Conquering Cancer Multi-Drug Resistance Using Curcumin and Cisplatin Prodrug-Encapsulated Mesoporous Silica Nanoparticles for Synergistic Chemo- and Photodynamic Therapies

Abstract

Recently, the development of anti-cancer approaches using different physical or chemical pathways has shifted from monotherapy to synergistic therapy, which can enhance therapeutic effects. As a result, enormous efforts have been devoted to developing various delivery systems encapsulated with dual agents for synergistic effects and to combat cancer cells acquired drug resistance. In this study, we show how to make Institute of Bioengineering and Nanotechnology (IBN)-1-based mesoporous silica nanoparticles (MSNs) for multifunctional drug delivery to overcome drug resistance cancer therapy. Initially, curcumin (Cur)-embedded IBN-1 nanocomposites (IBN-1-Cur) are synthesized in a simple one-pot co-condensation and then immobilized with the prodrug of Cisplatin (CP) on the carboxylate-modified surface (IBN-1-Cur-CP) to achieve photodynamic therapy (PDT) and chemotherapy in one platform, respectively, in the fight against multidrug resistance (MDR) of MES-SA/DX5 cancer cells. The Pluronic F127 triblock copolymer, as the structure-directing agent, in nanoparticles acts as a p-glycoprotein (p-gp) inhibitor. These designed hybrid nanocomposites with excellent structural properties are efficiently internalized by the endocytosis and successfully deliver Cur and CP molecules into the cytosol. Furthermore, the presence of Cur photosensitizer in the nanochannels of MSNs resulted in increased levels of cellular reactive oxygen species (ROS) under light irradiation. Thus, IBN-1-Cur-CP showed excellent anti-cancer therapy in the face of MES-SA/DX5 resistance cancer cells, owing to the synergistic effects of chemo- and photodynamic treatment.

Keywords: Cisplatin; mesoporous silica nanoparticles; p-glycoprotein; photodynamic therapy; reactive oxygen species.

Figure 1

A schematic representation of the synthesis of IBN-1-Cur, subsequent surface modifications, and CP species loading.

Figure 2

(A) Nitrogen adsorption–desorption isotherms of (a) IBN-1-Cur, (b) IBN-1-Cur-2N, (c) IBN-1-Cur-2N (calcination), (d) IBN-1-Cur-GA, and (e) IBN-1-Cur-CP samples. (B) Pore size distribution of the IBN-1-Cur-2N (calcined sample). (C) Photographic representation of aqueous solutions containing (a) IBN-1-Cur, (b) IBN-1-Cur-2N, (c) IBN-1-Cur-GA, and (d) IBN-1-Cur-CP samples.

Figure 3

TEM images of (A) IBN-1-Cur-GA and (B) IBN-1-Cur-CP.

Figure 4

FT-IR spectra of; (a) as-synthesized IBN-1-Cur, (b) IBN-1-Cur-2N, (c) IBN-1-Cur-GA, and (d) IBN-1-Cur-CP.

Figure 5

UV-vis ninhydrin absorption spectra of; (a) pure ninhydrin, (b) IBN-1-Cur-2N, (c) IBN-1-Cur-GA, and (d) IBN-1-Cur-CP samples. The photographs of the sample tubes are shown in the inset figure.

Figure 6

Photostability studies of Cur, (A) UV-vis spectrum analysis of absorption bands of free Cur and IBN-1-Cur-CP samples by UV light irradiation with time up to 7 min in DMSO: H₂O (1:1 v/v) medium; (B) The samples of (a) free Cur (λ_max at 438 nm) and (b) IBN-1-Cur-CP (λ_max at 444 nm) irradiation under UV light up to 7 min, calculating the percentage photo-degradation rate; and (C) UV-vis absorbance values of Cur showing the leakage of Cur content from the IBN-1-Cur-CP formulation in cell culture medium for 24 h.

Figure 7

(A) The pH-dependent (pH 5.0 and 7.4) CP release for 24 h, (B) a diagram illustrating the mechanism of CP release in cancer cells, and highly active monoaqua CP binding to DNA.

Figure 8

The photodegradation effect of DPBF through the generation of singlet oxygen species from IBN-1-Cur-CP exposed to light irradiation at different periods. The inset figure represents the time-dependent photobleaching of DPBF absorbance at 412 nm upon a light irradiation in the presence of IBN-1-Cur-CP at the time point of black-0, red-5, green-10, blue-15, cyan-20, and magenta-25 min.

Figure 9

The cell viability of MES-SA/Dx5 cells treated with different concentrations of IBN-1-Cur-CP nanoformulation in the presence and absence of a light source.

Figure 10

IBN-1-Cur-CP (50 µg/mL) treatment in MES-SA/Dx5 cancer cells in the (a) absence and (b) presence of light irradiation as measured by the trypan blue assay (scale bar 200 μm).

Figure 11

(A) IBN-1-Cur-CP nanoparticles (50 µg/mL) cellular uptake with DAPI nuclear staining (blue), scale bar 20 μm, and (B) schematic illustration of IBN-1-Cur-CP cellular uptake, pH-sensitive drug release, and involvement in chemo- and photodynamic therapy in MES-SA/DX5 cells.

Figure 12

(A) Flow cytometry and (B) fluorescence microscopy of DCFDA assay to determine ROS in MES-SA/Dx5 cancer cells of (a) control; (b) IBN-1-Cur-CP, and (c) IBN-1-Cur-CP sample with light irradiation at the nanoparticle concentration of (50 μg/mL).

Figure 13

MMP assay on MES-SA/DX5 cells using the JC-1 staining method. (A) MMP depolarization was examined using a fluorescence microscope after cells were treated with IBN-1-Cur, IBN-1-Cur-CP (dark), and IBN-1-Cur-CP (light) (50 g/mL), a scale bar of 100 μm. (B) Quantitative analysis of the ratio of red/green fluorescent percentage intensity using a microplate reader.