Peptide-guided delivery improves the therapeutic efficacy and safety of glucocorticoid drugs for treating acute lung injury

Hong Guo; Jibin Guan; Xian Wu; Yushuang Wei; Jiaqi Zhao; Yan Zhou; Faqian Li; Hong Bo Pang

doi:10.1016/j.ymthe.2023.01.003

Peptide-guided delivery improves the therapeutic efficacy and safety of glucocorticoid drugs for treating acute lung injury

Hong Guo, Jibin Guan, Xian Wu, Yushuang Wei, Jiaqi Zhao, Yan Zhou, Faqian Li, Hong Bo Pang

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

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions with excessive inflammation in the lung. Glucocorticoids had been widely used for ALI/ARDS, but their clinical benefit remains unclear. Here, we tackled the problem by conjugating prednisolone (PSL) with a targeting peptide termed CRV. Systemically administered CRV selectively homes to the inflamed lung of a murine ALI model, but not healthy organs or the lung of healthy mice. The expression of the CRV receptor, retinoid X receptor β, was elevated in the lung of ALI mice and patients with interstitial lung diseases, which may be the basis of CRV targeting. We then covalently conjugated PSL and CRV with a reactive oxygen species (ROS)-responsive linker in the middle. While being intact in blood, the ROS linker was cleaved intracellularly to release PSL for action. In vitro, CRV-PSL showed an anti-inflammatory effect similar to that of PSL. In vivo, CRV conjugation increased the amount of PSL in the inflamed lung but reduced its accumulation in healthy organs. Accordingly, CRV-PSL significantly reduced lung injury and immune-related side effects elsewhere. Taken together, our peptide-based strategy for targeted delivery of glucocorticoids for ALI may have great potential for clinical translation.

Original language	English (US)
Pages (from-to)	875-889
Number of pages	15
Journal	Molecular Therapy
Volume	31
Issue number	3
DOIs	https://doi.org/10.1016/j.ymthe.2023.01.003
State	Published - Mar 1 2023

Bibliographical note

Funding Information:
Research reported in this publication was supported by grants from the National Institutes of Health (R01CA214550, R01GM133885, R21EB022652) and the State of Minnesota (MNP#19.08). The lung tissues of human subjects were obtained from the Clinical & Translational Science Institute, which was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. We also thank Dr. Yingchun Zhao, Dr. Yupeng Li in the Masonic Cancer Center, and Dr. Ning Xie in the Lillehei Heart Institute, University of Minnesota, for their kind help with instruments. Portions of this work were conducted in the Flow Cytometry Resources, University of Minnesota. H.-B.P. designed the project. H.G. J.G. X.W. Y.W. J.Z. Y.Z. and F.L. carried out the rest of the study. H.G. and H.-B.P. wrote the manuscript. H.-B.P. is a shareholder of Lisata Therapeutics, Inc.

Funding Information:
Research reported in this publication was supported by grants from the National Institutes of Health ( R01CA214550 , R01GM133885 , R21EB022652 ) and the State of Minnesota ( MNP#19.08 ). The lung tissues of human subjects were obtained from the Clinical & Translational Science Institute, which was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences , grant UL1TR002494 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences. We also thank Dr. Yingchun Zhao, Dr. Yupeng Li in the Masonic Cancer Center, and Dr. Ning Xie in the Lillehei Heart Institute, University of Minnesota, for their kind help with instruments. Portions of this work were conducted in the Flow Cytometry Resources, University of Minnesota.

Publisher Copyright:
© 2023 The American Society of Gene and Cell Therapy

Keywords

acute lung injury
glucocorticoids
peptide-guided drug delivery

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

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10.1016/j.ymthe.2023.01.003

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title = "Peptide-guided delivery improves the therapeutic efficacy and safety of glucocorticoid drugs for treating acute lung injury",

abstract = "Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions with excessive inflammation in the lung. Glucocorticoids had been widely used for ALI/ARDS, but their clinical benefit remains unclear. Here, we tackled the problem by conjugating prednisolone (PSL) with a targeting peptide termed CRV. Systemically administered CRV selectively homes to the inflamed lung of a murine ALI model, but not healthy organs or the lung of healthy mice. The expression of the CRV receptor, retinoid X receptor β, was elevated in the lung of ALI mice and patients with interstitial lung diseases, which may be the basis of CRV targeting. We then covalently conjugated PSL and CRV with a reactive oxygen species (ROS)-responsive linker in the middle. While being intact in blood, the ROS linker was cleaved intracellularly to release PSL for action. In vitro, CRV-PSL showed an anti-inflammatory effect similar to that of PSL. In vivo, CRV conjugation increased the amount of PSL in the inflamed lung but reduced its accumulation in healthy organs. Accordingly, CRV-PSL significantly reduced lung injury and immune-related side effects elsewhere. Taken together, our peptide-based strategy for targeted delivery of glucocorticoids for ALI may have great potential for clinical translation.",

keywords = "acute lung injury, glucocorticoids, peptide-guided drug delivery",

author = "Hong Guo and Jibin Guan and Xian Wu and Yushuang Wei and Jiaqi Zhao and Yan Zhou and Faqian Li and Pang, {Hong Bo}",

