Platinum(II)-Dendrimer Conjugates: Synthesis and Investigations on Cytotoxicity, Cellular Distribution, Platinum Release, DNA, and Protein Binding

A set of polyamidoamine dendrimers were modified in such a way that they are able to act as carrier and drug delivery systems for cytostatics. The terminal binding of the non-proteinogenic D,L-2,3-diaminopropionic acid allowed the attachment of the cytotoxic PtX2 moiety (X = Cl, 1: A(PtI2)(2), A(PtCl2)(2), B(PtI2)(2), B(PtCl2)(2)), while the 2-carboxypentanedioic acid acted as leaving group for [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) ((m-4F-Pt)(3)C, (m-4F-Pt)(3)D). Polyethylene glycol) chains at C(PtI2)(3) and C(PtCl2)(3) as well as (m-4F-Pt)(3)C and (m-4F-Pt)(3)D mediated sufficient water solubility. Additional dansyl residues (B(PtI2)(2) and (m-4F-Pt)(3)D) made a simultaneous determination of platinum (graphite furnace atomic absorption spectroscopy (GF-AAS)) and dendrimer (fluorimetry) possible. The ethylenediamine-terminated dendrimers were typically accumulated into MCF-7 cells in clathrin-dependent pathways and targeted the platinum moieties to the nuclear compartment. The highest intracellular platinum concentration and DNA binding caused the dendrimers A(PtX2)(2) and B(PtX2)(2). A coordinative DNA binding, however, is very unlikely because of low cytotoxic effects. (m-4FPt)(3)C and (m-4F-Pt)(3)D are labile conjugates and liberated the m-4F-Pt moiety in biological systems. The effects of these dendrimers were similar to that of the reference compounds m-4F-PtCl2 and m-4F-Pt(H2O)(2).