Endosomal ph-responsive fe-based hyaluronate nanoparticles for doxorubicin delivery

Yangmun Bae; Yoonyoung Kim; Eun Seong Lee

doi:10.3390/molecules26123547

Endosomal ph-responsive fe-based hyaluronate nanoparticles for doxorubicin delivery

Yangmun Bae, Yoonyoung Kim, Eun Seong Lee

Department of Biomedical-Chemical Engineering

The Catholic University of Korea

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

11 Scopus citations

Abstract

In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl₂/4H₂O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 10² (DOX@HA/Fe NPs, without DMA), ~8.1 × 10² (DOX@aHA-DMA_0.36/Fe NPs), and ~9.3 × 10² (DOX@aHA-DMA_0.60/Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe²⁺ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.

Original language	English
Article number	3547
Journal	Molecules
Volume	26
Issue number	12
DOIs	https://doi.org/10.3390/molecules26123547
State	Published - 1 Jun 2021

Bibliographical note

Funding Information:
Funding: This work was financially supported by the 2021 Research Fund of the Catholic University of Korea, by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (grant number: NRF-2021R1A2B5B01001932).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

CD44 receptor-mediated endocytosis
Endosomal pH-responsive hyaluronate
Fe-based nanoparticles
Tumor therapy

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10.3390/molecules26123547

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title = "Endosomal ph-responsive fe-based hyaluronate nanoparticles for doxorubicin delivery",

abstract = "In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl2/4H2O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 102 (DOX@HA/Fe NPs, without DMA), ~8.1 × 102 ([email protected]/Fe NPs), and ~9.3 × 102 ([email protected]/Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe2+ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.",

keywords = "CD44 receptor-mediated endocytosis, Endosomal pH-responsive hyaluronate, Fe-based nanoparticles, Tumor therapy",

author = "Yangmun Bae and Yoonyoung Kim and Lee, {Eun Seong}",

note = "Funding Information: Funding: This work was financially supported by the 2021 Research Fund of the Catholic University of Korea, by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (grant number: NRF-2021R1A2B5B01001932). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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month = jun,

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doi = "10.3390/molecules26123547",

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AU - Bae, Yangmun

AU - Kim, Yoonyoung

AU - Lee, Eun Seong

N1 - Funding Information: Funding: This work was financially supported by the 2021 Research Fund of the Catholic University of Korea, by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (grant number: NRF-2021R1A2B5B01001932). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl2/4H2O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 102 (DOX@HA/Fe NPs, without DMA), ~8.1 × 102 ([email protected]/Fe NPs), and ~9.3 × 102 ([email protected]/Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe2+ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.

AB - In this study, we report pH-responsive metal-based biopolymer nanoparticles (NPs) for tumor-specific chemotherapy. Here, aminated hyaluronic acid (aHA) coupled with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive moiety) (aHA-DMA) was electrostatically complexed with ferrous chloride tetrahydrate (FeCl2/4H2O, as a chelating metal) and doxorubicin (DOX, as an antitumor drug model), producing DOX-loaded Fe-based hyaluronate nanoparticles (DOX@aHA-DMA/Fe NPs). Importantly, the DOX@aHA-DMA/Fe NPs improved tumor cellular uptake due to HA-mediated endocytosis for tumor cells overexpressing CD44 receptors. As a result, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) was ~7.9 × 102 (DOX@HA/Fe NPs, without DMA), ~8.1 × 102 ([email protected]/Fe NPs), and ~9.3 × 102 ([email protected]/Fe NPs). Furthermore, the DOX@aHA-DMA/Fe NPs were destabilized due to ionic repulsion between Fe2+ and DMA-detached aHA (i.e., positively charged free aHA) in the acidic environment of tumor cells. This event accelerated the release of DOX from the destabilized NPs. Our results suggest that these NPs can be promising tumor-targeting drug carriers responding to acidic endosomal pH.

KW - CD44 receptor-mediated endocytosis

KW - Endosomal pH-responsive hyaluronate

KW - Fe-based nanoparticles

KW - Tumor therapy

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JO - Molecules

JF - Molecules

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ER -

Endosomal ph-responsive fe-based hyaluronate nanoparticles for doxorubicin delivery

Abstract

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Keywords

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