19 Citations (Scopus)

Abstract

CD44-specific and redox-responsive nanoparticles were prepared by coating a bioreducible chitosan-based nanoparticles with hyaluronic acid for intracellular glutathione-triggered reactive oxygen species (ROS) production and doxorubicin (DOX) release. Chitosan (CS) was conjugated with a copper chelator, D-penicillamine (D-pen), to obtain a CS-SS-D-pen conjugate through the formation of a disulfide bond. D-pen release from the conjugate was triggered by intracellular glutathione (GSH) via reducing biologically reversible disulfide bonds. Self-assembled CS-SS-D-pen nanoparticles were prepared through ionotropic gelation with tripolyphosphate and subsequently coated with hyaluronic acid (HA). The HA-coated CS-SS-D-pen NPs were reduced by GSH to release free D-pen and trigger ROS production via a series of reactions involving Cu(II)-catalyzed D-pen oxidation and H2O2 generation. DOX was loaded into the HA-coated CS-SS-D-pen NPs by a method involving the complexation of DOX with Cu(II) ions. The Cu(II)-DOX complex-loaded NPs exhibited redox-responsive release properties which accelerated DOX release at a higher glutathione level (10mM). Confocal fluorescence microscopy demonstrated that the Cu(II)-DOX-loaded NPs effectively delivered DOX to human colon adenocarcinoma cells (HT-29) by active targeting via HA-CD44 interactions. Intracellular ROS generated from the HA-coated CS-SS-D-pen NPs sensitized cancer cells to DOX-induced cytotoxicity. In vitro cytotoxicity assays revealed that Cu(II)-DOX-loaded NPs sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells compared to CD44 low-expressing HCT-15 cells. Statement of Significance: In this manuscript, we develop a CD44-targetable loaded with nanoparticles Cu(II)-DOX complex. The nanoparticles exhibited redox-responsive properties, which triggered reactive oxygen species (ROS) production and accelerated DOX release. The Cu(II)-DOX-loaded nanoparticle sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells.To our knowledge, this is the first report showing the combination of CD44-targeting and redox-responsive property for triggering ROS production and subsequent drug release. We believe our findings would appeal to the readership of Acta Biomaterialia because the study bring new and interesting ideals in the development of specific and stimuli-responsive nanoparticles as drug carrier for cancer therapy.

Original languageEnglish
JournalActa Biomaterialia
DOIs
Publication statusAccepted/In press - Oct 19 2015

Fingerprint

Hyaluronic acid
Chitosan
Nanoparticles
Doxorubicin
Oxidation-Reduction
Reactive Oxygen Species
Penicillamine
Oxygen
Cytotoxicity
Hyaluronic Acid
HT29 Cells
Ionotropic gelation
Glutathione
Confocal microscopy
Fluorescence microscopy
Complexation
Disulfides
Assays
Cells
Copper

Keywords

  • CD44-targeting
  • Chitosan
  • Doxorubicin
  • Hyaluronic acid
  • Nanoparticles

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Biotechnology
  • Biochemistry
  • Molecular Biology

Cite this

CD44-specific nanoparticles for redox-triggered reactive oxygen species production and doxorubicin release. / Lin, Cheng-Wei; Lu, Kun Ying; Wang, Sin Yu; Sung, Hsing W.; Mi, Fwu-Long.

In: Acta Biomaterialia, 19.10.2015.

Research output: Contribution to journalArticle

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abstract = "CD44-specific and redox-responsive nanoparticles were prepared by coating a bioreducible chitosan-based nanoparticles with hyaluronic acid for intracellular glutathione-triggered reactive oxygen species (ROS) production and doxorubicin (DOX) release. Chitosan (CS) was conjugated with a copper chelator, D-penicillamine (D-pen), to obtain a CS-SS-D-pen conjugate through the formation of a disulfide bond. D-pen release from the conjugate was triggered by intracellular glutathione (GSH) via reducing biologically reversible disulfide bonds. Self-assembled CS-SS-D-pen nanoparticles were prepared through ionotropic gelation with tripolyphosphate and subsequently coated with hyaluronic acid (HA). The HA-coated CS-SS-D-pen NPs were reduced by GSH to release free D-pen and trigger ROS production via a series of reactions involving Cu(II)-catalyzed D-pen oxidation and H2O2 generation. DOX was loaded into the HA-coated CS-SS-D-pen NPs by a method involving the complexation of DOX with Cu(II) ions. The Cu(II)-DOX complex-loaded NPs exhibited redox-responsive release properties which accelerated DOX release at a higher glutathione level (10mM). Confocal fluorescence microscopy demonstrated that the Cu(II)-DOX-loaded NPs effectively delivered DOX to human colon adenocarcinoma cells (HT-29) by active targeting via HA-CD44 interactions. Intracellular ROS generated from the HA-coated CS-SS-D-pen NPs sensitized cancer cells to DOX-induced cytotoxicity. In vitro cytotoxicity assays revealed that Cu(II)-DOX-loaded NPs sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells compared to CD44 low-expressing HCT-15 cells. Statement of Significance: In this manuscript, we develop a CD44-targetable loaded with nanoparticles Cu(II)-DOX complex. The nanoparticles exhibited redox-responsive properties, which triggered reactive oxygen species (ROS) production and accelerated DOX release. The Cu(II)-DOX-loaded nanoparticle sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells.To our knowledge, this is the first report showing the combination of CD44-targeting and redox-responsive property for triggering ROS production and subsequent drug release. We believe our findings would appeal to the readership of Acta Biomaterialia because the study bring new and interesting ideals in the development of specific and stimuli-responsive nanoparticles as drug carrier for cancer therapy.",
keywords = "CD44-targeting, Chitosan, Doxorubicin, Hyaluronic acid, Nanoparticles",
author = "Cheng-Wei Lin and Lu, {Kun Ying} and Wang, {Sin Yu} and Sung, {Hsing W.} and Fwu-Long Mi",
year = "2015",
month = "10",
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journal = "Acta Biomaterialia",
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T1 - CD44-specific nanoparticles for redox-triggered reactive oxygen species production and doxorubicin release

AU - Lin, Cheng-Wei

AU - Lu, Kun Ying

AU - Wang, Sin Yu

AU - Sung, Hsing W.

