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タイトル: Molecular Design of Bisphosphonate-Modified Proteins for Efficient Bone Targeting In Vivo.
著者: Katsumi, Hidemasa
Sano, Jun-ichi
Nishikawa, Makiya
Hanzawa, Keiko
Sakane, Toshiyasu
Yamamoto, Akira
著者名の別形: 西川, 元也
発行日: 19-Aug-2015
出版者: Public Library of Science
誌名: PLOS ONE
巻: 10
号: 8
論文番号: e0135966
抄録: To establish a rational molecular design for bisphosphonate (BP)-modified proteins for efficient bone targeting, a pharmacokinetic study was performed using a series of alendronate (ALN), a nitrogen-containing BP, modified proteins with various molecular weights and varying degrees of modification. Four proteins with different molecular weight—yeast glutathione reductase (GR; MW: 112, 000 Da), bovine serum albumin (BSA; MW: 67, 000 Da), recombinant human superoxide dismutase (SOD; MW: 32, 000 Da), and chicken egg white lysozyme (LZM; MW: 14, 000 Da)—were modified with ALN to obtain ALN-modified proteins. Pharmacokinetic analysis of the tissue distribution of the ALN-modified and unmodified proteins was performed after radiolabeling them with indium-111 ([111]In) by using a bifunctional chelating agent. Calculation of tissue uptake clearances revealed that the bone uptake clearances of [111]In-ALN-modified proteins were proportional to the degree of ALN modification. [111]In-GR-ALN and BSA-ALN, the two high-molecular-weight proteins, efficiently accumulated in bones, regardless of the degree of ALN modification. Approximately 36 and 34% of the dose, respectively, was calculated to be delivered to the bones. In contrast, the maximum amounts taken up by bone were 18 and 13% of the dose for [111]In-SOD-ALN(32) and LZM-ALN(9), respectively, because of their high renal clearance. [111]In-SOD modified with both polyethylene glycol (PEG) and ALN ([111]In-PEG-SOD-ALN) was efficiently delivered to the bone. Approximately 36% of the dose was estimated to be delivered to the bones. In an experimental bone metastasis mouse model, treatment with PEG-SOD-ALN significantly reduced the number of tumor cells in the bone of the mice. These results indicate that the combination of PEG and ALN modification is a promising approach for efficient bone targeting of proteins with a high total-body clearance.
著作権等: © 2015 Katsumi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
URI: http://hdl.handle.net/2433/214559
DOI(出版社版): 10.1371/journal.pone.0135966
PubMed ID: 26287482
出現コレクション:学術雑誌掲載論文等

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