Biodegradable Manganese-Doped Calcium Phosphate Nanotheranostics for Traceable Cascade Reaction-Enhanced Anti-Tumor Therapy

TLDR

Glucose oxidase has emerged as a key enzyme catalyst for cancer therapy in recent years. The study develops biodegradable, tumor‑acidity‑responsive GOx‑MnCaP nanoparticles loaded with doxorubicin for MRI‑guided, cascade‑reaction‑enhanced cooperative cancer treatment. GOx oxidizes tumor glucose to generate H₂O₂, which Mn²⁺ converts into hydroxyl radicals via a Fenton‑like reaction, while the resulting acidity accelerates nanoparticle degradation and Mn²⁺ release for MRI monitoring. In 4T1‑bearing mice, the DOX‑loaded GOx‑MnCaP nanotheranostics achieved superior tumor suppression with minimal side effects, demonstrating translational potential.

Abstract

Glucose oxidase (GOx) has been recognized as a "star" enzyme catalyst involved in cancer treatment in the past few years. Herein, GOx is mineralized with manganese-doped calcium phosphate (MnCaP) to form spherical nanoparticles (GOx-MnCaP NPs) by an in situ biomimetic mineralization method, followed by the loading of doxorubicin (DOX) to construct a biodegradable, biocompatible, and tumor acidity-responsive nanotheranostics for magnetic resonance imaging (MRI) and cascade reaction-enhanced cooperative cancer treatment. The GOx-driven oxidation reaction can effectively eliminate intratumoral glucose for starvation therapy, and the elevated H2O2 is then converted into highly toxic hydroxyl radicals via a Mn2+-mediated Fenton-like reaction for chemodynamic therapy (CDT). Moreover, the acidity amplification due to the gluconic acid generation will in turn accelerate the degradation of the nanoplatform and promote the Mn2+-H2O2 reaction for enhanced CDT. Meanwhile, the released Mn2+ ions can be used for MRI to monitor the treatment process. After carrying the anticancer drug, the DOX-loaded GOx-MnCaP can integrate starvation therapy, Mn2+-mediated CDT, and DOX-induced chemotherapy together, which showed greatly improved therapeutic efficacy than each monotherapy. Such an orchestrated cooperative cancer therapy demonstrated high-efficiency tumor suppression on 4T1 tumor-bearing mice with minimal side effects. Our findings suggested that the DOX-loaded GOx-MnCaP nanotheranostics with excellent biodegradability and biocompatibility hold clinical translation potential for cancer management.