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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...

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Autores principales: Braunová, Alena, Kaňa, Martin, Kudláčová, Júlia, Kostka, Libor, Bouček, Jan, Betka, Jan, Šírová, Milada, Etrych, Tomáš
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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.
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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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