐poly(α,β‐aspartic acid) block copolymer in an aqueous medium . Langmuir , 15 , 377 – 383 ( 1999. ). [Google Scholar]
  • 19.Newman , M. S. , Colbern , G. T. , Working , P. K. , Engbers , C. . and Amantea , M. A.Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long circulating, pegylated liposomes (SPI‐077) in tumor‐bearing mice . Cancer Chemother. Pharma-col. , 43 , 1 – 7 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 20.Singh , G.A possible cellular mechanism of cisplatin‐induced nephrotoxicity . Toxicology , 58 , 71 – 80 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 21.Fillastre , J. P. . and Raguenez‐Viotte , G.Cisplatin nephrotoxicity . Toxicol. Lett. , 46 , 163 – 175 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 22.Ban , M. , Hettich , D. . and Huguet , N.Nephrotoxicity mechanism of cis‐platinum (II) diamine dichloride in mice . Toxicol. Lett. , 71 , 161 – 168 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 23.Araki , H. , Tani , T. . and Kodama , M.Antitumor effect of cisplatin incorporated into polylactic acid microcapsules . Artif. Organs , 23 , 161 – 168 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 24.Kumagai , S. , Sugiyama , T. , Nishida , T. , Ushijima , K. . and Yakushiji , M.Improvement of intraperitoneal chemotherapy for rat ovarian cancer using cisplatin‐containing micro‐spheres . Jpn. J. Cancer Res. , 87 , 412 – 417 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Ohya , Y. , Masunaga , T. , Baba , T. . and Ouchi , T.Synthesis and cytotoxic activity of dextran‐immobilizing platinum (II) complex through chelate‐type coordination bond . JMS Pure Appl. Chem. , A33 , 1005 – 1016 ( 1996. ). [Google Scholar]
  • 26.Gianasi , E. , Wasil , M. , Evagorou , E. G. , Keddle , A. , Wilson , G. . and Duncan , R.HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivo . Eur. J. Cancer , 35 , 994 – 1002 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 27.Bader , H. , Ringsdorf , H . and Schmidt , B.Water‐soluble polymers in medicine . Angew. Makromol. Chem. , 123/124 , 457 – 485 ( 1984. ). [Google Scholar]
  • 28.Levi , F. A. , Hrushesky , W. J. M. , Borch , R. R , Pleasants , M. E. , Kennedy , B. J. . and Halberg , F.Cisplatin urinary pharmacokinetics and nephrotoxicity: a common circadian mechanism . Cancer Treat. Rep. , 66 , 1933 – 1938 ( 1982. ). [PubMed] [Google Scholar]
  • 29.Levi , F. A. , Hrushesky , W. J. M. , Halberg , F. , Langerin , T. R. , Haus , E. . and Kennedy , B. J.Lethal nephrotoxicity and hematologic toxicity of cis‐diamminedichloroplatinum ameliorated by optimal circadian timing and hydration . Eur. J. Cancer Oncol. , 18 , 471 – 477 ( 1982. ). [DOI] [PubMed] [Google Scholar]

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