A nanodrug loading indocyanine green and metformin dually alleviating tumor hypoxia for enhanced chemodynamic/sonodynamic therapy

Abstract

As an emerging therapeutic method, the application of sonodynamic therapy (SDT) is hindered by its intrinsic unsatisfactory efficiency, the tumor hypoxia and low tumor specificity. Here, we reported the design of a tumor-targeting multifunctional nanodrug for O₂-generation/O₂-economization dually enhanced SDT/chemodynamic therapy (CDT) combination therapy. After the co-encapsulation of sonosensitizer indocyanine green (ICG) and oxidative phosphorylation inhibitor metformin (Met) into hollow MnO₂ (H-MnO₂) nanoparticles, ICG/Met@H-MnO₂@MPN-FA (IMMMF) was conveniently prepared through the formation of metal-phenolic networks (MPNs) between Fe³⁺ and folic acid (FA) immobilized tannic acid (TA, TA-FA) onto its surface. In vitro experiments indicated its selective uptake by 4T1 cells via the specific folate receptors-FA interactions. Responding to glutathione (GSH) and the acidic environment, the decomposition of IMMMF led to the release of Mn²⁺ and Fe²⁺ for enhanced CDT, and ICG for SDT. Furthermore, Met was continuously released to reduce O₂ consumption for enhanced SDT. More importantly, IMMMF catalyzed the endogenous H₂O₂ into O₂ for further enhanced SDT. Expectedly, both in vitro and in vivo antitumor assays confirmed its satisfactory therapeutic efficiency via CDT/SDT synergistic therapy. Hence, this intelligent sonocatalytic nanoagent emerges as a promising candidate for CDT-enhanced SDT, which also provides a novel strategy for dually alleviating tumor hypoxia with better therapy.

Keywords: Chemodynamic therapy; Hypoxia alleviation; Manganese dioxide nanoparticle; Metal–phenolic networks; Metformin; Sonodynamic therapy.