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Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates

Third-generation poly(amidoamine) dendrimer (PAMAM) was modified by stepwise primary amine group amidation with d-glucoheptono-1,4-lactone. The physicochemical properties of the conjugates—size, ζ potential in lysosomal pH 5 and in neutral aqueous solutions, as well as intramolecular dynamics by dif...

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Autores principales: Czerniecka-Kubicka, Anna, Tutka, Piotr, Pyda, Marek, Walczak, Małgorzata, Uram, Łukasz, Misiorek, Maria, Chmiel, Ewelina, Wołowiec, Stanisław
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284344/
https://www.ncbi.nlm.nih.gov/pubmed/32456066
http://dx.doi.org/10.3390/pharmaceutics12050473
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author Czerniecka-Kubicka, Anna
Tutka, Piotr
Pyda, Marek
Walczak, Małgorzata
Uram, Łukasz
Misiorek, Maria
Chmiel, Ewelina
Wołowiec, Stanisław
author_facet Czerniecka-Kubicka, Anna
Tutka, Piotr
Pyda, Marek
Walczak, Małgorzata
Uram, Łukasz
Misiorek, Maria
Chmiel, Ewelina
Wołowiec, Stanisław
author_sort Czerniecka-Kubicka, Anna
collection PubMed
description Third-generation poly(amidoamine) dendrimer (PAMAM) was modified by stepwise primary amine group amidation with d-glucoheptono-1,4-lactone. The physicochemical properties of the conjugates—size, ζ potential in lysosomal pH 5 and in neutral aqueous solutions, as well as intramolecular dynamics by differential scanning calorimetry—were determined. Internalization and toxicity of the conjugates against normal human fibroblasts BJ were monitored in vitro in order to select an appropriate carrier for a drug delivery system. It was found that initial glucoheptoamidation (up to 1/3 of amine groups of neat dendrimers available) resulted in increase of conjugate size and ζ potential. Native or low substituted dendrimer conjugates accumulated efficiently in fibroblast cells at nontoxic 1 µM concentration. Further substitution of dendrimer caused consistent decrease of size and ζ potential, cell accumulation, and toxicity. All dendrimers are amorphous at 36.6 °C as determined by differential scanning calorimetry (DSC). The optimized dendrimer, half-filled with glucoheptoamide substituents, was applied as carrier bearing two covalently attached cytisine molecules: a rigid and hydrophobic alkaloid. The conjugate with 2 cytisine and 16 glucoheptoamide substituents showed fast accumulation and no toxicity up to 200 µM concentration. The half-glucoheptoamidated PAMAM dendrimer was selected as a promising anticancer drug carrier for further applications.
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spelling pubmed-72843442020-08-13 Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates Czerniecka-Kubicka, Anna Tutka, Piotr Pyda, Marek Walczak, Małgorzata Uram, Łukasz Misiorek, Maria Chmiel, Ewelina Wołowiec, Stanisław Pharmaceutics Article Third-generation poly(amidoamine) dendrimer (PAMAM) was modified by stepwise primary amine group amidation with d-glucoheptono-1,4-lactone. The physicochemical properties of the conjugates—size, ζ potential in lysosomal pH 5 and in neutral aqueous solutions, as well as intramolecular dynamics by differential scanning calorimetry—were determined. Internalization and toxicity of the conjugates against normal human fibroblasts BJ were monitored in vitro in order to select an appropriate carrier for a drug delivery system. It was found that initial glucoheptoamidation (up to 1/3 of amine groups of neat dendrimers available) resulted in increase of conjugate size and ζ potential. Native or low substituted dendrimer conjugates accumulated efficiently in fibroblast cells at nontoxic 1 µM concentration. Further substitution of dendrimer caused consistent decrease of size and ζ potential, cell accumulation, and toxicity. All dendrimers are amorphous at 36.6 °C as determined by differential scanning calorimetry (DSC). The optimized dendrimer, half-filled with glucoheptoamide substituents, was applied as carrier bearing two covalently attached cytisine molecules: a rigid and hydrophobic alkaloid. The conjugate with 2 cytisine and 16 glucoheptoamide substituents showed fast accumulation and no toxicity up to 200 µM concentration. The half-glucoheptoamidated PAMAM dendrimer was selected as a promising anticancer drug carrier for further applications. MDPI 2020-05-22 /pmc/articles/PMC7284344/ /pubmed/32456066 http://dx.doi.org/10.3390/pharmaceutics12050473 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
Czerniecka-Kubicka, Anna
Tutka, Piotr
Pyda, Marek
Walczak, Małgorzata
Uram, Łukasz
Misiorek, Maria
Chmiel, Ewelina
Wołowiec, Stanisław
Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates
title Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates
title_full Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates
title_fullStr Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates
title_full_unstemmed Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates
title_short Stepwise Glucoheptoamidation of Poly(Amidoamine) Dendrimer G3 to Tune Physicochemical Properties of the Potential Drug Carrier: In Vitro Tests for Cytisine Conjugates
title_sort stepwise glucoheptoamidation of poly(amidoamine) dendrimer g3 to tune physicochemical properties of the potential drug carrier: in vitro tests for cytisine conjugates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284344/
https://www.ncbi.nlm.nih.gov/pubmed/32456066
http://dx.doi.org/10.3390/pharmaceutics12050473
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