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Yoshida M, Tabata Y: Tumor targeting of protein through poly (ethylene glycol) conjugation with metal coordination. J Nanosci Nanotechnol. 2010 Feb;10(2):877-85.
The objective of this study is to introduce a new and simple conjugation method of protein with poly (ethylene glycol) (PEG) based on metal coordination. A chelating residue N,N-bis (carboxymethyl)-L-lysine (NTA) was chemically introduced into one terminal of PEG with another terminal of methoxy group (MeO-PEG). Cu2+ or Zn2+ ions were chelated into the NTA residue of MeO-PEG-NTA prepared. Chromatographic experiments revealed that transferrin (Tf) was conjugated to the MeO-PEG-NTA based on Cu2+ ions coordination. The amount of PEG conjugated increased with an increase in that added. Fluorescently labeled Tf was conjugated by the MeO-PEG-NTA with Cu2+ or Zn2+ coordination and injected intravenously into tumor-bearing mice. The Tf conjugated with the MeO-PEG-NTA based on Cu2+ coordination was accumulated in the tumor site to a significantly great extent compared with the free Tf and Tf conjugated with the Zn2+ coordinated MeO-PEG-NTA. A body distribution assay with radiolabeled Tf demonstrated that PEG conjugation with Cu2+ coordination enabled Tf to prolong the blood circulation and enhance the tumor accumulation. When interferon (IFN) was conjugated with the Cu (2+)-coordinated MeO-PEG-NTA and subcutaneously injected into tumor-bearing mice, the in vivo tumor growth was significantly suppressed compared with the injection of free IFN and IFN conjugated by Zn (2+)-coordinated MeO-PEG-NTA. It is concluded that the Cu (2+)-coordinated PEG conjugation can modify the body distribution of protein only by simple mixing in aqueous solution. The PEG conjugation with metal coordination could increase the in vivo half-life period of proteins in the blood, and consequently enhance the accumulation amount at the tumor site. |
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