AU - Mi, Fwu-Long

PY - 2015/10/19

Y1 - 2015/10/19

N2 - CD44-specific and redox-responsive nanoparticles were prepared by coating a bioreducible chitosan-based nanoparticles with hyaluronic acid for intracellular glutathione-triggered reactive oxygen species (ROS) production and doxorubicin (DOX) release. Chitosan (CS) was conjugated with a copper chelator, D-penicillamine (D-pen), to obtain a CS-SS-D-pen conjugate through the formation of a disulfide bond. D-pen release from the conjugate was triggered by intracellular glutathione (GSH) via reducing biologically reversible disulfide bonds. Self-assembled CS-SS-D-pen nanoparticles were prepared through ionotropic gelation with tripolyphosphate and subsequently coated with hyaluronic acid (HA). The HA-coated CS-SS-D-pen NPs were reduced by GSH to release free D-pen and trigger ROS production via a series of reactions involving Cu(II)-catalyzed D-pen oxidation and H2O2 generation. DOX was loaded into the HA-coated CS-SS-D-pen NPs by a method involving the complexation of DOX with Cu(II) ions. The Cu(II)-DOX complex-loaded NPs exhibited redox-responsive release properties which accelerated DOX release at a higher glutathione level (10mM). Confocal fluorescence microscopy demonstrated that the Cu(II)-DOX-loaded NPs effectively delivered DOX to human colon adenocarcinoma cells (HT-29) by active targeting via HA-CD44 interactions. Intracellular ROS generated from the HA-coated CS-SS-D-pen NPs sensitized cancer cells to DOX-induced cytotoxicity. In vitro cytotoxicity assays revealed that Cu(II)-DOX-loaded NPs sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells compared to CD44 low-expressing HCT-15 cells. Statement of Significance: In this manuscript, we develop a CD44-targetable loaded with nanoparticles Cu(II)-DOX complex. The nanoparticles exhibited redox-responsive properties, which triggered reactive oxygen species (ROS) production and accelerated DOX release. The Cu(II)-DOX-loaded nanoparticle sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells.To our knowledge, this is the first report showing the combination of CD44-targeting and redox-responsive property for triggering ROS production and subsequent drug release. We believe our findings would appeal to the readership of Acta Biomaterialia because the study bring new and interesting ideals in the development of specific and stimuli-responsive nanoparticles as drug carrier for cancer therapy.

AB - CD44-specific and redox-responsive nanoparticles were prepared by coating a bioreducible chitosan-based nanoparticles with hyaluronic acid for intracellular glutathione-triggered reactive oxygen species (ROS) production and doxorubicin (DOX) release. Chitosan (CS) was conjugated with a copper chelator, D-penicillamine (D-pen), to obtain a CS-SS-D-pen conjugate through the formation of a disulfide bond. D-pen release from the conjugate was triggered by intracellular glutathione (GSH) via reducing biologically reversible disulfide bonds. Self-assembled CS-SS-D-pen nanoparticles were prepared through ionotropic gelation with tripolyphosphate and subsequently coated with hyaluronic acid (HA). The HA-coated CS-SS-D-pen NPs were reduced by GSH to release free D-pen and trigger ROS production via a series of reactions involving Cu(II)-catalyzed D-pen oxidation and H2O2 generation. DOX was loaded into the HA-coated CS-SS-D-pen NPs by a method involving the complexation of DOX with Cu(II) ions. The Cu(II)-DOX complex-loaded NPs exhibited redox-responsive release properties which accelerated DOX release at a higher glutathione level (10mM). Confocal fluorescence microscopy demonstrated that the Cu(II)-DOX-loaded NPs effectively delivered DOX to human colon adenocarcinoma cells (HT-29) by active targeting via HA-CD44 interactions. Intracellular ROS generated from the HA-coated CS-SS-D-pen NPs sensitized cancer cells to DOX-induced cytotoxicity. In vitro cytotoxicity assays revealed that Cu(II)-DOX-loaded NPs sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells compared to CD44 low-expressing HCT-15 cells. Statement of Significance: In this manuscript, we develop a CD44-targetable loaded with nanoparticles Cu(II)-DOX complex. The nanoparticles exhibited redox-responsive properties, which triggered reactive oxygen species (ROS) production and accelerated DOX release. The Cu(II)-DOX-loaded nanoparticle sensitized cells to DOX-induced cytotoxicity in CD44-overexpressing HT-29 cells.To our knowledge, this is the first report showing the combination of CD44-targeting and redox-responsive property for triggering ROS production and subsequent drug release. We believe our findings would appeal to the readership of Acta Biomaterialia because the study bring new and interesting ideals in the development of specific and stimuli-responsive nanoparticles as drug carrier for cancer therapy.

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KW - Doxorubicin

KW - Hyaluronic acid

KW - Nanoparticles

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