Iron-Based Metal-Organic Frameworks as Multiple Cascade Synergistic Therapeutic Effect Nano-Drug Delivery Systems for Effective Tumor Elimination

Abstract

Efforts have been made to improve the therapeutic efficiency of tumor treatments, and metal-organic frameworks (MOFs) have shown excellent potential in tumor therapy. Monotherapy for the treatment of tumors has limited effects due to the limitation of response conditions and inevitable multidrug resistance, which seriously affect the clinical therapeutic effect. In this study, we chose to construct a multiple cascade synergistic tumor drug delivery system MIL-101(Fe)-DOX-TCPP-MnO₂@PDA-Ag (MDTM@P-Ag) using MOFs as drug carriers. Under near-infrared (NIR) laser irradiation, 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) and Ag NPs loaded on MDTM@P-Ag can be activated to generate cytotoxic reactive oxygen species (ROS) and achieve photothermal conversion, thus effectively inducing the apoptosis of tumor cells and achieving a combined photodynamic/photothermal therapy. Once released at the tumor site, manganese dioxide (MnO₂) can catalyze the decomposition of hydrogen peroxide (H₂O₂) in the acidic microenvironment of the tumor to generate oxygen (O₂) and alleviate the hypoxic environment of the tumor. Fe³⁺/Mn²⁺ will mediate a Fenton/Fenton-like reaction to generate cytotoxic hydroxyl radicals (·OH), while depleting the high concentration of glutathione (GSH) in the tumor, thus enhancing the chemodynamic therapeutic effect. The successful preparation of the tumor drug delivery system and its good synergistic chemodynamic/photodynamic/photothermal therapeutic effect in tumor treatment can be demonstrated by the experimental results of material characterization, performance testing and in vitro experiments.

Keywords: chemodynamic therapy; metal organic framework; photodynamic therapy; starvation therapy.

Scheme 1

A schematic illustration of MDTM@P−Ag nano-drug delivery system and its mechanisms of multiple cascade synergistic chemodynamic/photodynamic/photothermal therapy.

Figure 1

SEM images of (A) MIL−101(Fe), (B) MDTM, (C) MDTM@P−Ag. (D) SEM image of MDTM@P−Ag and elemental mappings of the corresponding SEM image. (E) XRD patterns of MIL−101(Fe), MD, MDT, MDTM, MDTM@P−Ag. (F) FT-IR spectra of MIL−101(Fe), MD, MDT, MDTM and MDTM@P−Ag. (G) Zeta potentials of MIL−101(Fe), MD, MDT, MDTM, MDTM@P−Ag (n = 3). (H) XPS spectra of the Fe element in MIL−101(Fe) and MDTM@P−Ag. (I) XPS spectra of the Mn element in MDTM@P−Ag. (J) XPS spectra of the Ag element in MDTM@P−Ag.

Figure 2

(A) The standard curve of DOX calculated by the absorbance at 490 nm. (B) The ability of MDTM@P−Ag to release DOX at different pH (n = 3). (C) The UV–vis absorption spectra of TMB without H₂O₂, with H₂O₂ and with both H₂O₂ and MIL−101(Fe) or MDTM@P−Ag. (D) The UV–vis absorption spectra of DTNB at different concentrations of MDTM treated with GSH. (E) The UV–vis absorption changes of DPBF at 410 nm during 10 min of irradiation with the 660 nm laser. (F) Capacity of different concentrations of MDTM@P−Ag to react with H₂O₂ to produce O₂.

Figure 3

(A) Temperature changes of MDTM@P−Ag with different concentrations under an 808 nm laser. (B) Heating/cooling curves of deionized water and MDTM@P−Ag under an 808 nm laser. (C) Heating/cooling cycle curves of MDTM@P−Ag under an 808 nm laser. (D) Heat map for temperature changes of MDTM@P−Ag with different concentrations under an 808 nm laser.

Figure 4

(A) The cell viability of HepG2 cells after treatment with different concentrations of different materials. (B) GSH contents in HepG2 cells after treatment with PBS, MIL−101(Fe), MDTM@P−Ag and MDTM@P−Ag + L, respectively. (C) Flow cytometry analysis of HepG2 cells after treatment with different materials, determined by Annexin V-FITC/PI staining (*** p < 0.001. n = 3).

Figure 5

(A) Fluorescence images of the generation of ROS in HepG2 cells stained with DCFH-DA after treatment with different materials. (B) Fluorescence images of HepG2 cells stained with JC-1 after treatment with different materials (the scale bar is 200 μm).