Metal-based coordination compounds, including the well-known cytostatic drug cisplatin, are widely used in the anticancer therapy. Generally, they exhibit high cytotoxicity not only towards malignant cells, but also towards non-malignant cells, which represents main problem of their clinical use. Herein, we describe the synthesis, characterization and biological testing of three trinuclear nickel(II) coordination compounds. Central nickel atoms are bridged by trithiocyanurate anion and coordinated by triamine and bis-benzimidazoles, respectively. To delineate a potential usage in anticancer therapy, we encapsulated the most cytotoxic complex into biomacromolecular protein cage apoferritin (FRT), forming FRTNi. FRT encapsulation markedly decreased the hemotoxicity of free Ni compounds. Despite FRTNi can be internalized through passive targeting by enhanced permeability and retention effect, we further introduced active targeting utilizing folate receptor (FR) via folic acid (FA)-modified FRT (FRTNiFA). Using breast cancer cell lines T-47D (FR+), MCF-7 (FR-) and non-malignant mammary gland derived cell line HBL-100 (FR-), we show pronounced FR-dependent internalization of FRTNiFA. Overall, we demonstrate that the FRT macromolecular nanocarrier provides a very low off-target toxicity, which could enable the use of highly toxic Ni compounds in cancer nanomedicine.

Department of 10 ray Crystallography and Crystal Chemistry Institute of General and Ecological Chemistry Lodz University of Technology Zeromskiego 116 PL 90 924 Lodz Poland

Department of Biochemistry Faculty of Science Charles University Hlavova 2030 8 CZ 128 43 Prague 2 Czech Republic

Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czech Republic; Central European Institute of Technology Brno University of Technology Purkynova 656 123 CZ 612 00 Brno Czech Republic

Department of Pediatric Hematology and Oncology s Charles University and University Hospital Motol 5 Uvalu 84 1 CZ 150 06 Prague 5 Czech Republic

Faculty of Chemistry University of Wroclaw 14 F Joliot Curie PL 50 383 Wroclaw Poland

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