DOI: 10.1002/marc.70341 ISSN: 1022-1336

Biocompatible Sulfobetaine Polymer‐Artemisinin Conjugates Inducing Ferroptosis in Cancer Cells: Synthesis by Mechanochemical Solid‐State Polymerization and Characterization

Naoki Doi, Yukinori Yamauchi, Yasushi Sasai, Ryosuke Nagai, Ayaka Koike, Madoka Ikawa, Toru Yoshimoto, Satoshi Yamada, Masayuki Kuzuya, Shin‐ichi Kondo
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ABSTRACT

Artemisinin derivatives (ARTs) induce ferrous iron‐dependent cell death (ferroptosis) by generating free radicals. Since the concentration of ferrous ions within cancer cells is high, the specific delivery of ARTs into cancer cells is advantageous for cancer therapy. Herein, we fabricate the biocompatible sulfobetaine polymer‐ARTs conjugates through the mechanochemical solid‐state copolymerization of sulfobetaine methacrylate (SBMA) and ARTs‐conjugated monomer. A polymer conversion rate of more than 90% is achieved within 60 min of copolymerization. The number average molecular weight and heterogeneity of resulting water‐soluble PSBMA‐ARTs conjugates are 8,000 g mol −1 and 1.10, respectively. The progressive changes in ESR spectrum intensity with DMPO as a spin trapping agent reveal that the PSBMA‐ARTs conjugates ferrous ion‐dependently produce free radicals. The PSBMA‐ARTs conjugates indicate the cytotoxic activities against human hepatoblastoma cell lines, and the IC 50 of artesunate and PSBMA‐ARTs conjugates are 136 and 211 µ

M
, respectively. Furthermore, it is demonstrated that PSBMA‐ARTs conjugates internalized into cells generate the free radicals and induce the lipid peroxidation in cell membranes or intracellularly involved in ferroptosis, determined by the live‐cell imaging with C11‐BODIPY. This novel drug carrier, which does not require drug release, is a promising cancer ferroptosis inducer for expanding pharmaceutical treatment strategies.

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