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Open AccessArticle

Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation

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Biological Nanochemistry Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary
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Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, H-1083 Budapest, Práter utca 50/a, Hungary
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1st Department of Internal Medicine and Oncology, Semmelweis University, H-1083 Budapest, Hungary
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Department of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, Hungary
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CROmed Translational Research Centers Ltd., H-1047 Budapest, Hungary
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Institute of Translational Medicine, Semmelweis University, H-1094 Budapest, Hungary
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Institute of Radiochemistry and Radioecology, University of Pannonia, H-8200 Veszprém, Hungary
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Department of Experimental Pharmacology, National Institute of Oncology, H-1122 Budapest, Hungary
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Helmholz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, D-01328 Dresden, Germany
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Institute of Atomic and Subatomic Physics, Atominstitut, TU Wien, A-1020 Vienna, Stadionallee 2, Austria
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Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
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Institute of Cancer Research, Medical University Vienna, A-1090 Vienna, Austria
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Laboratory for Environmental Chemistry and Bioanalytics, Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest, Pázmány Péter Stny. 1/A, Hungary
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Authors to whom correspondence should be addressed.
Pharmaceutics 2020, 12(5), 466; https://doi.org/10.3390/pharmaceutics12050466
Received: 30 March 2020 / Revised: 1 May 2020 / Accepted: 15 May 2020 / Published: 20 May 2020
(This article belongs to the Section Drug Delivery and Controlled Release)
Liposomes containing copper and the copper ionophore neocuproine were prepared and characterized for in vitro and in vivo anticancer activity. Thermosensitive PEGylated liposomes were prepared with different molar ratios of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and hydrogenated soybean phosphatidylcholine (HSPC) in the presence of copper(II) ions. Optimal, temperature dependent drug release was obtained at 70:30 DPPC to HSPC weight ratio. Neocuproine (applied at 0.2 mol to 1 mol phospholipid) was encapsulated through a pH gradient while using unbuffered solution at pH 4.5 inside the liposomes, and 100 mM HEPES buffer pH 7.8 outside the liposomes. Copper ions were present in excess, yielding 0.5 mM copper-(neocuproine)2 complex and 0.5 mM free copper. Pre-heating to 45 °C increased the toxicity of the heat-sensitive liposomes in short-term in vitro experiments, whereas at 72 h all investigated liposomes exhibited similar in vitro toxicity to the copper(II)-neocuproine complex (1:1 ratio). Thermosensitive liposomes were found to be more effective in reducing tumor growth in BALB/c mice engrafted with C26 cancer cells, regardless of the mild hyperthermic treatment. Copper uptake of the tumor was verified by PET/CT imaging following treatment with [64Cu]Cu-neocuproine liposomes. Taken together, our results demonstrate the feasibility of targeting a copper nanotoxin that was encapsulated in thermosensitive liposomes containing an excess of copper. View Full-Text
Keywords: neocuproine; themosensitive liposomal formulation; mild hyperthermia; copper nanotoxin; MRPS; in vivo antitumor effect neocuproine; themosensitive liposomal formulation; mild hyperthermia; copper nanotoxin; MRPS; in vivo antitumor effect
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MDPI and ACS Style

Gaál, A.; Garay, T.M.; Horváth, I.; Máthé, D.; Szöllősi, D.; Veres, D.S.; Mbuotidem, J.; Kovács, T.; Tóvári, J.; Bergmann, R.; Streli, C.; Szakács, G.; Mihály, J.; Varga, Z.; Szoboszlai, N. Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation. Pharmaceutics 2020, 12, 466. https://doi.org/10.3390/pharmaceutics12050466

AMA Style

Gaál A, Garay TM, Horváth I, Máthé D, Szöllősi D, Veres DS, Mbuotidem J, Kovács T, Tóvári J, Bergmann R, Streli C, Szakács G, Mihály J, Varga Z, Szoboszlai N. Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation. Pharmaceutics. 2020; 12(5):466. https://doi.org/10.3390/pharmaceutics12050466

Chicago/Turabian Style

Gaál, Anikó; Garay, Tamás M.; Horváth, Ildikó; Máthé, Domokos; Szöllősi, Dávid; Veres, Dániel S.; Mbuotidem, Jeremiah; Kovács, Tibor; Tóvári, József; Bergmann, Ralf; Streli, Christina; Szakács, Gergely; Mihály, Judith; Varga, Zoltán; Szoboszlai, Norbert. 2020. "Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation" Pharmaceutics 12, no. 5: 466. https://doi.org/10.3390/pharmaceutics12050466

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