Polymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling

Sivák, Ladislav; Šubr, Vladimír; Kovarova, Jirina; Dvořáková, Barbora; Šírová, Milada; Řı́hová, Blanka; Randárová, Eva; Kraus, Michal; Tomala, Jakub; Studenovský, Martin; Vondráčková, Michaela; Sedláček, Radislav; Makovický, Petr; Fučíková, Jitka; Vošáhlíková, Šárka; Špíšek, Radek; Kostka, Libor; Etrych, Tomáš; Kovář, Marek

doi:10.1016/j.jconrel.2021.03.015

Cited by 11 publications

(13 citation statements)

References 53 publications

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“…The hydrazone bond is generally recognized as a suitable pH-sensitive linker in the literature . Indeed, it has been previously proved that the hydrolysis rate of the hydrazone bond between Dox and the pHPMA carrier is not influenced by the polymer carrier architecture (star, grafted, , or micellar carriers) or its dispersity. , As expected, the drug release kinetics of Star-Dox and Star-RD were comparable to those of the linear conjugates, with only a minor release of Dox (8%) or RD (6%) in the pH 7.4 buffer within 24 h incubation, whereas the hydrazone bond was rapidly hydrolyzed at pH 5.0 with 73% Dox release and 76% RD release within 24 h.…”

Section: Resultssupporting

confidence: 67%

“…HPMA-based linear copolymer conjugates bearing Dox and a Rit derivative (5-methyl-4-oxohexanoic acid Rit ester; RD henceforth) attached via a hydrazone bond showed increased Dox cytotoxicity in neuroblastoma cell lines resistant to Dox. , Linear HPMA copolymer conjugate bearing RD also showed remarkable anticancer activity in mice bearing CT26 and B16F10 tumors and showed a considerable therapeutic effect on human FaDu head and neck carcinoma xenografts …”

Section: Introductionmentioning

confidence: 99%

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Simultaneous Delivery of Doxorubicin and Protease Inhibitor Derivative to Solid Tumors via Star-Shaped Polymer Nanomedicines Overcomes P-gp- and STAT3-Mediated Chemoresistance

et al. 2022

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The derivative of protease inhibitor ritonavir (5-methyl-4-oxohexanoic acid ritonavir ester; RD) was recently recognized as a potent P-gp inhibitor and cancerostatic drug inhibiting the proteasome and STAT3 signaling. Therefore, we designed high-molecular-weight HPMA copolymer conjugates with a PAMAM dendrimer core bearing both doxorubicin (Dox) and RD (Star-RD + Dox) to increase the circulation half-life to maximize simultaneous delivery of Dox and RD into the tumor. Star-RD inhibited P-gp activity, potently sensitizing both low- and high-P-gp-expressing cancer cells to the cytostatic and proapoptotic activity of Dox in vitro. Star-RD + Dox possessed higher cytostatic and proapoptotic activities compared to Star-Dox and the equivalent mixture of Star-Dox and Star-RD in vitro. Star-RD + Dox efficiently inhibited STAT3 signaling and induced caspase-3 activation and DNA fragmentation in cancer cells in vivo. Importantly, Star-RD + Dox was found to have superior antitumor activity in terms of tumor growth inhibition and increased survival of mice bearing P-gp-expressing tumors.

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Section: Resultssupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Simultaneous Delivery of Doxorubicin and Protease Inhibitor Derivative to Solid Tumors via Star-Shaped Polymer Nanomedicines Overcomes P-gp- and STAT3-Mediated Chemoresistance

et al. 2022

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“…The most characteristic of these abnormalities is the increased expression of Bcl-2 family proteins ( Housman et al, 2014 ; Hu et al, 2016 ). Targeting these anti-apoptotic factors to improve the killing efficiency of chemotherapeutics against tumor cells is a promising tumor therapy strategy ( Pan et al, 2020 ; Wang H. et al, 2020 ; Xie et al, 2020 ; Sivak et al, 2021 ). For instance, Sivak, L. et al described a polymer biomaterial composed of the antiretroviral drug ritonavir derivative (5-methyl-4-oxohexanoic acid ritonavir ester; RD), covalently bound to the HPMA copolymer carrier via a pH-sensitive hydrazone bond (P-RD).…”

Section: Nddss For Reactivating the Apoptosis Pathway Of Tumor Cellsmentioning

confidence: 99%

“…Importantly, RD inhibited STAT3 phosphorylation in CT26 cells (murine colon adenocarcinoma) in vitro and the expression of the NF-κB p65 subunit, Bcl-2, and Mcl-1 in vitro . P-RD nanomedicine showed significant antitumor activity in CT26 and B16F10 tumor-bearing mice ( Sivak et al, 2021 ). Additionally, Pan.…”

Section: Nddss For Reactivating the Apoptosis Pathway Of Tumor Cellsmentioning

confidence: 99%

Recent Progress of Novel Nanotechnology Challenging the Multidrug Resistance of Cancer

Zhang

Han

et al. 2022

Front. Pharmacol.

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Multidrug resistance (MDR) of tumors is one of the clinical direct reasons for chemotherapy failure. MDR directly leads to tumor recurrence and metastasis, with extremely grievous mortality. Engineering a novel nano-delivery system for the treatment of MDR tumors has become an important part of nanotechnology. Herein, this review will take those different mechanisms of MDR as the classification standards and systematically summarize the advances in nanotechnology targeting different mechanisms of MDR in recent years. However, it still needs to be seriously considered that there are still some thorny problems in the application of the nano-delivery system against MDR tumors, including the excessive utilization of carrier materials, low drug-loading capacity, relatively narrow targeting mechanism, and so on. It is hoped that through the continuous development of nanotechnology, nano-delivery systems with more universal uses and a simpler preparation process can be obtained, for achieving the goal of defeating cancer MDR and accelerating clinical transformation.

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“…However, P-MBZ-A conjugate in combination with IL-2co showed considerably higher antitumour efficacy, achieving stronger tumour growth inhibition and prolonged survival to 162% of controls. An experimental group treated with IL-2co alone was not included since such immunotherapy given as late as 14 days post-tumour-cell inoculation has no effect [33]. Finally, we determined whether immunotherapy based on complexes of IL-2 and anti-IL-2 mAb S4B6 (IL-2co) can increase the therapeutic effect of P-MBZ-A conjugate.…”

Section: Antitumour Activity Of P-mbz-a Conjugate In Vivomentioning

confidence: 99%

HPMA Copolymer Mebendazole Conjugate Allows Systemic Administration and Possesses Antitumour Activity In Vivo

et al. 2022

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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.

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Polymer-ritonavir derivate nanomedicine with pH-sensitive activation possesses potent anti-tumor activity in vivo via inhibition of proteasome and STAT3 signaling

Cited by 11 publications

References 53 publications

Simultaneous Delivery of Doxorubicin and Protease Inhibitor Derivative to Solid Tumors via Star-Shaped Polymer Nanomedicines Overcomes P-gp- and STAT3-Mediated Chemoresistance

Simultaneous Delivery of Doxorubicin and Protease Inhibitor Derivative to Solid Tumors via Star-Shaped Polymer Nanomedicines Overcomes P-gp- and STAT3-Mediated Chemoresistance

Recent Progress of Novel Nanotechnology Challenging the Multidrug Resistance of Cancer

HPMA Copolymer Mebendazole Conjugate Allows Systemic Administration and Possesses Antitumour Activity In Vivo

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