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Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release

Injectable, covalently cross-linked hydrogels have been widely investigated in drug delivery systems due to their superior mechanical properties and long-term stability. Conventional covalently cross-linked hydrogels are formed by chemical reactions that may interfere with natural biochemical proces...

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Autores principales: Zhang, Zhen, He, Chaoliang, Chen, Xuesi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240560/
https://www.ncbi.nlm.nih.gov/pubmed/32290336
http://dx.doi.org/10.3390/polym12040884
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author Zhang, Zhen
He, Chaoliang
Chen, Xuesi
author_facet Zhang, Zhen
He, Chaoliang
Chen, Xuesi
author_sort Zhang, Zhen
collection PubMed
description Injectable, covalently cross-linked hydrogels have been widely investigated in drug delivery systems due to their superior mechanical properties and long-term stability. Conventional covalently cross-linked hydrogels are formed by chemical reactions that may interfere with natural biochemical processes. In this work, we developed an injectable polypeptide hydrogel via an inverse electron demand Diels-Alder reaction between norbornene modified poly(L-glutamic acid) (PLG-Norb) and tetrazine functionalized four-arm poly(ethylene glycol) (4aPEG-T) for localized release of cisplatin (CDDP). The rapid and bioorthogonal click reaction allowed for hydrogel formation within a few minutes after mixing the two polymer solutions in phosphate buffer saline (PBS). Dynamic mechanical analysis suggested that the storage modulus of the hydrogel could be readily tuned by changing the polymer concentration and the molar ratio of the two functional groups. The carboxyl groups of PLG-Norb were used to form polymer–metal complexation with CDDP, and the controlled release of the antitumor drug was achieved in PBS. The CDDP-loaded hydrogel displayed an antitumor effect against MCF-7 cells in vitro, through S phase cell cycle arrest. After subcutaneous injection in rats, the hydrogel was rapidly formed in situ and showed good stability in vivo. In an MCF-7-bearing nude mice model, the CDDP-loaded hydrogel exhibited an improved antitumor effect with reduced systemic toxicity. Overall, the injectable click polypeptide hydrogel shows considerable potential as a platform for localized and sustained delivery of antitumor drugs.
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spelling pubmed-72405602020-06-11 Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release Zhang, Zhen He, Chaoliang Chen, Xuesi Polymers (Basel) Article Injectable, covalently cross-linked hydrogels have been widely investigated in drug delivery systems due to their superior mechanical properties and long-term stability. Conventional covalently cross-linked hydrogels are formed by chemical reactions that may interfere with natural biochemical processes. In this work, we developed an injectable polypeptide hydrogel via an inverse electron demand Diels-Alder reaction between norbornene modified poly(L-glutamic acid) (PLG-Norb) and tetrazine functionalized four-arm poly(ethylene glycol) (4aPEG-T) for localized release of cisplatin (CDDP). The rapid and bioorthogonal click reaction allowed for hydrogel formation within a few minutes after mixing the two polymer solutions in phosphate buffer saline (PBS). Dynamic mechanical analysis suggested that the storage modulus of the hydrogel could be readily tuned by changing the polymer concentration and the molar ratio of the two functional groups. The carboxyl groups of PLG-Norb were used to form polymer–metal complexation with CDDP, and the controlled release of the antitumor drug was achieved in PBS. The CDDP-loaded hydrogel displayed an antitumor effect against MCF-7 cells in vitro, through S phase cell cycle arrest. After subcutaneous injection in rats, the hydrogel was rapidly formed in situ and showed good stability in vivo. In an MCF-7-bearing nude mice model, the CDDP-loaded hydrogel exhibited an improved antitumor effect with reduced systemic toxicity. Overall, the injectable click polypeptide hydrogel shows considerable potential as a platform for localized and sustained delivery of antitumor drugs. MDPI 2020-04-10 /pmc/articles/PMC7240560/ /pubmed/32290336 http://dx.doi.org/10.3390/polym12040884 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Zhen
He, Chaoliang
Chen, Xuesi
Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release
title Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release
title_full Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release
title_fullStr Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release
title_full_unstemmed Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release
title_short Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release
title_sort injectable click polypeptide hydrogels via tetrazine-norbornene chemistry for localized cisplatin release
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240560/
https://www.ncbi.nlm.nih.gov/pubmed/32290336
http://dx.doi.org/10.3390/polym12040884
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AT hechaoliang injectableclickpolypeptidehydrogelsviatetrazinenorbornenechemistryforlocalizedcisplatinrelease
AT chenxuesi injectableclickpolypeptidehydrogelsviatetrazinenorbornenechemistryforlocalizedcisplatinrelease