Published March 28, 2021 | Version v1
Journal article Open

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

  • 1. BioSense Institute, University of Novi Sad, Dr Zorana Đinđića 1, 21000 Novi Sad, Serbia
  • 2. Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
  • 3. Department of Civil, Geo and Environmental Engineering, Chair of Urban Water Systems Engineering, Technical University of Munich, Am Coulombwall 3, 85748 Garching, Germany
  • 4. Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia
  • 5. Department of Engineering and Natural Sciences, University of Applied Sciences Merseburg, Eberhard-Leibnitz-Strasse 2, 06217 Merseburg, Germany


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.


The authors acknowledge financial support from the German Academic Exchange Service (DAAD) [grant number: 57393212]. The authors would like to thank the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support (Grant No: 451-03-9/2021-14/200358 (N.Ž.K. and M. M) and Grant No. 451-03-9/2021-14/200026 (M.V.P.)). This Research was supported by the Science Fund of the Republic of Serbia, PROMIS, #6060755, PRECAST (N.Ž.K. and M.M) and has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement 952259 (NANOFACTS) and grant agreement No: 739570 (ANTARES).



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