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Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship
Multidrug resistance (MDR) is often caused by the overexpression of efflux pumps, such as ABC transporters, in particular, P-glycoprotein (P-gp). Here, we investigate the di- and tri- block amphiphilic polymer systems based on polypropylene glycol (PPO) and copolymers of (N-(2-hydroxypropyl)methacry...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920990/ https://www.ncbi.nlm.nih.gov/pubmed/31694350 http://dx.doi.org/10.3390/pharmaceutics11110579 |
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author | Braunová, Alena Kaňa, Martin Kudláčová, Júlia Kostka, Libor Bouček, Jan Betka, Jan Šírová, Milada Etrych, Tomáš |
author_facet | Braunová, Alena Kaňa, Martin Kudláčová, Júlia Kostka, Libor Bouček, Jan Betka, Jan Šírová, Milada Etrych, Tomáš |
author_sort | Braunová, Alena |
collection | PubMed |
description | Multidrug resistance (MDR) is often caused by the overexpression of efflux pumps, such as ABC transporters, in particular, P-glycoprotein (P-gp). Here, we investigate the di- and tri- block amphiphilic polymer systems based on polypropylene glycol (PPO) and copolymers of (N-(2-hydroxypropyl)methacrylamide) (PHPMA) as potential macromolecular inhibitors of P-gp, and concurrently, carriers of drugs, passively targeting solid tumors by the enhanced permeability and retention (EPR) effect. Interestingly, there were significant differences between the effects of di- and tri- block polymer-based micelles, with the former being significantly more thermodynamically stable and showing much higher P-gp inhibition ability. The presence of Boc-protected hydrazide groups or the Boc-deprotection method did not affect the physico-chemical or biological properties of the block copolymers. Moreover, diblock polymer micelles could be loaded with free PPO containing 5–40 wt % of free PPO, which showed increased P-gp inhibition in comparison to the unloaded micelles. Loaded polymer micelles containing more than 20 wt % free PPO showed a significant increase in toxicity; thus, loaded diblock polymer micelles containing 5–15 wt % free PPO are potential candidates for in vitro and in vivo application as potent MDR inhibitors and drug carriers. |
format | Online Article Text |
id | pubmed-6920990 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69209902019-12-24 Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship Braunová, Alena Kaňa, Martin Kudláčová, Júlia Kostka, Libor Bouček, Jan Betka, Jan Šírová, Milada Etrych, Tomáš Pharmaceutics Article Multidrug resistance (MDR) is often caused by the overexpression of efflux pumps, such as ABC transporters, in particular, P-glycoprotein (P-gp). Here, we investigate the di- and tri- block amphiphilic polymer systems based on polypropylene glycol (PPO) and copolymers of (N-(2-hydroxypropyl)methacrylamide) (PHPMA) as potential macromolecular inhibitors of P-gp, and concurrently, carriers of drugs, passively targeting solid tumors by the enhanced permeability and retention (EPR) effect. Interestingly, there were significant differences between the effects of di- and tri- block polymer-based micelles, with the former being significantly more thermodynamically stable and showing much higher P-gp inhibition ability. The presence of Boc-protected hydrazide groups or the Boc-deprotection method did not affect the physico-chemical or biological properties of the block copolymers. Moreover, diblock polymer micelles could be loaded with free PPO containing 5–40 wt % of free PPO, which showed increased P-gp inhibition in comparison to the unloaded micelles. Loaded polymer micelles containing more than 20 wt % free PPO showed a significant increase in toxicity; thus, loaded diblock polymer micelles containing 5–15 wt % free PPO are potential candidates for in vitro and in vivo application as potent MDR inhibitors and drug carriers. MDPI 2019-11-05 /pmc/articles/PMC6920990/ /pubmed/31694350 http://dx.doi.org/10.3390/pharmaceutics11110579 Text en © 2019 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 Braunová, Alena Kaňa, Martin Kudláčová, Júlia Kostka, Libor Bouček, Jan Betka, Jan Šírová, Milada Etrych, Tomáš Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship |
title | Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship |
title_full | Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship |
title_fullStr | Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship |
title_full_unstemmed | Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship |
title_short | Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship |
title_sort | micelle-forming block copolymers tailored for inhibition of p-gp-mediated multidrug resistance: structure to activity relationship |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920990/ https://www.ncbi.nlm.nih.gov/pubmed/31694350 http://dx.doi.org/10.3390/pharmaceutics11110579 |
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