A novel metal-organic coordination polymer based on Ru complexes for photoredox catalysis and photodynamic therapy of breast cancer

Abstract

This study introduces the synthesis and application of a novel metal-organic coordination polymer for photocatalytic cancer therapy. The material was prepared via coordination between Ru(dcbpy)₃Cl₂ and manganese ions, forming sheet-like nanostructures with strong visible-light absorption and high photostability. Upon light irradiation, Mn-Ru MOCPs not only produce singlet oxygen via a type II photodynamic pathway but also efficiently catalyze the oxidation of intracellular NADH with a high photocatalytic turnover frequency (TOF) of 175 h^-1. Moreover, the material facilitates the photocatalytic reduction of cytochrome c in the presence of NADH, triggering multimodal therapeutic effects including ROS erupt, NADH and ATP depletion, loss of mitochondrial membrane potential, and ultimately apoptosis. Both intracorporeal and extracorporeal experiments exhibited significant light-induced anticancer activity against 4T1 breast cancer cells and xenograft tumor models, with good biocompatibility and tumor-targeting capability.

Keywords: Metal-organic coordination polymer; Photodynamic therapy; Photoredox catalysis; Ru-based metal complexes.

Graphical abstract

Scheme 1

Schematic illustration of the Mn-Ru MOCPs' synthesis and its function as an MRI contrast agent, enabling guided photo-catalytic anticancer therapy.

Fig. 1

Preparation and Characterization of Mn-Ru MOCPs: (a) the synthesis procedures; (b) TEM; and (c) elemental mapping images of Mn-Ru MOCPs; (d) FTIR vibration spectra and (e) absorption (solid) and fluorescence (dashed) spectra for Ru(dcbpy)₃Cl₂ and Mn-Ru MOCPs; (f) high-resolution Ru 3d and (g) Mn 2p XPS spectra of Mn-Ru MOCPs; (h) photographs of Mn-Ru MOCPs dispersed in PBS at different times (concentration: 500 μg mL⁻¹).

Fig. 2

Phototherapy performance of Mn-Ru MOCPs: (a) the DPBF absorption and (b) the SOSG fluorescence changes of Ru-Mn MOCPs at different periods of laser irradiation; (c) ESR spectra trapped by TEMP of Ru-Mn MOCPs solution under different conditions; (d) the absorption and (e) emission spectra of Ru-Mn MOCPs after different laser irradiation durations in PBS solution; (f) the absorption spectra of Ru-Mn MOCPs at different periods of laser irradiation in the presence of NADH; the inserted photo shows the results of the Quantofix peroxide test rod after photocatalysis; (g) the dependence of lnA/A₀ at 339 nm in Figure (f) on irradiation time; (h) ESR spectra trapped by CYPMPO of Ru-Mn MOCPs solution with/without laser irradiation; (i) the absorption spectra after different irradiation times for Ru-Mn MOCPs (10 μg mL⁻¹) mediated photocatalytic reduction of oxidized cyt c (10 μM) by NADH (50 μM), the arrows indicate the direction of the absorbance change over time.

Fig. 3

Assessment of cellular uptake and distribution of Mn-Ru MOCPs and therapeutic efficacy of Mn-Ru MOCPs in vitro: (a) cell viabilities of 4T1cells after 24 h (green columns) and 48 h (orange columns) incubated with the Mn-Ru MOCPs at different concentrations (mean ± SD, n = 3); (b) dose-dependent viability of 4T1 cells treated with the Mn-Ru MOCPs at different concentrations under laser (orange columns) or dark (green columns) conditions; (c) time-dependent accumulation of Mn-Ru MOCPs (80 μg mL⁻¹) in 4T1 cells, as visualized by CLSM. red fluorescence indicates the probes; blue: DAPI (nuclei), scale bar: 10 μm; (d) subcellular localization of Mn-Ru MOCPs in 4T1 cells, scale bar: 10 μm; (e) semi-quantitative analysis via line-scanning intensity profiles, scale bar: 10 μm; (f) cellular Ru uptake quantified by ICP-MS (mean ± SD, n = 3).

Fig. 4

Assessment of Mitochondrial membrane potential, intracellullar NADH and ATP, and ROS generation of Mn-Ru MOCPs (80 μg mL⁻¹) in vitro: (a) assessment of mitochondrial membrane potential in 4T1 cells via JC-1 staining following various treatments, scale bar: 200 μm; (b) the intracellular NADH and (c) ATP level in 4T1 cells following a 12 h incubation with the Mn-Ru MOCPs with (orange columns) or without (green columns) the laser illumination; (d) the measurement of intracellular ROS of 4T1 cells by DCFH-DA staining under various treatments, scale bar: 50 μm; (e) the intracellular H₂O₂ level of 4T1 cells after 12 h incubated with the Mn-Ru MOCPs with (orange columns) or without (green columns) the laser illumination.

Fig. 5

Assessment of in vitro therapy of Mn-Ru MOCPs: (a) live/dead double staining of 4T1 cells using Calcein AM/PI, scale bar: 200 μm) and (b) Annexin V-FITC/PI (scale bar: 100 μm) after different treatments; (c) the fluorescence semi-quantitative analysis of different groups in Figure b; (d) flow cytometry analysis results of apoptosis in 4T1 cells (Annexin V-FITC and PI staining), the upper is blank control, the under cells were treated with Mn-Ru MOCPs with laser irradiation.

Fig. 6

In vivo distribution of Mn-Ru MOCPs: (a) T1-weighted MRI and (b) relaxation rate r₁ of Mn-Ru MOCPs with different concentrations of Mn; (c) schedule of T1 MRI in mice using Mn-Ru MOCPs; (d) serial in vivo MRI of the tumor-bearing mice after Mn-Ru MOCPs administration; (e) time-dependent quantitative analysis of signal intensity in tumor regions (circled).

Fig. 7

Therapeutic efficacy of Mn-Ru MOCPs in vivo: (a) schedule of the tumor-bearing mouse therapeutic profile; (b) final tumor weight, (c) tumor volume, and (d) body weight of tumor-bearing mice receiving various treatments, (mean ± SD, n = 4); (e) representative hematoxylin-eosin and (f) TUNEL staining of tumor sections of various treatment group, scale bar: 100 μm; hematoxylin-eosin staining of (g) heart, (h) liver, (i) spleen, (j) lung, and (k) kidney organs after different treatment, scale bar: 100 μm.