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Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug

Water-soluble amphiphilic random copolymers composed of tri(ethylene glycol) methacrylate (TEGMA) or poly(ethylene glycol) methyl ether methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) were synthesized by ARGET-ATRP, and their self-assembling and thermoresponsive behavior in water was stud...

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Autores principales: Calosi, Matteo, Guazzelli, Elisa, Braccini, Simona, Lessi, Marco, Bellina, Fabio, Galli, Giancarlo, Martinelli, Elisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880340/
https://www.ncbi.nlm.nih.gov/pubmed/35215686
http://dx.doi.org/10.3390/polym14040774
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author Calosi, Matteo
Guazzelli, Elisa
Braccini, Simona
Lessi, Marco
Bellina, Fabio
Galli, Giancarlo
Martinelli, Elisa
author_facet Calosi, Matteo
Guazzelli, Elisa
Braccini, Simona
Lessi, Marco
Bellina, Fabio
Galli, Giancarlo
Martinelli, Elisa
author_sort Calosi, Matteo
collection PubMed
description Water-soluble amphiphilic random copolymers composed of tri(ethylene glycol) methacrylate (TEGMA) or poly(ethylene glycol) methyl ether methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) were synthesized by ARGET-ATRP, and their self-assembling and thermoresponsive behavior in water was studied by dynamic light scattering (DLS) and UV-vis spectroscopy. The copolymer ability to self-fold in single-chain nano-sized structures (unimer micelles) in aqueous solutions was exploited to encapsulate Combretastatin A-4 (CA-4), which is a very hydrophobic anticancer drug. The cloud point temperature (T(cp)) was found to linearly decrease with increasing drug concentration in the drug/copolymer system. Moreover, while CA-4 was preferentially incorporated into the unimer micelles of TEGMA-ran-FA, the drug was found to induce multi-chain, submicro-sized aggregation of PEGMA-ran-FA. Anyway, the encapsulation efficiency was very high (≥81%) for both copolymers. The drug release was evaluated in PBS aqueous solutions both below and above T(cp) for TEGMA-ran-FA copolymer and below T(cp), but at two different drug loadings, for PEGMA-ran-FA copolymer. In any case, the release kinetics presented similar profiles, characterized by linear trends up to ≈10–13 h and ≈7 h for TEGMA-ran-FA and PEGMA-ran-FA, respectively. Then, the release rate decreased, reaching a plateau. The release from TEGMA-ran-FA was moderately faster above T(cp) than below T(cp), suggesting that copolymer thermoresponsiveness increased the release rate, which occurred anyway by diffusion below T(cp). Cytotoxicity tests were carried out on copolymer solutions in a wide concentration range (5–60 mg/mL) at 37 °C by using Balb/3T3 clone A31 cells. Interestingly, it was found that the concentration-dependent micro-sized aggregation of the amphiphilic random copolymers above T(cp) caused a sort of “cellular asphyxiation” with a loss of cell viability clearly visible for TEGMA-ran-FA solutions (T(cp) below 37 °C) with higher copolymer concentrations. On the other hand, cells in contact with the analogous PEGMA-ran-FA (T(cp) above 37 °C) presented a very good viability (≥75%) with respect to the control at any given concentration.
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spelling pubmed-88803402022-02-26 Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug Calosi, Matteo Guazzelli, Elisa Braccini, Simona Lessi, Marco Bellina, Fabio Galli, Giancarlo Martinelli, Elisa Polymers (Basel) Article Water-soluble amphiphilic random copolymers composed of tri(ethylene glycol) methacrylate (TEGMA) or poly(ethylene glycol) methyl ether methacrylate (PEGMA) and perfluorohexylethyl acrylate (FA) were synthesized by ARGET-ATRP, and their self-assembling and thermoresponsive behavior in water was studied by dynamic light scattering (DLS) and UV-vis spectroscopy. The copolymer ability to self-fold in single-chain nano-sized structures (unimer micelles) in aqueous solutions was exploited to encapsulate Combretastatin A-4 (CA-4), which is a very hydrophobic anticancer drug. The cloud point temperature (T(cp)) was found to linearly decrease with increasing drug concentration in the drug/copolymer system. Moreover, while CA-4 was preferentially incorporated into the unimer micelles of TEGMA-ran-FA, the drug was found to induce multi-chain, submicro-sized aggregation of PEGMA-ran-FA. Anyway, the encapsulation efficiency was very high (≥81%) for both copolymers. The drug release was evaluated in PBS aqueous solutions both below and above T(cp) for TEGMA-ran-FA copolymer and below T(cp), but at two different drug loadings, for PEGMA-ran-FA copolymer. In any case, the release kinetics presented similar profiles, characterized by linear trends up to ≈10–13 h and ≈7 h for TEGMA-ran-FA and PEGMA-ran-FA, respectively. Then, the release rate decreased, reaching a plateau. The release from TEGMA-ran-FA was moderately faster above T(cp) than below T(cp), suggesting that copolymer thermoresponsiveness increased the release rate, which occurred anyway by diffusion below T(cp). Cytotoxicity tests were carried out on copolymer solutions in a wide concentration range (5–60 mg/mL) at 37 °C by using Balb/3T3 clone A31 cells. Interestingly, it was found that the concentration-dependent micro-sized aggregation of the amphiphilic random copolymers above T(cp) caused a sort of “cellular asphyxiation” with a loss of cell viability clearly visible for TEGMA-ran-FA solutions (T(cp) below 37 °C) with higher copolymer concentrations. On the other hand, cells in contact with the analogous PEGMA-ran-FA (T(cp) above 37 °C) presented a very good viability (≥75%) with respect to the control at any given concentration. MDPI 2022-02-16 /pmc/articles/PMC8880340/ /pubmed/35215686 http://dx.doi.org/10.3390/polym14040774 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Calosi, Matteo
Guazzelli, Elisa
Braccini, Simona
Lessi, Marco
Bellina, Fabio
Galli, Giancarlo
Martinelli, Elisa
Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug
title Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug
title_full Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug
title_fullStr Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug
title_full_unstemmed Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug
title_short Self-Assembled Amphiphilic Fluorinated Random Copolymers for the Encapsulation and Release of the Hydrophobic Combretastatin A-4 Drug
title_sort self-assembled amphiphilic fluorinated random copolymers for the encapsulation and release of the hydrophobic combretastatin a-4 drug
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880340/
https://www.ncbi.nlm.nih.gov/pubmed/35215686
http://dx.doi.org/10.3390/polym14040774
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