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Synthesis of a poly(vinylpyrrolidone-co -dimethyl maleic anhydride) co-polymer and its application for renal drug targeting

Nature Biotechnology volume 21, pages 399–404 (2003)Cite this article

Abstract

We have synthesized a polymeric drug carrier, polyvinylpyrrolidone-co-dimethyl maleic anhydride [poly(VP-co-DMMAn)], for use in renal drug delivery. About 80% of the 10-kDa poly(VP-co-DMMAn) selectively accumulated in the kidneys 24 h after intravenous administration to mice. Although this accumulated poly(VP-co-DMMAn) was gradually excreted in the urine, about 40% remained in the kidneys 96 h after treatment. Poly(VP-co-DMMAn) was taken up by the renal proximal tubular epithelial cells and no cytotoxicity was noted. Higher doses did not produce toxicity in the kidneys or other tissues. In contrast, polyvinylpyrrolidone of the same molecular weight did not show any tissue-specific distribution. Poly(VP-co-DMMAn)-modified superoxide dismutase accumulated in the kidneys after intravenous administration and accelerated recovery from acute renal failure in a mouse model. In contrast, polyvinylpyrrolidone-modified superoxide dismutase and native superoxide dismutase were not as effective. Thus, poly(VP-co-DMMAn) is a useful candidate as a targeting carrier for renal drug delivery systems.

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Figure 1: Synthesis of poly(VP-co-DMMAn) and its plasma clearance.
Figure 2: Tissue distribution of poly(VP-co-DMMAn) after intravenous injection.
Figure 3: Histological sections of renal tissues in mice receiving an injection of fluorescein-labeled poly(VP-co-DMMAn).
Figure 4: Poly(VP-co-DMMAn) uptake in human RPTEC.
Figure 5: In vitro cytotoxicity and in vivo toxicity of poly(VP-co-DMMAn).
Figure 6: Chemical modification of SOD with poly(VP-co-DMMAn) and its application to HgCl2-induced ARF.

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Acknowledgements

We thank Ira Pastan for advice, discussion, and assistance. This study was supported in part by a Grant-in-Aid for Scientific Research (13672385) from the Ministry of Education, Science and Culture of Japan, and in part by Health Sciences Research Grants for Research on Health Sciences focusing on Drug Innovation from the Japan Health Sciences Foundation (KH63124).

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Author notes

  1. Haruhiko Kamada and Yasuo Tsutsumi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Haruhiko Kamada, Yasuo Tsutsumi, Keiko Sato-Kamada, Yoko Yamamoto, Yasuo Yoshioka, Takayuki Okamoto, Shinsaku Nakagawa & Tadanori Mayumi

  2. Division of Basic Science, Laboratory of Molecular Biology (Ira Pastan's Laboratory), National Cancer Institute, National Institutes of Health, Building 37, Room 4E16, 37 Convent Drive MSC 4255, Bethesda, 20892-4255, MD

    Satoshi Nagata

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Correspondence to Yasuo Tsutsumi.

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Kamada, H., Tsutsumi, Y., Sato-Kamada, K. et al. Synthesis of a poly(vinylpyrrolidone-co -dimethyl maleic anhydride) co-polymer and its application for renal drug targeting. Nat Biotechnol 21, 399–404 (2003). https://doi.org/10.1038/nbt798

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