Synthesis, characterization, and tumor selectivity of a polyphosphazene-platinum(II) conjugate.
A new amphiphilic poly(organophosphazene) was synthesized by stepwise nucleophilic substitutions with a hydrophilic methoxy poly(ethylene glycol) with an average molecular weight of 350 (MPEG350) and a hydrophobic glycyl-L-glutamate as side groups, and then an antitumor (dach)platinum(II) (dach: trans-(+/-)-1,2-diaminocyclohexane) moiety was conjugated to the polymer using the dipeptide as a spacer. This polymeric platinum conjugate was found to be accumulated in the tumor tissue to a remarkably greater extent than in the normal tissue (tumor/tissue ratio >4), probably due to the excellent EPR effect and the long circulating properties of the polymer conjugate (t1/2beta=6.2 h and AUC=4020 nmol h/ml) compared with carboplatin (t1/2beta=0.42 h and AUC=120 nmol h/ml). The polymer conjugate also exhibited high in vitro cytotoxicity comparable to cisplatin against several human tumor cells tested.
Song
Rita
R
Department of Chemistry, Division of Nano Science, Ewha Womans University, Seoul 120-750, South Korea.
Joo Jun
Yong
Y
Ik Kim
Ju
J
Jin
Changbae
C
Sohn
Youn Soo
YS
D000465:Algorithms; D000818:Animals; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011108:Polymers / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D009943:Organophosphorus Compounds; D009944:Organoplatinum Compounds; D011108:Polymers; C108974:poly(phosphazene)