HPMA copolymer mebendazole conjugate allows systemic administration and possesses antitumour activity in vivo

Studenovský, Martin; Rumlerová, Anna; Kovářová, Jiřina; Dvořáková, Barbora; Sivák, Ladislav; Kostka, Libor; Berdár, Daniel; Etrych, Tomáš; Kovář, Marek

doi:https://dx.doi.org/10.3390/pharmaceutics14061201

Number of the records: 1

HPMA copolymer mebendazole conjugate allows systemic administration and possesses antitumour activity in vivo

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SYSNO ASEP	0558143
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	HPMA copolymer mebendazole conjugate allows systemic administration and possesses antitumour activity in vivo
Author(s)	Studenovský, Martin (UMCH-V)_{RID, ORCID} Rumlerová, Anna (UMCH-V) Kovářová, Jiřina (MBU-M) Dvořáková, Barbora (MBU-M)_RID Sivák, Ladislav (MBU-M)_RID Kostka, Libor (UMCH-V)_{RID, ORCID} Berdár, Daniel (MBU-M) Etrych, Tomáš (UMCH-V)_{RID, ORCID} Kovář, Marek (MBU-M)_{RID, ORCID}
Article number	1201
Source Title	Pharmaceutics. - : MDPI Roč. 14, č. 6 (2022)
Number of pages	11 s.
Language	eng - English
Country	CH - Switzerland
Keywords	mebendazole ; drug delivery ; cancer therapy
Subject RIV	CD - Macromolecular Chemistry
OECD category	Polymer science
Subject RIV - cooperation	Institute of Microbiology - Pharmacology ; Medidal Chemistry
R&D Projects	GA19-05649S GA ČR - Czech Science Foundation (CSF)
	LTAUSA18083 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Method of publishing	Open access
Institutional support	UMCH-V - RVO:61389013 ; MBU-M - RVO:61388971
UT WOS	000816333500001
EID SCOPUS	85131853709
DOI	10.3390/pharmaceutics14061201
Annotation	Mebendazole and other benzimidazole antihelmintics, such as albendazole, fenbendazole, or flubendazole, have been shown to possess antitumour activity, primarily due to their microtubule-disrupting activity. However, the extremely poor water-solubility of mebendazole and other benzimidazoles, resulting in very low bioavailability, is a serious drawback of this class of drugs. Thus, the investigation of their antitumour potential has been limited so far to administering repeated high doses given peroral (p.o.) or to using formulations, such as liposomes. Herein, we report a fully biocompatible, water-soluble, HPMA copolymer-based conjugate bearing mebendazole (P-MBZ, Mw 28–33 kDa) covalently attached through a biodegradable bond, enabling systemic administration. Such an approach not only dramatically improves mebendazole solubility but also significantly prolongs the half-life and ensures tumour accumulation via an enhanced permeation and retention (EPR) effect in vivo. This P-MBZ has remarkable cytostatic and cytotoxic activities in EL-4 T-cell lymphoma, LL2 lung carcinoma, and CT-26 colon carcinoma mouse cell lines in vitro, with corresponding IC50 values of 1.07, 1.51, and 0.814 µM, respectively. P-MBZ also demonstrated considerable antitumour activity in EL-4 tumour-bearing mice when administered intraperitoneal (i.p.), either as a single dose or using 3 intermittent doses. The combination of P-MBZ with immunotherapy based on complexes of IL-2 and anti-IL-2 mAb S4B6, potently stimulating activated and memory CD8+ T cells, as well as NK cells, further improved the therapeutic effect.
Workplace	Institute of Macromolecular Chemistry
Contact	Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358
Year of Publishing	2023
Electronic address	https://www.mdpi.com/1999-4923/14/6/1201

Number of the records: 1