HPMA copolymer mebendazole conjugate allows systemic administration and possesses antitumour activity in vivo
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F22%3A00558143" target="_blank" >RIV/61388971:_____/22:00558143 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/61389013:_____/22:00558143
Výsledek na webu
<a href="https://www.mdpi.com/1999-4923/14/6/1201" target="_blank" >https://www.mdpi.com/1999-4923/14/6/1201</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/pharmaceutics14061201" target="_blank" >10.3390/pharmaceutics14061201</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
HPMA copolymer mebendazole conjugate allows systemic administration and possesses antitumour activity in vivo
Popis výsledku v původním jazyce
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.
Název v anglickém jazyce
HPMA copolymer mebendazole conjugate allows systemic administration and possesses antitumour activity in vivo
Popis výsledku anglicky
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.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30104 - Pharmacology and pharmacy
Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Ostatní
Rok uplatnění
2022
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Pharmaceutics
ISSN
1999-4923
e-ISSN
1999-4923
Svazek periodika
14
Číslo periodika v rámci svazku
6
Stát vydavatele periodika
CH - Švýcarská konfederace
Počet stran výsledku
11
Strana od-do
1201
Kód UT WoS článku
000816333500001
EID výsledku v databázi Scopus
2-s2.0-85131853709