Brigitte Kircher

Loading of Dicarboxylatoplatinum(II)‐NHC Complexes in Bacterial Ghosts as an Advanced Development in Cancer Therapy

ABSTRACT This study aimed to improve the drug‐like properties of benzimidazole‐based Pt(II)‐N‐heterocyclic carbene (NHC) complexes, particularly by enhancing their water solubility and delivery to cancer cells. Accordingly, four new Pt(II) complexes of the benzimidazol‐2‐ylidene type, featuring monodentate carboxylato ligands, were prepared and their structures confirmed through a combination of spectroscopic and crystallographic techniques. Their stability in aqueous solution and cell culture medium was investigated by 1 H NMR spectroscopy and HPLC‐MS analysis. Cytotoxicity was assessed using the MTT assay in ovarian cancer cell lines (A2780wt (cisplatin sensitive) and A2780cis (cisplatin resistant)) and a noncancerous bone marrow stromal cell line (HS‐5). Most complexes exhibited cytotoxicity comparable to or exceeding that of carboplatin, with preferential activity toward cancer cells. Loading of all four Pt(II) complexes into bacterial ghost cells (BGs) derived from two different nonpathogenic bacterial strains, Escherichia coli (E. coli) Nissle 1917 and E. coli NM522 notably enhanced the intracellular accumulation and cytotoxicity. Furthermore, mechanistic studies demonstrated that all tested compounds, regardless of formulation, induced apoptosis. Their potential to trigger immunogenic cell death was also evaluated, though only a modest effect was observed on selected hallmarks. Collectively, these findings highlight the potential of dicarboxylatoplatinum(II)‐NHC complexes, particularly loaded into BG‐based formulations, as promising anticancer drug candidates.

Synthesis and biological evaluation of salophen nickel(II) and cobalt(III) complexes as potential anticancer compounds

AbstractRecent in vitro investigations of N,N′‐bis(salicylidene)‐1,2‐phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL‐60 leukemia, and cisplatin‐sensitive and ‐resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1−3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4−6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin‐1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin‐1, but even enhanced upon simultaneous application to the tumor cells.