Biotinylated Polymer-Ruthenium Conjugates: In Vitro and In Vivo Studies in a Triple-Negative Breast Cancer Model

Abstract

The need for new therapeutic approaches for triple-negative breast cancer is a clinically relevant problem that needs to be solved. Using a multi-targeting approach to enhance cancer cell uptake, we synthesized a new family of ruthenium(II) organometallic complexes envisaging simultaneous active and passive targeting, using biotin and polylactide (PLA), respectively. All compounds with the general formula, [Ru(η5-CpR)(P)(2,2′-bipy-4,4′-PLA-biotin)][CF3SO3], where R is -H or -CH3 and P is P(C6H5)3, P(C6H4F)3 or P(C6H4OCH3)3, were tested against triple-negative breast cancer cells MDA-MB-231 showing IC50 values between 2.3–14.6 µM, much better than cisplatin, a classical chemotherapeutic drug, in the same experimental conditions. We selected compound 1 (where R is H and P is P(C6H5)3), for further studies as it was the one showing the best biological effect. In a competitive assay with biotin, we showed that cell uptake via SMVT receptors seems to be the main transport route into the cells for this compound, validating the strategy of including biotin in the design of the compound. The effects of the compound on the hallmarks of cancer show that the compound leads to apoptosis, interferes with proliferation by affecting the formation of cell colonies in a dose-dependent manner and disrupts the cell cytoskeleton. Preliminary in vivo assays in N: NIH(S)II-nu/nu mice show that the concentrations of compound 1 used in this experiment (maximum 4 mg/Kg) are safe to use in vivo, although some signs of liver toxicity are already found. In addition, the new compound shows a tendency to control tumor growth, although not significantly. In sum, we showed that compound 1 shows promising anti-cancer effects, bringing a new avenue for triple-negative breast cancer therapy.

Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent

“…It measures the growth and/or proliferation inhibitory potency in cultured cells, thereby estimating the cytotoxicity of a complex. While the in vitro assay is certainly the easiest and most cost-effective, it does not take into account the essential pharmacokinetic and pharmacodynamic processes that operate in vivo and therefore fails to predict the true (pre)­clinical potential of a drug candidate. − Several highly cytotoxic metal complexes identified using cell-based in vitro assay failed to show appreciable antitumor activity in animal xenograft models due to poor pharmacokinetics. − Therefore, along with in vitro cytotoxicity screening, it is essential to evaluate the lead candidates for tolerability, efficacy, biodistribution, toxicity, etc., in suitable animal models at the early developmental stage of any new class of anticancer agent for assessing the true potential to enter (pre)­clinical studies. Encouragingly, in recent times, more and more metal-based antitumor agents have been investigated using a combination of in vitro as well as in vivo assays.…”

Insights into Mechanisms and Promising Triple Negative Breast Cancer Therapeutic Potential for a Water-Soluble Ruthenium Compound

“…We also demonstrated the impressive antimigratory, anti-invasive, and antiangiogenic properties of Ru-IM in TNBC cell lines . Cellular uptake studies showed good overall cellular uptake, with subcellular studies revealing increased mitochondria accumulation (52.7%) Preliminary in vivo efficacy studies of Ru-IM in a MDA-MB-231 mouse xenograft model (female NOD.SCID mice) afforded 56% tumor reduction following a 28-day efficacy trial with a dosing schedule of 5 mg/kg every other day. , While tumor growth inhibition in TNBC mouse models has been reported for other metal-based compounds, − tumor shrinkage in these in vivo models is unique to Ru-IM . Further evaluation also showed low systemic toxicity, with preferential accumulation of Ru in tumor tissue .…”

Fine-tuning the cytotoxicity of ruthenium(ii) arene compounds to enhance selectivity against breast cancers

“…26 Note that many other ruthenium complexes also display activity against breast cancers in vivo. [27][28][29] Since RAPTA compounds display promising activity in MCF-7 and MDA-MB-231 breast cancer cells but are not strongly cytotoxic, we hypothesized that more cytotoxic RAPTAlike complexes might offer enhanced activity against breast cancers while potentially retaining selectivity. Hence, we report a study assessing the in vitro effects of a series of rutheniumarene (RAPTA-type or RAPTA-like) compounds on MCF-7 and MDA-MB-231 breast cancer cell lines and non-tumorigenic L929 fibroblasts.…”

“…26 Note that many other ruthenium complexes also display activity against breast cancers in vivo. 27–29…”