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Abstract
Albendazole (ABZ) is a benzamidazole derivative that binds to β-tubulin and inhibits the polymerisation of microtubules. ABZ has a remarkable activity against a variety of tumour cell lines including colorectal, liver, and ovarian cancer cells. In pre-clinical models, ABZ has been shown to have both anti-tumour and anti-angiogenic activities. Nevertheless, poor aqueous solubility of ABZ limits its absorption, and as a result, its efficacy. Therefore, the first aim of this project was to improve the aqueous solubility of ABZ. Using a combination of ionisation with acid and complexation with hydroxypropyl-β-cyclodextrin (HPβCD), a relatively high concentration of ABZ in solution was achieved. Comparison of pharmacokinetic profiles of ABZ/HPβCD with a conventional formulation of ABZ in hydroxypropyl methylcellulose (ABZ/HPMC) in nude mice revealed that complexation with HPβCD results in a significantly higher peak plasma concentration (Cmax) and area under the curve (AUC) of ABZ and its metabolites. Moreover, in mice-bearing human colorectal cancer cells, HCT-116, ABZ/HPβCD treatment led to a significant delay in tumour growth with increase in survival of animals as compared with vehicle and ABZ/HPMC treatments.
The second aim of this research was to improve the efficacy of ABZ using combination therapy. To this end, the interaction between ABZ and different chemotherapeutic agents were assessed using the Sulforhodamine B assay (SRB) and quantified by median effect analysis method. Among the tested agents, a synergistic anti-proliferative effect was observed with the combination of ABZ and 2-methoxyestradiol (2ME) in HCT-116 and DU145. Of interest, 2ME, a microtubule targeting agent binds to similar colchicine-binding site of β-tubulin as ABZ and inhibits microtubules polymerisation. Synergistic interaction of ABZ and 2ME was accompanied with the activation of extrinsic pathway of apoptosis.
In vivo, the combination of low concentration of ABZ with 2ME resulted in an increase in the survival rate of mice-bearing HCT-116 tumours. This effect was accompanied by a decrease in plasma and tumour vascular endothelial growth factor (VEGF) as well as a reduction in microvessel density. In addition, combination therapy led to a significant decrease in proliferation rate of the tumour and an increase in apoptosis. Noticeably, high concentration of ABZ, in combination with 2ME, resulted in an antagonistic effect on tumour growth and survival of the animals.
Taken together, the solubility and anti-tumour efficacy of ABZ was highly increased by complexation with HPβCD, leading to the conclusion that the formulation may be suitable for parenteral administration. Moreover, combination of ABZ and 2ME has shown promising results in pre-clinical model. Additionally, the finding that the combination of two microtubule-binding agents that share the same binding site can act synergistically in vitro and in vivo may lead to the development of new therapeutic strategies in cancer treatment.