Characterization of Mechanochemical Solid-State Polymerization for Development of Sulfobetaine Polymer–Drug Conjugates: Design and Synthesis of Artemisinin-Conjugated Novel Methacrylamide Derivatives

Artemisinin derivatives (ARTs) induce ferrous iron-dependent cell death (ferroptosis) by generating free radicals. Polymer-ARTs conjugates would be advantageous for cancer therapy. In this paper, we designed and synthesized the three types of ART-conjugated novel methacrylamide derivatives with or without a spacer between the aromatic group and the methacrylamide moiety for mechanochemical solid-state polymerization. The polymer conversion rate of ART-ethyl-MA and ART-methyl-MA for 90 min polymerization was achieved at 78 and 49%, respectively. However, ART-MA, which does not have a spacer, could not polymerize owing to the lowest unoccupied molecular orbital (LUMO) expanding from the methacrylamide moiety to the aromatic sites. The resulting poly(ART-ethyl-MA) produced the thermodynamically stable end-chain radicals through the main-chain scission via mechanical energy, and the generated mechanoradicals would play a role as an initiator of the surrounding monomers. The biocompatible sulfobetaine polymer-ARTs conjugates were fabricated through the mechanochemical solid-state copolymerization of sulfobetaine methacrylate (SBMA) and ART-ethyl-MA. The number average molecular weight and heterogeneity of the resulting water-soluble PSBMA-ARTs conjugates were 8000 g mol^-1 and 1.10, respectively. These results suggest that the design of solid monomers suitable for mechanochemical solid-state polymerization would require a molecular structure susceptible to single solid-state electron transfer (SSET) and the stability of mechanoradicals generated by the main-chain scission of resulting polymer. The mechanochemical solid-state copolymerization of zwitterionic monomer and hydrophobic monomer would be advantageous for the development of biocompatible polymer-drug conjugates.