Mesoporous Silica Nanoparticles Enhance the Anticancer Efficacy of Platinum(IV)-Phenolate Conjugates in Breast Cancer Cell Lines
Ivana Predarska,
Mohamad Saoud,
Dijana Drača,
Ibrahim Morgan,
Teodora Komazec,
Thomas Eichhorn,
Ekatarina Mihajlović,
Duško Dunđerović,
Sanja Mijatović,
Danijela Maksimović-Ivanić,
Evamarie Hey-Hawkins,
Goran N. Kaluđerović
Affiliations
Ivana Predarska
Faculty of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Mohamad Saoud
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
Dijana Drača
Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Ibrahim Morgan
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
Teodora Komazec
Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Thomas Eichhorn
Department of Engineering and Natural Sciences, University of Applied Sciences Merseburg, Eberhard-Leibnitz-Str. 2, 06217 Merseburg, Germany
Ekatarina Mihajlović
Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Duško Dunđerović
Institute of Pathology, School of Medicine, University of Belgrade, dr Subotića 1, 11000 Belgrade, Serbia
Sanja Mijatović
Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Danijela Maksimović-Ivanić
Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia
Evamarie Hey-Hawkins
Faculty of Chemistry and Mineralogy, Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Goran N. Kaluđerović
Department of Engineering and Natural Sciences, University of Applied Sciences Merseburg, Eberhard-Leibnitz-Str. 2, 06217 Merseburg, Germany
The main reasons for the limited clinical efficacy of the platinum(II)-based agent cisplatin include drug resistance and significant side effects. Due to their better stability, as well as the possibility to introduce biologically active ligands in their axial positions constructing multifunctional prodrugs, creating platinum(IV) complexes is a tempting strategy for addressing these limitations. Another strategy for developing chemotherapeutics with lower toxicity relies on the ability of nanoparticles to accumulate in greater quantities in tumor tissues through passive targeting. To combine the two approaches, three platinum(IV) conjugates based on a cisplatin scaffold containing in the axial positions derivatives of caffeic and ferulic acid were prepared and loaded into SBA-15 to produce the corresponding mesoporous silica nanoparticles (MSNs). The free platinum(IV) conjugates demonstrated higher or comparable activity with respect to cisplatin against different human breast cancer cell lines, while upon immobilization, superior antiproliferative activity with markedly increased cytotoxicity (more than 1000-fold lower IC50 values) compared to cisplatin was observed. Mechanistic investigations with the most potent conjugate, cisplatin-diacetyl caffeate (1), and the corresponding MSNs (SBA-15|1) in a 4T1 mouse breast cancer cell line showed that these compounds induce apoptotic cell death causing strong caspase activation. In vivo, in BALB/c mice, 1 and SBA-15|1 inhibited the tumor growth while decreasing the necrotic area and lowering the mitotic rate.
