Ion interference strategy cooperated with cascade chemodynamic/gas/chemo therapeutic functions of Mn/Ca/Pt-installed hydrogel network for breast cancer treatment

초록

Essential mineral ions-crosslinked hyaluronic acid (HA)-based hydrogel including platinum drug was designed for providing quadruple ion interference/cascade chemodynamic/gas/chemotherapy functions. MnS, CaO<inf>2</inf>, and cisplatin (CDDP) were incorporated into the hyaluronic acid-dopamine (HD) dispersion as gel crosslinkers and therapeutic cargos. Ca2+ overload from CaO<inf>2</inf> can destroy mitochondrial balance, leading to calcicoptosis. Moreover, CaO<inf>2</inf> can generate H<inf>2</inf>O<inf>2</inf> spontaneously and it may be converted to hydroxyl radicals by Mn2+ (from MnS) based on Fenton-like reaction (for chemodynamic therapy). Simultaneously, Mn2+ might be oxidized into Mn4+ by Ca2+ and H<inf>2</inf>O<inf>2</inf> (both from CaO<inf>2</inf>), and Mn4+ can consume GSH and downregulate GPX4 level for the initiation of non-ferrous ferroptosis. H<inf>2</inf>S released from MnS serves as a gas therapy agent and disrupts mitochondrial homeostasis, as induced by CaO<inf>2</inf> overload. In addition, CDDP was incorporated into the hydrogel network to enhance chemotherapeutic efficacy. Ca and Mn ions coordination with catechol groups of HD polymer also attributed to hydrogel crosslinking. One-pot hydrogel system equipped with rheological modulation, immediate and homogeneous gelation, injectability, self-healing, and biodegradability can ensure prolonged therapeutic actions and acceptable systemic safety following peritumoral injection. It is expected that devised hydrogel system can be applied as combined ion interference/cascade chemodynamic/gas/chemo modalities to neoadjuvant and adjuvant cancer therapy. © 2025 Elsevier B.V.

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