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\u2032-bis(acrylamido)acetic acid sodium salt to yield PAA-1, polyaddition of amino-\u3b2-cyclodextrin and 2-methylpiperazine to 2,2\u2032-bis(acrylamido)acetic acid to give PAA-2 and polyaddition of the same amino-\u3b2-cyclodextrin and 2-methylpiperazine to 1,4-bis(acryloyl)piperazine to produce PAA-3. These polymers were reacted with cisplatin to give products containing between 8\u201370 wt.-% platinum. The amount of platinum released from the conjugates during incubation at pH 5.5 and pH 7.4 varied between 0\u201320%/72 h. PAA-3-Pt showed pH-dependent platinum release. The PAA-platinates were generally less toxic towards lung tumour cell lines in vitro. The IC50 for cisplatin being 2\u20135 \u3bcg/mL and for the PAA-platinates 1\u2013130 \u3bcg/mL, this was only to be expected due to their very different cellular pharmacokinetics. 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 cisplatin, PAA-2-Pt did show toxicity on repeated dosing, suggesting further investigations are needed to establish the biocompatibility of PAAs containing pendant \u3b2-cyclodextrin. PAA-1-Pt is suitable for further in vivo preclinical study in a range of solid tumour models