title: Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin.
abstract: We have developed poly(amidoamine) (PAMAM) dendrimers that have poly(ethylene glycol) (PEG) grafts at all dendrimer chain ends. To obtain PEG-modified dendrimers with sites for conjugation of anticancer drugs for this study, we prepared PAMAM G4 dendrimers that have a glutamic acid (Glu) residue at every chain end of dendrimer; PEG chains were attached to amino groups of Glu residues. We then combined the anticancer drug adriamycin to side chains of the Glu residues using an amide bond, [PEG-Glu(ADR)-G4], or hydrazone bond, [PEG-Glu(NHN-ADR)-G4]. For the dendrimers bearing adriamycin through amide linkage, adriamycin was released only slightly at pH 7.4 and 5.5. Although a negligible level of release occurred at pH 7.4 for dendrimers with adriamycin via hydrazone linkage, a remarkable extent of adriamycin release was induced at pH 5.5, which corresponds to the pH of late endosome. These adriamycin-bearing dendrimers showed much lower toxicity to HeLa cells than did free adriamycin. However, compared to PEG-Glu(ADR)-G4, PEG-Glu(NHN-ADR)-G4 exhibited 7 times higher cytotoxicity, suggesting the importance of pH-sensitive hydrazone linkage for high cytotoxicity. Furthermore, the PEG-modified dendrimers exhibited an equivalent level of toxicity to that of adriamycin-resistant SBC-3/ADR100 cells and their parent adriamycin-sensitive SBC-3 cells.
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan. kono@chem.osakafu-u.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Kono
authors.forename: Chie
authors.initials: C
authors.lastname: Kojima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Eiko
authors.initials: E
authors.lastname: Nishisaka
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.forename: Shinobu
authors.initials: S
authors.lastname: Watarai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Harada
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry* / Q000633:toxicity*; D004317:Doxorubicin / Q000737:chemistry* / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011073:Polyamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012680:Sensitivity and Specificity
chemical_list: D050091:Dendrimers; D011073:Polyamines; D011092:Polyethylene Glycols; D004317:Doxorubicin