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

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.

Gelatin-Graphene Oxide Nanocomposite Hydrogels for Kluyveromyces lactis Encapsulation: Potential Applications in Probiotics and Bioreactor Packings

“…Much progress has been made to achieve specific delivery goals regarding selectivity, bioavailability, and guided transport and targeting [44][45][46]. For instance, carbon-based nanomaterials such as graphene oxide, reduced graphene oxide, graphene quantum dots, graphene nanoribbons, silica-based nanocarriers, and inorganic nanoparticles [42,43,47,48] have been used to infiltrate tumors with the aid of cell-penetrating agents, and due to enhanced permeation and retention (EPR) mechanisms, they remain inside them for a more extended period [49][50][51].…”

Ruthenium-based antitumor drugs and delivery systems from monotherapy to combination therapy

“…The release of RuNHC was pH-dependent, with a release rate of 59.71% at pH 5.0, but almost no release at pH = 7.4. In 2021, Goran N. Kaluđerović and Nikola Ž. Knežević et al 139 also constructed a pH-responsive mesoporous silica nanocarrier for the release of ruthenium metal therapeutics. In Fig.…”

Are smart delivery systems the solution to overcome the lack of selectivity of current metallodrugs in cancer therapy?

“…Knežević and coworkers reported the passive delivery of [Ru(η 6 -p-cym)(TMH) Cl 2 ] (H1[Ru]) or [Ru(η 6 -p-cym)(DTPH)Cl 2 ] (H2 [Ru], where TMH = (2-thienylmethyl)hydrazine; DTPH = (5,6-dimethylthieno[2,3d]pyrimidin-4-yl)hydrazine) upon exposure to the tumour's acidic conditions. 102 For that, each complex was individually conjugated to the surface of mesoporous silica nanoparticles (MSN-H1[Ru] and MSN-H2[Ru], respectively) through weakly acidic-responsive hydrazone linkages ( pH < 6.5), cf. Fig.…”

“…The results found are encouraging for further investigation into the utilization of pH-responsive delivery systems for precision cancer therapy. 102 Lin and co-workers also explored the targeted and controlled delivery of a ruthenium organometallic complex by using silica nanoparticles. 103 The [Ru(η 6 -p-cym)(NHCI)Cl 2 ] ( p-cym = para-cymene; NHCI = (1,3-bis(4-(tert-butyl)benzyl)-2,3-dihydro-1H-imidazole) was loaded (26%) into mesoporous silica nanoparticles (90 nm), posteriorly coated with a chitosan-PEG-biotin conjugate.…”