Polymeric micelles with pendant dicarboxylato chelating ligands prepared via a michael addition for cis -platinum drug delivery

A new monomer with a neighboring carboxylate functional group was prepared via carbon Michael addition between ethylene glycol dimethacrylate and malonate. The monomer, 1,1-di-tert-butyl 3-(2-(methacryloyloxy)ethyl) butane-1,1,3-tricarboxylate (MAETC), was polymerized in a controlled manner using RAFT polymerization. After deprotection and the conjugation of platinum drugs, a macromolecular Pt complex was created, which was found to be insoluble in water. 195Pt NMR revealed that the desired complex has been formed next to a minor fraction of other Pt complexes. Block copolymers were prepared using poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMEMA) as macroRAFT agent for chain extension with the synthesized monomer to yield three different block copolymers with varying PMAETC block lengths. Subsequent conjugation to platinum resulted in amphiphilic block copolymers, which can ultimately generate micelles. The length of the core block had significant contribution to the micelle sizes with the micelle size increasing with an increase of the hydrophobic block length. The polymers prior to platinum conjugation were found to be nontoxic when in contact with A549, a lung cancer cell line. After conjugation with the platinum drug, the micelle with the shortest PMAETC block length was found to have the highest toxicity, which may be due to the fastest cisplatin release when compared to the longer PMAETC block lengths.