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Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy

Frequent injections at high concentrations are often required for many therapeutic proteins due to their short in vivo half-life, which usually leads to unsatisfactory therapeutic outcomes, adverse side effects, high cost, and poor patient compliance. Herein we report a supramolecular strategy, self...

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Autores principales: Xu, Zhikun, Zhang, Xiaozhan, Dong, Wang, lv, Huifang, Zuo, Lijie, Zhu, Lifei, Wang, Ruining, Ma, Xia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206137/
https://www.ncbi.nlm.nih.gov/pubmed/37234918
http://dx.doi.org/10.3389/fmolb.2023.1172100
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author Xu, Zhikun
Zhang, Xiaozhan
Dong, Wang
lv, Huifang
Zuo, Lijie
Zhu, Lifei
Wang, Ruining
Ma, Xia
author_facet Xu, Zhikun
Zhang, Xiaozhan
Dong, Wang
lv, Huifang
Zuo, Lijie
Zhu, Lifei
Wang, Ruining
Ma, Xia
author_sort Xu, Zhikun
collection PubMed
description Frequent injections at high concentrations are often required for many therapeutic proteins due to their short in vivo half-life, which usually leads to unsatisfactory therapeutic outcomes, adverse side effects, high cost, and poor patient compliance. Herein we report a supramolecular strategy, self-assembling and pH regulated fusion protein to extend the in vivo half-life and tumor targeting ability of a therapeutically important protein trichosanthin (TCS). TCS was genetically fused to the N-terminus of a self-assembling protein, Sup35p prion domain (Sup35), to form a fusion protein of TCS-Sup35 that self-assembled into uniform spherical TCS-Sup35 nanoparticles (TCS-Sup35 NP) rather than classic nanofibrils. Importantly, due to the pH response ability, TCS-Sup35 NP well retained the bioactivity of TCS and possessed a 21.5-fold longer in vivo half-life than native TCS in a mouse model. As a result, in a tumor-bearing mouse model, TCS-Sup35 NP exhibited significantly improved tumor accumulation and antitumor activity without detectable systemic toxicity as compared with native TCS. These findings suggest that self-assembling and pH responding protein fusion may provide a new, simple, general, and effective solution to remarkably improve the pharmacological performance of therapeutic proteins with short circulation half-lives.
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spelling pubmed-102061372023-05-25 Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy Xu, Zhikun Zhang, Xiaozhan Dong, Wang lv, Huifang Zuo, Lijie Zhu, Lifei Wang, Ruining Ma, Xia Front Mol Biosci Molecular Biosciences Frequent injections at high concentrations are often required for many therapeutic proteins due to their short in vivo half-life, which usually leads to unsatisfactory therapeutic outcomes, adverse side effects, high cost, and poor patient compliance. Herein we report a supramolecular strategy, self-assembling and pH regulated fusion protein to extend the in vivo half-life and tumor targeting ability of a therapeutically important protein trichosanthin (TCS). TCS was genetically fused to the N-terminus of a self-assembling protein, Sup35p prion domain (Sup35), to form a fusion protein of TCS-Sup35 that self-assembled into uniform spherical TCS-Sup35 nanoparticles (TCS-Sup35 NP) rather than classic nanofibrils. Importantly, due to the pH response ability, TCS-Sup35 NP well retained the bioactivity of TCS and possessed a 21.5-fold longer in vivo half-life than native TCS in a mouse model. As a result, in a tumor-bearing mouse model, TCS-Sup35 NP exhibited significantly improved tumor accumulation and antitumor activity without detectable systemic toxicity as compared with native TCS. These findings suggest that self-assembling and pH responding protein fusion may provide a new, simple, general, and effective solution to remarkably improve the pharmacological performance of therapeutic proteins with short circulation half-lives. Frontiers Media S.A. 2023-05-10 /pmc/articles/PMC10206137/ /pubmed/37234918 http://dx.doi.org/10.3389/fmolb.2023.1172100 Text en Copyright © 2023 Xu, Zhang, Dong, lv, Zuo, Zhu, Wang and Ma. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Xu, Zhikun
Zhang, Xiaozhan
Dong, Wang
lv, Huifang
Zuo, Lijie
Zhu, Lifei
Wang, Ruining
Ma, Xia
Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy
title Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy
title_full Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy
title_fullStr Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy
title_full_unstemmed Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy
title_short Self-assembling and pH-responsive protein nanoparticle as potential platform for targeted tumor therapy
title_sort self-assembling and ph-responsive protein nanoparticle as potential platform for targeted tumor therapy
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206137/
https://www.ncbi.nlm.nih.gov/pubmed/37234918
http://dx.doi.org/10.3389/fmolb.2023.1172100
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