AbstractsOther

Novel macromolecular ruthenium chemotherapeutics were designed, synthesised and investigated in comparison to small drugs. Ruthenium possesses unique properties that have led to the development of exceptionally promising anticancer and antimetastatic therapeutics. The ruthenium(III) and ruthenium(II) drugs, NAMI-A [trans-RuCl4(DMSO)Im]-ImH+ and RAPTA-C [RuCl2(p-cymene)(PTA)], respectively, are two such candidates. The amplified benefit that can be gained by incorporating drugs into macromolecules has not previously been investigated for ruthenium agents. Two novel approaches to the synthesis of two types of rationally designed polymers, both containing ruthenium, were developed based on the ruthenium anticancer drugs NAMI-A and RAPTA-C. Both approaches utilised a distinct ligand of each drug. The first approach relied on the polymerisation of 4-vinyl imidazole via RAFT polymerisation. This created a macromolecular ligand for ruthenium(III) to which a ruthenium precursor could be subsequently conjugated. The second approach used the inherent activity of the amide group on the PTA ligand of RAPTA-C to allow for conjugation to poly(2-iodoethyl methacrylate) via the substitution of the reactive halide. Two pathways were investigated to conjugate RAPTA-C to the polymer and both routes were tested using n-butyl iodide as a model compound. 1D and 2D NMR experiments were used to assess the conjugation and elucidate the superior pathway: a two-step reaction involving the conjugation of PTA via its reactive amine and subsequent complexation to form RAPTA-C. Nano-sized carriers were designed to increase the cell uptake of these macromolecular drugs – micelles and nanotubes. Amphiphilic block copolymers incorporating NAMI-A or RAPTA-C were developed and self-assembled into micelles. RAPTA-C was also attached to cyclopeptide-polymer conjugates and self-assembled into nanotubes. A 1.5-times increase in cytotoxicity was found for NAMI-A micelles, and an outstanding 10-fold increase was found for both RAPTA-C micelles and nanotubes, when compared to the free drugs. An initial exploration into the antimetastatic activity revealed that the NAMI-A and RAPTA-C polymeric micelles significantly improved the inhibitory effects on both the migration and invasion of human breast cancer cells, indicating that it is highly probable that these nanoparticles will inhibit metastases in vivo. Thus, this work provides a substantial basis for the progression of these macromolecular chemotherapeutics into advanced biological studies.