Synthesis, characterisation and antitumour activity of platinum(II) complexes of novel functionalised poly(amido amine)s

Polyamidoamine polymers were prepared by hydrogen-transfer polyaddition of 2-methylpiperazine to 2,2'-bis(acrylamido)acetic acid sodium salt to yield PAA-1, polyaddition of amino-beta-cyclodextrin and 2-methylpiperazine to 2, 2'-bis(acrylamido)acetic acid to give PAA-2 and polyaddition of the same am ino-beta-cyclodextrin and 2-methylpiperazine to 1,4-bis(acryloyl)piperazine to produce PAA-3. These polymers were reacted with cisplatin to give produ cts containing between 8-70 wt.-% platinum. The amount of platinum released from the conjugates during incubation at pH 5.5 and pH 7.4 varied between 0-20%/72 h. PAA-3-Pt showed pH-dependent platinum release. The PAA-platinat es were generally less toxic towards lung tumour cell lines in vitro. The I C50 for cisplatin being 2-5 mu g/mL and for the PAA-platinates 1-130 mu g/m L, this was only to be expected due to their very different cellular pharma cokinetics. In vivo experiments showed that the PAA-1-Pt and PAA-2-Pt were equi-active compared with cisplatin against an i.p. L1210 leukaemia model, confirming their ability to liberate biologically active platinum species. Whereas PAA-1-Pt was significantly less toxic than cispiatin. PAA-2-Pt did show toxicity on repeated dosing, suggesting further investigations are nee ded to establish the biocompatibility of PAAs containing pendant beta-cyclo dextrin. PAA-1-Pt is suitable for further in vivo preclinical study in a ra nge of solid tumour models.