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

Abstract

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.

EZH2 as a prognostic-related biomarker in lung adenocarcinoma correlating with cell cycle and immune infiltrates

“…Docetaxel, palbociclib, and angiogenesis-inhibitor were among the extensively used compounds for the treatment of tumor, as determined by their scores. Other drugs/molecules, such as MK-1775 [ 34 , 35 ], MK-5108 [ 36 ], fenbendazole [ 37 , 38 ], albendazole [ 39 ], BAY-K8644 [ 40 ], evodiamine [ 41 ], purvalanol-a [ 42 ], mycophenolic-acid [ 43 ], PHA-793887 [ 44 ], cyclopamine [ 45 ], is a possible treatment for lung adenocarcinoma (Tables 5 , 6 ). To determine the therapeutic potential of these drugs/molecules in patients with lung adenocarcinoma with high EZH2 expression, additional research is necessary.…”

“…Docetaxel, palbociclib, and angiogenesis-inhibitor were among the extensively used compounds for the treatment of tumor, as determined by their scores. We have identified some potential drugs or molecules for the treatment of lung adenocarcinoma by reading the literature, such as MK-1775 [ 34 , 35 ], MK-5108 [ 36 ], fenbendazole [ 37 , 38 ], albendazole [ 39 ], BAY-K8644 [ 40 ], evodiamine [ 41 ], purvalanol-a [ 42 ], mycophenolic-acid [ 43 ], PHA-793887 [ 44 ], and cyclopamine [ 45 ] (Tables 5 , 6 ). Of interest is the WEE1 inhibitor MK-1775, which has shown potential chemotherapy or radiotherapy sensitivity in preclinical models, particularly, although not exclusively, in p53 mutated or deficient cancer cells [ 52 ].…”

Novel Anticancer Strategies II

“…Gabriele et al showed that the coating of melanin nanoparticles, otherwise known to be biologically benign to human cells with glucose enhanced their uptake with cancer cells cultured in low glucose concentrations, making them more susceptible to killing by laser illumination [ 21 ]. Other original papers published in this Special Issue reported drug delivery systems that have been improved to potentially enhance the effectiveness of complex cancer treatments [ 22 , 23 , 24 , 25 , 26 ].…”