Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy

C. S. Lee; T. W. Kim; Y. Kang; Y. Ju; J. Ryu; H. Kong; Y. S. Jang; D. E. Oh; S. J. Jang; H. Cho; S. Jeon; J. Kim; T. H. Kim

doi:10.1016/j.mtchem.2022.101083

Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy

C. S. Lee, T. W. Kim, Y. Kang, Y. Ju, J. Ryu, H. Kong, Y. S. Jang, D. E. Oh, S. J. Jang, H. Cho, S. Jeon, J. Kim, T. H. Kim

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Abstract

The integration of active targeted drug delivery and stimuli-dependent drug release in one nanocarrier holds great potential for enhancing anticancer efficacy and limiting adverse effects. Herein, we prepared hyaluronic acid (HA)-modified dendrimer encapsulating gold nanoparticles (AuDEN) as active targeted drug delivery nanocarriers for effective treatment of ovarian cancer. Resulting nanocarriers could load doxorubicin (DOX) efficiently with high drug loading content and chemical stability through self-assembly of thiolated DOX on the Au surface of nanocarriers. Surface-exposed HA in these nanocarriers made it possible to deliver the nanodrug (denoted as HA-AuDEN-DOX) to cluster determinant 44-overexpressing cancer cells. DOX was then released in an acidic tumor microenvironment with a high glutathione (GSH) concentration. HA-AuDEN-DOX greatly delayed DOX release under a physiological condition (pH 7.4), whereas a burst release of DOX was observed under an acidic condition (pH 5.6) in the presence of GSH. In comparison with free-DOX, HA-AuDEN-DOX showed enhanced cytotoxicity to cancer cells, demonstrating an enhanced cellular uptake and a superior IC₅₀ value of 2.72 μM. Importantly, cellular internalization pathways of HA-AuDEN-DOX to SK-OV-3 cells were estimated, showing the following quantitative values: receptor-mediated endocytosis, 31.5%; caveolae-mediated endocytosis, 28.7%; macropinocytosis, 26.1%. In vivo anticancer activity and biodistributions of HA-AuDEN-DOX were evaluated with an SK-OV-3 xenograft tumor-bearing mouse model, revealing an outstanding treatment-control (T/C) ratio of 66% (about four times higher than free-DOX treated value of 16.4%) for tumor growth inhibition. Compared to the administration of free-DOX, HA-AuDEN-DOX showed a decreased cardiotoxic effect. Furthermore, immunohistochemical study of Ki67 antigen expression revealed the effective suppression of cell proliferation in xenograft ovarian tumor tissues after HA-AuDEN-DOX treatment. These features highlight a promising application of HA-AuDEN-DOX for the treatment of ovarian cancer with cluster determinant 44 overexpression.

Original language	English
Article number	101083
Journal	Materials Today Chemistry
Volume	26
DOIs	https://doi.org/10.1016/j.mtchem.2022.101083
Publication status	Published - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Ltd

Keywords

Active targeting
AuDENs
CD44
Doxorubicin
Hyaluronic acid

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.mtchem.2022.101083

Cite this

Lee, C. S., Kim, T. W., Kang, Y., Ju, Y., Ryu, J., Kong, H., Jang, Y. S., Oh, D. E., Jang, S. J., Cho, H., Jeon, S., Kim, J., & Kim, T. H. (2022). Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy. Materials Today Chemistry, 26, Article 101083. https://doi.org/10.1016/j.mtchem.2022.101083

@article{f05b41da085548c3abce859f5edf7396,

title = "Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy",

abstract = "The integration of active targeted drug delivery and stimuli-dependent drug release in one nanocarrier holds great potential for enhancing anticancer efficacy and limiting adverse effects. Herein, we prepared hyaluronic acid (HA)-modified dendrimer encapsulating gold nanoparticles (AuDEN) as active targeted drug delivery nanocarriers for effective treatment of ovarian cancer. Resulting nanocarriers could load doxorubicin (DOX) efficiently with high drug loading content and chemical stability through self-assembly of thiolated DOX on the Au surface of nanocarriers. Surface-exposed HA in these nanocarriers made it possible to deliver the nanodrug (denoted as HA-AuDEN-DOX) to cluster determinant 44-overexpressing cancer cells. DOX was then released in an acidic tumor microenvironment with a high glutathione (GSH) concentration. HA-AuDEN-DOX greatly delayed DOX release under a physiological condition (pH 7.4), whereas a burst release of DOX was observed under an acidic condition (pH 5.6) in the presence of GSH. In comparison with free-DOX, HA-AuDEN-DOX showed enhanced cytotoxicity to cancer cells, demonstrating an enhanced cellular uptake and a superior IC50 value of 2.72 μM. Importantly, cellular internalization pathways of HA-AuDEN-DOX to SK-OV-3 cells were estimated, showing the following quantitative values: receptor-mediated endocytosis, 31.5%; caveolae-mediated endocytosis, 28.7%; macropinocytosis, 26.1%. In vivo anticancer activity and biodistributions of HA-AuDEN-DOX were evaluated with an SK-OV-3 xenograft tumor-bearing mouse model, revealing an outstanding treatment-control (T/C) ratio of 66% (about four times higher than free-DOX treated value of 16.4%) for tumor growth inhibition. Compared to the administration of free-DOX, HA-AuDEN-DOX showed a decreased cardiotoxic effect. Furthermore, immunohistochemical study of Ki67 antigen expression revealed the effective suppression of cell proliferation in xenograft ovarian tumor tissues after HA-AuDEN-DOX treatment. These features highlight a promising application of HA-AuDEN-DOX for the treatment of ovarian cancer with cluster determinant 44 overexpression.",

keywords = "Active targeting, AuDENs, CD44, Doxorubicin, Hyaluronic acid",

author = "Lee, {C. S.} and Kim, {T. W.} and Y. Kang and Y. Ju and J. Ryu and H. Kong and Jang, {Y. S.} and Oh, {D. E.} and Jang, {S. J.} and H. Cho and S. Jeon and J. Kim and Kim, {T. H.}",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

month = dec,

doi = "10.1016/j.mtchem.2022.101083",

language = "English",

volume = "26",

journal = "Materials Today Chemistry",

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T1 - Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy

AU - Lee, C. S.

