Pd@Pt-GOx/HA as a Novel Enzymatic Cascade Nanoreactor for High-Efficiency Starving-Enhanced Chemodynamic Cancer Therapy

Abstract

Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O2 for cancer starvation therapy, while the O2 produced from the decomposition of endogenous H2O2 by the Pd@Pt with the CAT-like activity could accelerate the O2-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H2O2 content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H2O2 to generate abundant highly toxic •OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.

Enzyme Mimics for Engineered Biomimetic Cascade Nanoreactors: Mechanism, Applications, and Prospects

“…Many different mechanisms are involved and as such cancer therapeutic strategies resulting from nanozyme-based cascade nanoreactors have been classified as ROS-induced, starvation-chemodynamic synergistic, starvation-PDT combined therapies, and other strategies. Cancer therapy ROS-mediated therapy PtAu@SiO 2 CAT and OXD [137] ROS-mediated therapy Cu 2−x Te SOD, POD, OXD, and GPx [138] ROS-mediated therapy MoO 3−x NUs CAT and OXD [29] ROS-mediated therapy PZIF67-AT SOD, POD, CAT, and GPx [73] ROS-mediated therapy SSNEs SOD, POD, CAT, OXD, and GPx [139] Starvation-chemodynamic synergistic therapy DMSN-Au-Fe 3 O 4 NPs GOx and POD [28] Starvation-chemodynamic synergistic therapy Fe 3 O 4 -GOD@SiO 2 -HA GOx and POD [48] Starvation-chemodynamic synergistic therapy MIONzyme-GOx GOx and POD [37] Starvation-chemodynamic synergistic therapy CD44 MMSN/AuNPs nanozymes GOx, POD, and GPx [66] Starvation-chemodynamic synergistic therapy Co-Fc@GOx GOx and POD [58] Starvation-chemodynamic synergistic therapy Fe@ZIF-8@GOx NRs GOx and POD [51] Starvation-chemodynamic synergistic therapy PGC-DOX GOx and POD [140] Starvation-chemodynamic synergistic therapy Au/FeMOF@CPT NPs GOx and POD [62] Starvation-chemodynamic synergistic therapy ZIF@GOx/GQDs GOx and POD [52] Starvation-chemodynamic synergistic therapy IrRu-GOx@PEG NPs GOx and POD [70] Starvation-chemodynamic synergistic therapy Pd@Pt-GOx GOx, POD, and CAT [141] Starvation-PDT combined therapy P@Pt@P-Au-FA…”

“…As such, a nanozyme‐mediated starvation‐chemodynamic synergistic therapeutic strategy was established for highly‐efficiency anticancer activity with minimal biotoxicity. [ 141 ]…”

Construction of Novel Nanocomposites (Cu-MOF/GOD@HA) for Chemodynamic Therapy

“…The loading of GOD reduces the zeta potential to −4.84 ± 0.19 mV, implying the deprotonation of the –NH 2 of the GOD. The increase of zeta potential to −7.84 ± 0.28 mV due to the presence of the –OH of HA [ 32 , 33 ]. Furthermore, the X-ray diffraction (XRD) spectra of Cu-MOF, Cu-MOF/GOD and Cu-MOF/GOD@HA indicates that the loading of GOD and coating of HA did not influence the crystal structure of Cu-MOF ( Figure S3 ).…”

Reactive oxygen species may influence on the crossroads of stemness, senescence, and carcinogenesis in a cell via the roles of APRO family proteins

“…Tumor cells frequently overexpress catalase and produce enormous concentrations of hydrogen peroxide [48]. The tumor cell itself escapes the toxic action of hydrogen peroxide then destroys neighboring healthy normal cells [49]. Increased ROS is responsible for the oxidation of negative feedback loop and hence control the actions of other signaling pathways in tumor cells growth by the PI3K/AKT pathway [50].…”