Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin.

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.