Tumor targeting of protein through poly(ethylene glycol) conjugation with metal coordination.
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.
Yoshida
Masataka
M
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawara-Cho Shogoin, Sakyo-Ku, Kyoto 606-8507, Japan.
Tabata
Yasuhiko
Y
D003300:Copper / Q000737:chemistry*; D016503:Drug Delivery Systems; D009682:Magnetic Resonance Spectroscopy; D011092:Polyethylene Glycols / Q000737:chemistry*; D011506:Proteins / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D011506:Proteins; D011092:Polyethylene Glycols; D003300:Copper; D015032:Zinc