Based on their drug delivery properties and activity against
tumors, we combined PAMAM
dendrimers with various
platinum(IV) complexes in order to provide an improved approach of anticancer treatment.
Platinum(IV) complexes were linked to terminal NH2 moieties of PAMAM
dendrimers of generation 2 (G2) and 4 (G4) via
amide bonds. Conjugates were characterized by 1H and 195Pt NMR spectroscopy, ICP-MS and in representative cases by pseudo-2D diffusion-ordered NMR spectroscopy. Additionally, the reduction behavior of conjugates in comparison to corresponding
platinum(IV) complexes was investigated, showing a faster reduction of conjugates. Cytotoxicity was evaluated via the MTT assay in human cell lines (A549, CH1/PA-1, SW480), revealing IC50 values in the low micromolar to high picomolar range. The synergistic combination of PAMAM
dendrimers and
platinum(IV) complexes resulted in up to 200 times increased cytotoxic activity of conjugates in consideration of the loaded
platinum(IV) units compared to their
platinum(IV) counterparts. The lowest IC50 value of 780 ± 260 pM in the CH1/PA-1
cancer cell line was detected for an
oxaliplatin-based G4
PAMAM dendrimer conjugate. Finally, in vivo experiments of a
cisplatin-based G4
PAMAM dendrimer conjugate were performed based on the best toxicological profile. A maximum
tumor growth inhibition effect of 65.6% compared to 47.6% for
cisplatin was observed as well as a trend of prolonged animal survival.