Thermoresponsive injectable self-healing hydrogel containing polydopamine-coated Fe/Mo-doped TiO2 nanoparticles for efficient synergistic sonodynamic-chemodynamic-photothermal-chemo therapy

A smart hydrogel loading multifunctional nanoparticles and anticancer drugs was designed to achieve synergistic therapy against tumors with high efficiency and specificity. The thermoresponsive injectable self-healing hydrogel was prepared through the Schiff base between aldehyde-functionalized poly(2-(2-methoxyethoxy) ethyl methacrylate)–co-oligo(ethylene glycol) methacrylate-co-2-hydroxyethyl methacrylate) (P(MEO2MA-co-OEGMA-co-HEMA), APMOH) and hydroxypropyl chitosan (HPCS). The polydopamine-coated Fe/Mo-doped titanium dioxide nanoparticles (PDA@dTiO2 NPs) were prepared and dispersed into the hydrogel with anticancer drug doxorubicin (DOX). PDA@dTiO2 NPs as sonosensitizers can convert oxygen into singlet oxygen (1O2) under ultrasound (US) irradiation, achieving sonodynamic therapy (SDT). They were also considered nanoenzymes, generating oxygen to supply an oxygen source for SDT, producing hydroxyl radical (·OH) to achieve chemodynamic therapy (CDT), and eliminating glutathione (GSH) to enhance the level of oxidative stress. After near-infrared (NIR) irradiation, the temperature of the hydrogel increased due to the photothermal ability of the polydopamine (PDA) layer. When the temperature reached the hydrogel's lower critical solution temperature (LCST), the hydrophilic-hydrophobic transformation occurred, and the hydrogel volume contracted. Consequently, the release rate of PDA@dTiO2 NPs and DOX increased, improving the therapeutic effects. The nanocomposite hydrogel system can achieve synergistic sonodynamic-chemodynamic-photothermal-chemo therapy (SDT-CDT-PTT-CT) for tumors, providing a novel platform for synergistic tumor treatment.