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Open AccessArticle

Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship

1
Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06 Prague 6, Czech Republic
2
Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague 4, Czech Republic
3
Department of Otorhinolaryngology and Head and Neck Surgery, First faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague 5, Czech Republic
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(11), 579; https://doi.org/10.3390/pharmaceutics11110579
Received: 1 October 2019 / Revised: 21 October 2019 / Accepted: 4 November 2019 / Published: 5 November 2019
(This article belongs to the Special Issue Advanced Polymeric Delivery Systems for Cancer Therapy)
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. View Full-Text
Keywords: polymer therapeutics; multidrug resistance; micelles; P-glycoprotein; solid tumors; block copolymers polymer therapeutics; multidrug resistance; micelles; P-glycoprotein; solid tumors; block copolymers
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MDPI and ACS Style

Braunová, A.; Kaňa, M.; Kudláčová, J.; Kostka, L.; Bouček, J.; Betka, J.; Šírová, M.; Etrych, T. Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship. Pharmaceutics 2019, 11, 579.

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