Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin
2008; Elsevier BV; Volume: 29; Issue: 11 Linguagem: Inglês
10.1016/j.biomaterials.2007.12.017
ISSN1878-5905
AutoresKenji Kono, Chie Kojima, Nobuyuki Hayashi, Eiko Nishisaka, Katsuyuki Kiura, Shinobu Watarai, Atsushi Harada,
Tópico(s)Advanced biosensing and bioanalysis techniques
ResumoWe 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.
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