Physicochemical properties and hematocompatibility of layered double hydroxide-based anticancer drug methotrexate delivery system

Sang Yong Jung; Hyoung Mi Kim; Soonjae Hwang; Do Gak Jeung; Ki Jong Rhee; Jae Min Oh

doi:10.3390/pharmaceutics12121210

Physicochemical properties and hematocompatibility of layered double hydroxide-based anticancer drug methotrexate delivery system

Sang Yong Jung, Hyoung Mi Kim, Soonjae Hwang, Do Gak Jeung, Ki Jong Rhee, Jae Min Oh

Biomedical Laboratory Science

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

A layered double hydroxide (LDH)-based anticancer delivery system was investigated in terms of crystalline phase, particle size, hydrodynamic radius, zeta potential, etc. through in vitro and in vivo study. Size controlled LDH with anticancer drug methotrexate (MTX) incorporation was successfully prepared through step-by-step hydrothermal reaction and ion-exchange reaction. The MTX-LDH was determined to have a neutral surface charge and strong agglomeration in the neutral aqueous condition due to the surface adsorbed MTX; however, the existence of proteins in the media dramatically reduced agglomeration, resulting in the hydrodynamic radius of MTX-LDH being similar to the primary particle size. The protein fluorescence quenching assay exhibited that MTX readily reduced the fluorescence of proteins, suggesting that the interaction between MTX and proteins was strong. On the other hand, MTX-LDH showed much less binding constant to proteins compared with MTX, implying that the protein interaction of MTX was effectively blocked by the LDH carrier. The in vivo hemolysis assay after intravenous injection of MTX-LDH showed neither significant reduction in red blood cell number nor membrane damage. Furthermore, the morphology of red blood cells in a mouse model did not change upon MTX-LDH injection. Scanning electron microscopy showed that the MTX-LDH particles were attached on the blood cells without serious denaturation of cellular morphology, taking advantage of the cell hitchhiking property.

Original language	English
Article number	1210
Pages (from-to)	1-14
Number of pages	14
Journal	Pharmaceutics
Volume	12
Issue number	12
DOIs	https://doi.org/10.3390/pharmaceutics12121210
Publication status	Published - 2020 Dec

Bibliographical note

Funding Information:
related analyses; D.-G.J. synthesized MTX-LDH; S.H. carried out the animal experiments; K.-J.R. planned the Funding: This work was supported by Radiation Technology R&D program through the National Research biological experiments and suggested the main discussion points; J.-M.O. performed conceptualization and supervised the writing process. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: The authors declare no conflict of interest. Funding: This work was supported by Radiation Technology R&D program through the National Research

Funding Information:
This work was supported by Radiation Technology R&D program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (2017M2A2A6A05016600, 2017M2A2A6A05093711).

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

All Science Journal Classification (ASJC) codes

Pharmaceutical Science

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10.3390/pharmaceutics12121210

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@article{faf9229234f243759abb36e2734176ea,

title = "Physicochemical properties and hematocompatibility of layered double hydroxide-based anticancer drug methotrexate delivery system",

abstract = "A layered double hydroxide (LDH)-based anticancer delivery system was investigated in terms of crystalline phase, particle size, hydrodynamic radius, zeta potential, etc. through in vitro and in vivo study. Size controlled LDH with anticancer drug methotrexate (MTX) incorporation was successfully prepared through step-by-step hydrothermal reaction and ion-exchange reaction. The MTX-LDH was determined to have a neutral surface charge and strong agglomeration in the neutral aqueous condition due to the surface adsorbed MTX; however, the existence of proteins in the media dramatically reduced agglomeration, resulting in the hydrodynamic radius of MTX-LDH being similar to the primary particle size. The protein fluorescence quenching assay exhibited that MTX readily reduced the fluorescence of proteins, suggesting that the interaction between MTX and proteins was strong. On the other hand, MTX-LDH showed much less binding constant to proteins compared with MTX, implying that the protein interaction of MTX was effectively blocked by the LDH carrier. The in vivo hemolysis assay after intravenous injection of MTX-LDH showed neither significant reduction in red blood cell number nor membrane damage. Furthermore, the morphology of red blood cells in a mouse model did not change upon MTX-LDH injection. Scanning electron microscopy showed that the MTX-LDH particles were attached on the blood cells without serious denaturation of cellular morphology, taking advantage of the cell hitchhiking property.",

