Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation
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 soy...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/12/5/466 |
| _version_ | 1797567508177223680 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Anikó Gaál |
| collection | DOAJ |
| description | 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)<sub>2</sub> 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 [<sup>64</sup>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. |
| first_indexed | 2024-03-10T19:43:02Z |
| format | Article |
| id | doaj.art-9b41118e9fb848bf881c307bc2b2ce49 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T19:43:02Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-9b41118e9fb848bf881c307bc2b2ce492023-11-20T01:05:38ZengMDPI AGPharmaceutics1999-49232020-05-0112546610.3390/pharmaceutics12050466Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome FormulationAnikó Gaál0Tamás M. Garay1Ildikó Horváth2Domokos Máthé3Dávid Szöllősi4Dániel S. Veres5Jeremiah Mbuotidem6Tibor Kovács7József Tóvári8Ralf Bergmann9Christina Streli10Gergely Szakács11Judith Mihály12Zoltán Varga13Norbert Szoboszlai14Biological Nanochemistry Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryFaculty of Information Technology and Bionics, Pázmány Péter Catholic University, H-1083 Budapest, Práter utca 50/a, HungaryDepartment of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, HungaryDepartment of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, HungaryDepartment of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, HungaryDepartment of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, HungaryInstitute of Translational Medicine, Semmelweis University, H-1094 Budapest, HungaryInstitute of Radiochemistry and Radioecology, University of Pannonia, H-8200 Veszprém, HungaryDepartment of Experimental Pharmacology, National Institute of Oncology, H-1122 Budapest, HungaryDepartment of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, HungaryInstitute of Atomic and Subatomic Physics, Atominstitut, TU Wien, A-1020 Vienna, Stadionallee 2, AustriaInstitute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok körútja 2, H-1117 Budapest, HungaryBiological Nanochemistry Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryBiological Nanochemistry Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryLaboratory for Environmental Chemistry and Bioanalytics, Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest, Pázmány Péter Stny. 1/A, HungaryLiposomes 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)<sub>2</sub> 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 [<sup>64</sup>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.https://www.mdpi.com/1999-4923/12/5/466neocuproinethemosensitive liposomal formulationmild hyperthermiacopper nanotoxinMRPSin vivo antitumor effect |
| spellingShingle | 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 Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation Pharmaceutics neocuproine themosensitive liposomal formulation mild hyperthermia copper nanotoxin MRPS in vivo antitumor effect |
| title | Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation |
| title_full | Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation |
| title_fullStr | Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation |
| title_full_unstemmed | Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation |
| title_short | Development and In Vivo Application of a Water-Soluble Anticancer Copper Ionophore System Using a Temperature-Sensitive Liposome Formulation |
| title_sort | development and in vivo application of a water soluble anticancer copper ionophore system using a temperature sensitive liposome formulation |
| topic | neocuproine themosensitive liposomal formulation mild hyperthermia copper nanotoxin MRPS in vivo antitumor effect |
| url | https://www.mdpi.com/1999-4923/12/5/466 |
| work_keys_str_mv | AT anikogaal developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT tamasmgaray developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT ildikohorvath developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT domokosmathe developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT davidszollosi developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT danielsveres developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT jeremiahmbuotidem developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT tiborkovacs developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT jozseftovari developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT ralfbergmann developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT christinastreli developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT gergelyszakacs developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT judithmihaly developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT zoltanvarga developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation AT norbertszoboszlai developmentandinvivoapplicationofawatersolubleanticancercopperionophoresystemusingatemperaturesensitiveliposomeformulation |