AU - Kim, T. W.

AU - Kang, Y.

AU - Ju, Y.

AU - Ryu, J.

AU - Kong, H.

AU - Jang, Y. S.

AU - Oh, D. E.

AU - Jang, S. J.

AU - Cho, H.

AU - Jeon, S.

AU - Kim, J.

AU - Kim, T. H.

PY - 2022/12

Y1 - 2022/12

N2 - The integration of active targeted drug delivery and stimuli-dependent drug release in one nanocarrier holds great potential for enhancing anticancer efficacy and limiting adverse effects. Herein, we prepared hyaluronic acid (HA)-modified dendrimer encapsulating gold nanoparticles (AuDEN) as active targeted drug delivery nanocarriers for effective treatment of ovarian cancer. Resulting nanocarriers could load doxorubicin (DOX) efficiently with high drug loading content and chemical stability through self-assembly of thiolated DOX on the Au surface of nanocarriers. Surface-exposed HA in these nanocarriers made it possible to deliver the nanodrug (denoted as HA-AuDEN-DOX) to cluster determinant 44-overexpressing cancer cells. DOX was then released in an acidic tumor microenvironment with a high glutathione (GSH) concentration. HA-AuDEN-DOX greatly delayed DOX release under a physiological condition (pH 7.4), whereas a burst release of DOX was observed under an acidic condition (pH 5.6) in the presence of GSH. In comparison with free-DOX, HA-AuDEN-DOX showed enhanced cytotoxicity to cancer cells, demonstrating an enhanced cellular uptake and a superior IC50 value of 2.72 μM. Importantly, cellular internalization pathways of HA-AuDEN-DOX to SK-OV-3 cells were estimated, showing the following quantitative values: receptor-mediated endocytosis, 31.5%; caveolae-mediated endocytosis, 28.7%; macropinocytosis, 26.1%. In vivo anticancer activity and biodistributions of HA-AuDEN-DOX were evaluated with an SK-OV-3 xenograft tumor-bearing mouse model, revealing an outstanding treatment-control (T/C) ratio of 66% (about four times higher than free-DOX treated value of 16.4%) for tumor growth inhibition. Compared to the administration of free-DOX, HA-AuDEN-DOX showed a decreased cardiotoxic effect. Furthermore, immunohistochemical study of Ki67 antigen expression revealed the effective suppression of cell proliferation in xenograft ovarian tumor tissues after HA-AuDEN-DOX treatment. These features highlight a promising application of HA-AuDEN-DOX for the treatment of ovarian cancer with cluster determinant 44 overexpression.

AB - The integration of active targeted drug delivery and stimuli-dependent drug release in one nanocarrier holds great potential for enhancing anticancer efficacy and limiting adverse effects. Herein, we prepared hyaluronic acid (HA)-modified dendrimer encapsulating gold nanoparticles (AuDEN) as active targeted drug delivery nanocarriers for effective treatment of ovarian cancer. Resulting nanocarriers could load doxorubicin (DOX) efficiently with high drug loading content and chemical stability through self-assembly of thiolated DOX on the Au surface of nanocarriers. Surface-exposed HA in these nanocarriers made it possible to deliver the nanodrug (denoted as HA-AuDEN-DOX) to cluster determinant 44-overexpressing cancer cells. DOX was then released in an acidic tumor microenvironment with a high glutathione (GSH) concentration. HA-AuDEN-DOX greatly delayed DOX release under a physiological condition (pH 7.4), whereas a burst release of DOX was observed under an acidic condition (pH 5.6) in the presence of GSH. In comparison with free-DOX, HA-AuDEN-DOX showed enhanced cytotoxicity to cancer cells, demonstrating an enhanced cellular uptake and a superior IC50 value of 2.72 μM. Importantly, cellular internalization pathways of HA-AuDEN-DOX to SK-OV-3 cells were estimated, showing the following quantitative values: receptor-mediated endocytosis, 31.5%; caveolae-mediated endocytosis, 28.7%; macropinocytosis, 26.1%. In vivo anticancer activity and biodistributions of HA-AuDEN-DOX were evaluated with an SK-OV-3 xenograft tumor-bearing mouse model, revealing an outstanding treatment-control (T/C) ratio of 66% (about four times higher than free-DOX treated value of 16.4%) for tumor growth inhibition. Compared to the administration of free-DOX, HA-AuDEN-DOX showed a decreased cardiotoxic effect. Furthermore, immunohistochemical study of Ki67 antigen expression revealed the effective suppression of cell proliferation in xenograft ovarian tumor tissues after HA-AuDEN-DOX treatment. These features highlight a promising application of HA-AuDEN-DOX for the treatment of ovarian cancer with cluster determinant 44 overexpression.

KW - Active targeting

KW - AuDENs

KW - CD44

KW - Doxorubicin

KW - Hyaluronic acid

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DO - 10.1016/j.mtchem.2022.101083

M3 - Article

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SN - 2468-5194

VL - 26

JO - Materials Today Chemistry

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ER -

Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy

Abstract

Bibliographical note

Keywords

UN SDGs

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