A Copper Silicate-Based Multifunctional Nanoplatform with Glutathione Depletion and Hypoxia Relief for Synergistic Photodynamic/Chemodynamic Therapy

Abstract

Chemodynamic therapy (CDT) alone cannot achieve sufficient therapeutic effects due to the excessive glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Developing a novel strategy to improve efficiency is urgently needed. Herein, we prepared a copper silicate nanoplatform (CSNP) derived from colloidal silica. The Cu(II) in CSNP can be reduced to Cu(I), which cascades to induce a subsequent CDT process. Additionally, benefiting from GSH depletion and oxygen (O₂) generation under 660 nm laser irradiation, CSNP exhibits both Fenton-like and hypoxia-alleviating activities, contributing to the effective generation of superoxide anion radical (^•O₂^-) and hydroxyl radical (^•OH) in the TME. Furthermore, given the suitable band-gap characteristic and excellent photochemical properties, CSNP can also serve as an efficient type-I photosensitizer for photodynamic therapy (PDT). The synergistic CDT/PDT activity of CSNP presents an efficient antitumor effect and biosecurity in both in vitro and in vivo experiments. The development of an all-in-one nanoplatform that integrates Fenton-like and photosensing properties could improve ROS production within tumors. This study highlights the potential of silicate nanomaterials in cancer treatment.

Keywords: antitumor; chemodynamic therapy; layered copper silicate; photodynamic therapy; reactive oxygen species; synergistic therapy; tumor hypoxia.

Figure 1

Therapeutic mechanism of CSNP for PDT under laser with tumor hypoxia modulation and GSH-triggered CDT.

Figure 2

(a) Power XRD spectrum of CSNP nanoplatform (JCPDS 27-0188). (b) High-resolution XPS spectra of Cu 2p in CSNP. (c) Wide-scan XPS spectrum of CSNP. (d) HAADF-STEM image and elemental mapping of Cu, Si, O of CSNP. Scale bar: 50 nm. (e) Size distribution of CSNP by DLS in DI water. (f) Surface zeta potential of CSNP in DI Water, PBS, and RPMI-1640 medium. (g) Tauc plots of (αhv)^1/2 vs. hv.

Figure 3

(a) Schematic diagram of the CDT process of CSNP as a natural Fenton-like nanoplatform and PDT process of electron/hole separation and photo-excited reaction of CSNP (NHE = normal hydrogen electrode); (b) GSH depletion curves of CSNP at different concentrations. (c) UV-vis-NIR spectrum of TMB solution containing CSNP and H₂O₂ at different pHs. (d) UV-vis-NIR spectrum of TMB solution (pH = 6.5) under different conditions (None, H₂O₂, and H₂O₂ + CSNP). (e) Comparison of CDT performance of without or with GSH. (f) Comparison of PDT performance of normoxia or hypoxia condition. (g) The fluorescence intensity of the solution with DCFH and CSNP under different 660 nm irradiation time.

Figure 4

(a) Cell viability of 293T and CT26 cells treated with varied concentrations of CSNP without laser exposure. (b) Phototoxicity of CSNP toward CT26 cells with different treatments. (c) The pictures of CT26 cells co-stained Calcein-AM/PI under different treatments by CLSM. Scale bar: 50 μm.

Figure 5

(a) Cellular uptake of PEG-Ce6-coated CSNP at different concentrations. (b) Detection of ^•O₂⁻ in CT26 cells with DHE probe under hypoxia (2% O₂) or normoxia (21% O₂) conditions. (c) Fluorescence images of ROS production in CT26 cells stained with DCFH-DA (a green ROS probe) following different treatments. Scale bar: 50 μm.

Figure 6

(a) Schematic illustration of the synergistic PDT and CDT regimen in a colorectal cancer mouse model. (b) Hemolysis rate at different concentrations of CSNP using saline and water as the negative and positive controls. (c) The growth curve of the tumor volume after different treatments. (d) Body weight change of CT26-bearing mice in the different treatments during 14 days. (e) Photographs of tumors dissected from living mice after various treatments. (f) Representative pictures of tumor tissue stained with hematoxylin-eosin from each group. Scale bar: 100 μm. (g) Blood analysis data of the CT26-bearing mice following an intratumoral injection of CSNP on Days 0 and 14 (CSNP at 10 mg/kg/dose; mean ± SD).