Dual-responsive and NIR-driven free radical nanoamplifier with glutathione depletion for enhanced tumor-specific photothermal/thermodynamic/chemodynamic synergistic Therapy

• Published in: Biomaterials science 2022-10, Vol.1 (2), p.5912-5924
• Main Authors: Chen, Fanghui, Zhang, Xichen, Wang, Zining, Xu, Chensen, Hu, Jinzhong, Liu, Ling, Zhou, Jiancheng, Sun, Baiwang
• Format: Article
• Language: English
• Subjects: Accumulation; Cancer; Cell death; Copper; Decomposition reactions; Depletion; Effectiveness; Free radicals; Glutathione; Hyaluronic acid; Hydrogen peroxide; Hydroxyl radicals; Hyperthermia; Nanoparticles; Redox reactions; Scavenging; Tannic acid; Thermodynamics; Tumors
• ISSN: 2047-4830; 2047-4849
• DOI: 10.1039/d2bm01025a

The efficacy of free radical-based therapeutic strategies is severely hindered by nonspecific accumulation, premature release and glutathione (GSH) scavenging effects. Herein, a tumor microenvironment-responsive MPDA/AIPH@Cu-TA@HA (abbreviated as MACTH) nanoplatform was constructed by coating Cu 2+ and tannic acid (TA) on the surface of azo initiator (AIPH)-loaded mesoporous polydopamine (MPDA) nanoparticles and further modifying them with hyaluronic acid (HA) to achieve tumor-specific photothermal/thermodynamic/chemodynamic synergistic therapy (PTT/TDT/CDT). Once accumulated and internalized into cancer cells through CD44 receptor-mediated active targeting and endocytosis, the HA shell of MACTH would be preliminarily degraded by hyaluronidase (HAase) to expose the Cu-TA metal-phenolic networks, which would further dissociate in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Cu 2+ and AIPH. On the one hand, the released Cu 2+ could deplete the overexpressed GSH via redox reactions and produce Cu + , which in turn catalyzes endogenous H 2 O 2 into highly cytotoxic hydroxyl radicals (&z.rad;OH) for CDT. On the other hand, the local hyperthermia generated by MACTH under 808 nm laser irradiation could not only augment CDT efficacy through accelerating the Cu + -mediated Fenton-like reaction, but also trigger the decomposition of AIPH to produce biotoxic alkyl radicals (&z.rad;R) for TDT. The consumption of GSH and accumulation of oxygen-independent free radicals (&z.rad;OH/&z.rad;R) synergistically amplified intracellular oxidative stress, resulting in substantial apoptotic cell death and significant tumor growth inhibition. Collectively, this study provides a promising paradigm for customizing stimuli-responsive free radical-based nanoplatforms to achieve accurate and efficacious cancer treatment. A hyaluronidase and pH dual-responsive nanoplatform (MACTH) was developed with NIR-triggered free radical generation and glutathione depletion for tumor-specific photothermal/thermodynamic/chemodynamic synergistic therapy.