Development and in vivo application of a water-soluble anticancer copper ionophore system using a temperature-sensitive liposome formulation

Anikó Gaál, Tamás M. Garay, Ildikó Horváth, Domokos Máthé, Dávid Szöllősi, Dániel S. Veres, Jeremiah Mbuotidem, Tibor Kovács, József Tóvári, Ralf Bergmann, Christina Streli, Gergely Szakács, Judith Mihály, Zoltán Varga, Norbert Szoboszlai

Research output: Contribution to journalArticlepeer-review

Abstract

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 [64 Cu]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.

Original languageEnglish (US)
Article number466
JournalPharmaceutics
Volume12
Issue number5
DOIs
StatePublished - May 2020
Externally publishedYes

Bibliographical note

Funding Information:
Funding: Supported by the ÚNKP-18-3-III-SE-17 (A.G.) New National Excellence Program of the Ministry of Human Capacities. The financial support of Ernst Mach Stipendien der Aktion Österreich-Ungarn under project No. ICM-2018-10557 (A.G.) and HunProtEx 2018-1.2.1-NKP-2018-00005 (Z.V., G.S.) are, hereby, acknowledged. Financial support from the 2019 Thematic Excellence Program (TUDFO/51757/2019-ITM) (J.T.) is greatly acknowledged. The study was supported by a grant of the Hungarian Government under contract number GINOP-2.3.2-15-2016-00016 (T.K.). Parts of the study were supported by the National Research, Development and Innovation Office of Hungary (NVKP-16-1-2016-0042) (D.M. and Je.M.).

Funding Information:
Supported by the ?NKP-18-3-III-SE-17 (A.G.) New National Excellence Program of the Ministry of Human Capacities. The financial support of Ernst Mach Stipendien der Aktion ?sterreich-Ungarn under project No. ICM-2018-10557 (A.G.) and HunProtEx 2018-1.2.1-NKP-2018-00005 (Z.V., G.S.) are, hereby, acknowledged. Financial support from the 2019 Thematic Excellence Program (TUDFO/51757/2019-ITM) (J.T.) is greatly acknowledged. The study was supported by a grant of the Hungarian Government under contract number GINOP-2.3.2-15-2016-00016 (T.K.). Parts of the study were supported by the National Research, Development and Innovation Office of Hungary (NVKP-16-1-2016-0042) (D.M. and Je.M.).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Copper nanotoxin
  • In vivo antitumor effect
  • MRPS
  • Mild hyperthermia
  • Neocuproine
  • Themosensitive liposomal formulation

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