note = "Funding Information: Research reported in this publication was supported by grants from the National Institutes of Health (R01CA214550, R01GM133885, R21EB022652) and the State of Minnesota (MNP#19.08). The lung tissues of human subjects were obtained from the Clinical & Translational Science Institute, which was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. We also thank Dr. Yingchun Zhao, Dr. Yupeng Li in the Masonic Cancer Center, and Dr. Ning Xie in the Lillehei Heart Institute, University of Minnesota, for their kind help with instruments. Portions of this work were conducted in the Flow Cytometry Resources, University of Minnesota. H.-B.P. designed the project. H.G. J.G. X.W. Y.W. J.Z. Y.Z. and F.L. carried out the rest of the study. H.G. and H.-B.P. wrote the manuscript. H.-B.P. is a shareholder of Lisata Therapeutics, Inc. Funding Information: Research reported in this publication was supported by grants from the National Institutes of Health ( R01CA214550 , R01GM133885 , R21EB022652 ) and the State of Minnesota ( MNP#19.08 ). The lung tissues of human subjects were obtained from the Clinical & Translational Science Institute, which was supported by the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences , grant UL1TR002494 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences. We also thank Dr. Yingchun Zhao, Dr. Yupeng Li in the Masonic Cancer Center, and Dr. Ning Xie in the Lillehei Heart Institute, University of Minnesota, for their kind help with instruments. Portions of this work were conducted in the Flow Cytometry Resources, University of Minnesota. Publisher Copyright: {\textcopyright} 2023 The American Society of Gene and Cell Therapy",

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doi = "10.1016/j.ymthe.2023.01.003",

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T1 - Peptide-guided delivery improves the therapeutic efficacy and safety of glucocorticoid drugs for treating acute lung injury

AU - Guo, Hong

AU - Guan, Jibin

AU - Wu, Xian

AU - Wei, Yushuang

AU - Zhao, Jiaqi

AU - Zhou, Yan

AU - Li, Faqian

AU - Pang, Hong Bo

N1 - Funding Information: Research reported in this publication was supported by grants from the National Institutes of Health (R01CA214550, R01GM133885, R21EB022652) and the State of Minnesota (MNP#19.08). The lung tissues of human subjects were obtained from the Clinical & Translational Science Institute, which was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. We also thank Dr. Yingchun Zhao, Dr. Yupeng Li in the Masonic Cancer Center, and Dr. Ning Xie in the Lillehei Heart Institute, University of Minnesota, for their kind help with instruments. Portions of this work were conducted in the Flow Cytometry Resources, University of Minnesota. H.-B.P. designed the project. H.G. J.G. X.W. Y.W. J.Z. Y.Z. and F.L. carried out the rest of the study. H.G. and H.-B.P. wrote the manuscript. H.-B.P. is a shareholder of Lisata Therapeutics, Inc. Funding Information: Research reported in this publication was supported by grants from the National Institutes of Health ( R01CA214550 , R01GM133885 , R21EB022652 ) and the State of Minnesota ( MNP#19.08 ). The lung tissues of human subjects were obtained from the Clinical & Translational Science Institute, which was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences , grant UL1TR002494 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences. We also thank Dr. Yingchun Zhao, Dr. Yupeng Li in the Masonic Cancer Center, and Dr. Ning Xie in the Lillehei Heart Institute, University of Minnesota, for their kind help with instruments. Portions of this work were conducted in the Flow Cytometry Resources, University of Minnesota. Publisher Copyright: © 2023 The American Society of Gene and Cell Therapy

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N2 - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions with excessive inflammation in the lung. Glucocorticoids had been widely used for ALI/ARDS, but their clinical benefit remains unclear. Here, we tackled the problem by conjugating prednisolone (PSL) with a targeting peptide termed CRV. Systemically administered CRV selectively homes to the inflamed lung of a murine ALI model, but not healthy organs or the lung of healthy mice. The expression of the CRV receptor, retinoid X receptor β, was elevated in the lung of ALI mice and patients with interstitial lung diseases, which may be the basis of CRV targeting. We then covalently conjugated PSL and CRV with a reactive oxygen species (ROS)-responsive linker in the middle. While being intact in blood, the ROS linker was cleaved intracellularly to release PSL for action. In vitro, CRV-PSL showed an anti-inflammatory effect similar to that of PSL. In vivo, CRV conjugation increased the amount of PSL in the inflamed lung but reduced its accumulation in healthy organs. Accordingly, CRV-PSL significantly reduced lung injury and immune-related side effects elsewhere. Taken together, our peptide-based strategy for targeted delivery of glucocorticoids for ALI may have great potential for clinical translation.

AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions with excessive inflammation in the lung. Glucocorticoids had been widely used for ALI/ARDS, but their clinical benefit remains unclear. Here, we tackled the problem by conjugating prednisolone (PSL) with a targeting peptide termed CRV. Systemically administered CRV selectively homes to the inflamed lung of a murine ALI model, but not healthy organs or the lung of healthy mice. The expression of the CRV receptor, retinoid X receptor β, was elevated in the lung of ALI mice and patients with interstitial lung diseases, which may be the basis of CRV targeting. We then covalently conjugated PSL and CRV with a reactive oxygen species (ROS)-responsive linker in the middle. While being intact in blood, the ROS linker was cleaved intracellularly to release PSL for action. In vitro, CRV-PSL showed an anti-inflammatory effect similar to that of PSL. In vivo, CRV conjugation increased the amount of PSL in the inflamed lung but reduced its accumulation in healthy organs. Accordingly, CRV-PSL significantly reduced lung injury and immune-related side effects elsewhere. Taken together, our peptide-based strategy for targeted delivery of glucocorticoids for ALI may have great potential for clinical translation.

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KW - glucocorticoids

KW - peptide-guided drug delivery

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Peptide-guided delivery improves the therapeutic efficacy and safety of glucocorticoid drugs for treating acute lung injury

Abstract

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Keywords

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