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. 2021 Mar 28;13(4):460.
doi: 10.3390/pharmaceutics13040460.

pH-Responsive Release of Ruthenium Metallotherapeutics from Mesoporous Silica-Based Nanocarriers

Minja Mladenović  1   2 , Ibrahim Morgan  3 , Nebojša Ilić  2   4 , Mohamad Saoud  3 , Marija V Pergal  5 , Goran N Kaluđerović  2   3 , Nikola Ž Knežević  1
Affiliations

pH-Responsive Release of Ruthenium Metallotherapeutics from Mesoporous Silica-Based Nanocarriers

Minja Mladenović et al. Pharmaceutics. .

Abstract

Ruthenium complexes are attracting interest in cancer treatment due to their potent cytotoxic activity. However, as their high toxicity may also affect healthy tissues, efficient and selective drug delivery systems to tumour tissues are needed. Our study focuses on the construction of such drug delivery systems for the delivery of cytotoxic Ru(II) complexes upon exposure to a weakly acidic environment of tumours. As nanocarriers, mesoporous silica nanoparticles (MSN) are utilized, whose surface is functionalized with two types of ligands, (2-thienylmethyl)hydrazine hydrochloride (H1) and (5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)hydrazine (H2), which were attached to MSN through a pH-responsive hydrazone linkage. Further coordination to ruthenium(II) center yielded two types of nanomaterials MSN-H1[Ru] and MSN-H2[Ru]. Spectrophotometric measurements of the drug release kinetics at different pH (5.0, 6.0 and 7.4) confirm the enhanced release of Ru(II) complexes at lower pH values, which is further supported by inductively coupled plasma optical emission spectrometry (ICP-OES) measurements. Furthermore, the cytotoxicity effect of the released metallotherapeutics is evaluated in vitro on metastatic B16F1 melanoma cells and enhanced cancer cell-killing efficacy is demonstrated upon exposure of the nanomaterials to weakly acidic conditions. The obtained results showcase the promising capabilities of the designed MSN nanocarriers for the pH-responsive delivery of metallotherapeutics and targeted treatment of cancer.

Keywords: cancer treatment; controlled drug delivery; mesoporous silica nanoparticles; pH-responsive drug delivery; ruthenium-based anticancer drugs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The schematic representation of (a) the synthesis process of the anticancer drug delivery systems for pH-responsive delivery of the cytotoxic ruthenium(II) complexes and (b) pH-forced hydrolysis of MSN-H1[Ru] and MSN-H2[Ru] and proposed structures of released metallotherapeutics.
Figure 2
Figure 2
(a) SEM micrograph of MSN; (b) BET N2 adsorption/desorption isotherms of the synthesized materials, with solid and dashed lines referring to the adsorption and desorption processes, respectively; (c) BJH average pore diameter distribution for synthesized materials and (d) SAXS patterns of prepared nanoparticles. Inset shows higher magnification of (110) and (200) reflections of MSN.
Figure 3
Figure 3
(a) FTIR spectra and (b,c) thermogravimetric analysis of the prepared materials.
Figure 4
Figure 4
(a) Release profiles of Ru(II)-based complexes from MSN-H1[Ru] (orange curves), MSN-H2[Ru] (green curves) and MSN[Ru] (blue curves) in PBS buffers with pH 5.0 (●), pH 6.0 (◆) and pH 7.4 (■) for 48 h, as measured by UV/VIS spectrophotometry at 410 nm; Release kinetics of (b) MSN[Ru]; (c) MSN-H1[Ru] and (d) MSN-H2[Ru] in PBS buffers with various pH values for 48 h, as measured by UV/VIS spectrophotometry at 410 nm, with absorbance values normalized to the absorbance of the supernatant from the same type of the material at 48 h and pH 5.0.
Figure 5
Figure 5
Viability of the B16F1 cells determined with CV and MTT assays treated (48 h) with different concentrations of investigated MSN on pH 5.0 and 7.2.
See this image and copyright information in PMC

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