Citrullinated peptide epitope targets therapeutic nanoparticles to human neutrophils

Sangita Khatri, Jonas Hansen, Ana Carina Loureiro Mendes, Ioannis S. Chronakis, Shu-Chen Hung, Elizabeth Mellins, Kira Astakhova*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Multiple drugs have been proposed for reducing harsh symptoms of human rheumatic diseases. However, a targeted therapy with mild to no side-effects is still missing. In this study, we have prepared and tested a series of therapeutic nanoparticles for specific targeting of human neutrophils associated with rheumatoid arthritis. In doing this, a series of citrullinated peptide epitopes derived from human proteins fibrinogen, vimentin and histone 3, were screened with regard to specific recognition of neutrophils. The most potent epitope proved to be a mutated fragment of an alpha chain in human fibrinogen. Next, a straightforward synthetic strategy was developed for nanoparticles decorated with this citrullinated peptide epitope and an antisense oligonucleotide targeting disease associated microRNA miR-125b-5p. Our study shows that the nanoparticles specifically recognize neutrophils and knock down miR-125b-5p, with no apparent toxicity to human cells. In contrast to organic dendrimers, chitosan-hyaluronic acid formulations do not activate human innate immune response. Our data proves that the strategy we report herein is effective in developing peptide epitopes for decorating delivery vesicles bearing biological drugs, targeted to a specific cell type.
Original languageEnglish
JournalBioconjugate Chemistry
Volume30
Issue number10
Pages (from-to)2584-2593
Number of pages10
ISSN1043-1802
DOIs
Publication statusPublished - 2019

Cite this

@article{638eb80697514fab8dd0b9fe4d6eb42c,
title = "Citrullinated peptide epitope targets therapeutic nanoparticles to human neutrophils",
abstract = "Multiple drugs have been proposed for reducing harsh symptoms of human rheumatic diseases. However, a targeted therapy with mild to no side-effects is still missing. In this study, we have prepared and tested a series of therapeutic nanoparticles for specific targeting of human neutrophils associated with rheumatoid arthritis. In doing this, a series of citrullinated peptide epitopes derived from human proteins fibrinogen, vimentin and histone 3, were screened with regard to specific recognition of neutrophils. The most potent epitope proved to be a mutated fragment of an alpha chain in human fibrinogen. Next, a straightforward synthetic strategy was developed for nanoparticles decorated with this citrullinated peptide epitope and an antisense oligonucleotide targeting disease associated microRNA miR-125b-5p. Our study shows that the nanoparticles specifically recognize neutrophils and knock down miR-125b-5p, with no apparent toxicity to human cells. In contrast to organic dendrimers, chitosan-hyaluronic acid formulations do not activate human innate immune response. Our data proves that the strategy we report herein is effective in developing peptide epitopes for decorating delivery vesicles bearing biological drugs, targeted to a specific cell type.",
author = "Sangita Khatri and Jonas Hansen and Mendes, {Ana Carina Loureiro} and Chronakis, {Ioannis S.} and Shu-Chen Hung and Elizabeth Mellins and Kira Astakhova",
year = "2019",
doi = "10.1021/acs.bioconjchem.9b00518",
language = "English",
volume = "30",
pages = "2584--2593",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
number = "10",

}

Citrullinated peptide epitope targets therapeutic nanoparticles to human neutrophils. / Khatri, Sangita; Hansen, Jonas; Mendes, Ana Carina Loureiro; Chronakis, Ioannis S.; Hung, Shu-Chen; Mellins, Elizabeth; Astakhova, Kira.

In: Bioconjugate Chemistry, Vol. 30, No. 10, 2019, p. 2584-2593.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Citrullinated peptide epitope targets therapeutic nanoparticles to human neutrophils

AU - Khatri, Sangita

AU - Hansen, Jonas

AU - Mendes, Ana Carina Loureiro

AU - Chronakis, Ioannis S.

AU - Hung, Shu-Chen

AU - Mellins, Elizabeth

AU - Astakhova, Kira

PY - 2019

Y1 - 2019

N2 - Multiple drugs have been proposed for reducing harsh symptoms of human rheumatic diseases. However, a targeted therapy with mild to no side-effects is still missing. In this study, we have prepared and tested a series of therapeutic nanoparticles for specific targeting of human neutrophils associated with rheumatoid arthritis. In doing this, a series of citrullinated peptide epitopes derived from human proteins fibrinogen, vimentin and histone 3, were screened with regard to specific recognition of neutrophils. The most potent epitope proved to be a mutated fragment of an alpha chain in human fibrinogen. Next, a straightforward synthetic strategy was developed for nanoparticles decorated with this citrullinated peptide epitope and an antisense oligonucleotide targeting disease associated microRNA miR-125b-5p. Our study shows that the nanoparticles specifically recognize neutrophils and knock down miR-125b-5p, with no apparent toxicity to human cells. In contrast to organic dendrimers, chitosan-hyaluronic acid formulations do not activate human innate immune response. Our data proves that the strategy we report herein is effective in developing peptide epitopes for decorating delivery vesicles bearing biological drugs, targeted to a specific cell type.

AB - Multiple drugs have been proposed for reducing harsh symptoms of human rheumatic diseases. However, a targeted therapy with mild to no side-effects is still missing. In this study, we have prepared and tested a series of therapeutic nanoparticles for specific targeting of human neutrophils associated with rheumatoid arthritis. In doing this, a series of citrullinated peptide epitopes derived from human proteins fibrinogen, vimentin and histone 3, were screened with regard to specific recognition of neutrophils. The most potent epitope proved to be a mutated fragment of an alpha chain in human fibrinogen. Next, a straightforward synthetic strategy was developed for nanoparticles decorated with this citrullinated peptide epitope and an antisense oligonucleotide targeting disease associated microRNA miR-125b-5p. Our study shows that the nanoparticles specifically recognize neutrophils and knock down miR-125b-5p, with no apparent toxicity to human cells. In contrast to organic dendrimers, chitosan-hyaluronic acid formulations do not activate human innate immune response. Our data proves that the strategy we report herein is effective in developing peptide epitopes for decorating delivery vesicles bearing biological drugs, targeted to a specific cell type.

U2 - 10.1021/acs.bioconjchem.9b00518

DO - 10.1021/acs.bioconjchem.9b00518

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C2 - 31524379

VL - 30

SP - 2584

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JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

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