Quinoline‐Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action

Abstract

The role of autophagy in cancer is often complex, ranging from tumor-promoting to -suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo-[3-(η 6 -p-cymene)-1-(quinolin-8-yl-acetate)-3,1,2-RuC 2 B 9 H 10 ](4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor-promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy-prone glioblastomas. [a] Dr. . Results from flow cytometric and fluorescence microscopy analysis, and wound healing assay of MCF-7 cells incubated (72 h) with 3 and 4 at 20 μM. (A) CFSE staining (left panel) and wound healing assay (right panel); (B) AnnV/PI double staining; (C) DAPI-stained cells observed under fluorescence microscope (magnification X200). Arrows indicate apoptotic cells; (D) ApoStat staining; (E) AO staining. Experiments were run in triplicate. One representative example per each experiment is shown. For each staining protocol, the respective control (untreated cells) is also shown. (FL1, green channel; FL2, orange channel; FL3, dark red channel).

Preparing (Metalla)carboranes for Nanomedicine

“…It is particularly striking that the term “toxicity” is practically exclusively used to indicate the ability of the (metalla)carborane‐based drug, with or without carrier, to promote cell death in the tumour cell line or tissue examined (acute toxicity), and is solely evaluated in terms of half‐maximal inhibitory concentration (IC 50 ). A handful of examples exist, where IC 50 values were calculated for (metalla)carborane and borate compounds against model cell cultures for immune response, based on simple in vitro colorimetric assays, which will be briefly discussed below [51,52,203a,b] . But to the best of our knowledge, no specific investigations on the immune response upon (metalla)carborane‐based treatment, with or without encapsulation in a carrier system, have been reported.…”

“…[50] As for the ruthenium complex, the observation of strong aggregation proclivity prompted further biophysical investigations on the self-assembly of neutral metallacarboranes, namely ruthena-and molybdacarboranes, with the main scope of finding an appropriate formulation strategy to ensure biological stability for in vitro cell assays. [47,51,52] Nonetheless, we just started to scratch the surface of a phenomenon that, for organic colloidal drug aggregates, has been investigated for over two decades. As for the latter, also (metalla)carborane colloidal drug aggregates can be seen as self-assemblies of pure active drugs with nanometre size.…”

“…The nido analogue of indoborin should ensure at least better chemical stability under biological conditions [50] . As for the ruthenium complex, the observation of strong aggregation proclivity prompted further biophysical investigations on the self‐assembly of neutral metallacarboranes, namely ruthena‐ and molybdacarboranes, with the main scope of finding an appropriate formulation strategy to ensure biological stability for in vitro cell assays [47,51,52] …”

Ruthenacarborane and Quinoline: A Promising Combination for the Treatment of Brain Tumors

“…We have recently published an extensive review on (metalla)carboranes as "new" nanomedicine platforms [12], urging the boron community to consistently treat such compounds as potential colloidal aggregators in aqueous environment, and as such to implement standardized and homogeneous biophysical and biological tests. In this short communication, we focus our attention on further biological testing of a small series of compounds (see Figure 1), using a consistent and complementary approach to our earlier investigations [13]. In fact, we had shown that ruthenacarborane complex 2, which contains a quinolyl residue, displays a dual mode of action in vitro against human glioblastoma LN229 cells, namely it strongly inhibited proliferation and cytoprotective autophagy, with IC 50 values in the same concentration range as for the clinically approved drug chloroquine, which is unfortunately often associated with the development of drug resistance mechanisms [14][15][16].…”

Ruthenium carboranyl complexes with 2,2′-bipyridine derivatives for potential bimodal therapy application

“…Examples of ruthenacarborane complexes for potential BNCT are scarcer and comprise the 'Ru(h 6 -arene)' moiety [42][43][44][45][46] bonded to the carborane through a dithiolate motif or the upper pentagonal face of the cluster. In this frame, taking into consideration the high stability and the cytotoxic properties of [Ru(h 5 -C 5 H 5 )(2,2 0 -bipyridine)(Z)] + complexes we decided to replace the (h 5 -C 5 H 5 ) À ligand by the bioisostere dicarbollide anion.…”