author = "Jung, {Sang Yong} and Kim, {Hyoung Mi} and Soonjae Hwang and Jeung, {Do Gak} and Rhee, {Ki Jong} and Oh, {Jae Min}",

note = "Funding Information: related analyses; D.-G.J. synthesized MTX-LDH; S.H. carried out the animal experiments; K.-J.R. planned the Funding: This work was supported by Radiation Technology R&D program through the National Research biological experiments and suggested the main discussion points; J.-M.O. performed conceptualization and supervised the writing process. All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: The authors declare no conflict of interest. Funding: This work was supported by Radiation Technology R&D program through the National Research Funding Information: This work was supported by Radiation Technology R&D program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (2017M2A2A6A05016600, 2017M2A2A6A05093711). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

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doi = "10.3390/pharmaceutics12121210",

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AU - Jung, Sang Yong

AU - Kim, Hyoung Mi

AU - Hwang, Soonjae

AU - Jeung, Do Gak

AU - Rhee, Ki Jong

AU - Oh, Jae Min

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PY - 2020/12

Y1 - 2020/12

N2 - A layered double hydroxide (LDH)-based anticancer delivery system was investigated in terms of crystalline phase, particle size, hydrodynamic radius, zeta potential, etc. through in vitro and in vivo study. Size controlled LDH with anticancer drug methotrexate (MTX) incorporation was successfully prepared through step-by-step hydrothermal reaction and ion-exchange reaction. The MTX-LDH was determined to have a neutral surface charge and strong agglomeration in the neutral aqueous condition due to the surface adsorbed MTX; however, the existence of proteins in the media dramatically reduced agglomeration, resulting in the hydrodynamic radius of MTX-LDH being similar to the primary particle size. The protein fluorescence quenching assay exhibited that MTX readily reduced the fluorescence of proteins, suggesting that the interaction between MTX and proteins was strong. On the other hand, MTX-LDH showed much less binding constant to proteins compared with MTX, implying that the protein interaction of MTX was effectively blocked by the LDH carrier. The in vivo hemolysis assay after intravenous injection of MTX-LDH showed neither significant reduction in red blood cell number nor membrane damage. Furthermore, the morphology of red blood cells in a mouse model did not change upon MTX-LDH injection. Scanning electron microscopy showed that the MTX-LDH particles were attached on the blood cells without serious denaturation of cellular morphology, taking advantage of the cell hitchhiking property.

AB - A layered double hydroxide (LDH)-based anticancer delivery system was investigated in terms of crystalline phase, particle size, hydrodynamic radius, zeta potential, etc. through in vitro and in vivo study. Size controlled LDH with anticancer drug methotrexate (MTX) incorporation was successfully prepared through step-by-step hydrothermal reaction and ion-exchange reaction. The MTX-LDH was determined to have a neutral surface charge and strong agglomeration in the neutral aqueous condition due to the surface adsorbed MTX; however, the existence of proteins in the media dramatically reduced agglomeration, resulting in the hydrodynamic radius of MTX-LDH being similar to the primary particle size. The protein fluorescence quenching assay exhibited that MTX readily reduced the fluorescence of proteins, suggesting that the interaction between MTX and proteins was strong. On the other hand, MTX-LDH showed much less binding constant to proteins compared with MTX, implying that the protein interaction of MTX was effectively blocked by the LDH carrier. The in vivo hemolysis assay after intravenous injection of MTX-LDH showed neither significant reduction in red blood cell number nor membrane damage. Furthermore, the morphology of red blood cells in a mouse model did not change upon MTX-LDH injection. Scanning electron microscopy showed that the MTX-LDH particles were attached on the blood cells without serious denaturation of cellular morphology, taking advantage of the cell hitchhiking property.

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Physicochemical properties and hematocompatibility of layered double hydroxide-based anticancer drug methotrexate delivery system

Abstract

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