Abstract
BackgroundThe poor prognosis of patients with drug resistant ovarian cancer and the lack of targeted therapy have raised the need for alternative treatments. Albendazole (ABZ) is an anti-parasite compound capable of impairing microtubule formation. We hypothesized that ABZ could be repurposed as a potential anti-angiogenic drug due to its potent inhibition of vascular endothelial growth factor (VEGF) in ovarian cancer with ascites. However, the poor aqueous solubility of ABZ limits its potential for cancer therapy. In this study, we have assembled ABZ with bovine serum albumin into nanoparticles with a size range of 7–10 nm (BSA-ABZ) and 200–250 nm (Nab-ABZ). We further examined the anticancer effects of ABZ carrying nanoparticles in ovarian cancer cells, in both in vitro and in vivo models.ResultsDrug release studies demonstrated that about 93% of ABZ was released from BSA-ABZ 10 nm in comparison to 83% from Nab-ABZ 200 nm at pH 7.4 in 8 days. In vitro cell proliferation studies showed that the BSA-ABZ 10 nm exhibited the highest killing efficacy of ovarian cancer cells with surprisingly least toxicity to healthy ovarian epithelial cells. Confocal microscopy and fluorescence activated cell sorting analysis (FACS) revealed more efficient internalization of the BSA-ABZ 10 nm by cancer cells. For in vivo studies, we examined the tumor growth, ascites formation and the expression of VEGF and secreted protein acidic and rich in cysteine (SPARC) in tumor samples and only VEGF in plasma samples. The BSA-ABZ 10 nm reduced the tumor burden significantly (p < 0.02) at a much lower drug dose (10 μg/ml) compare to free drug. Both formulations were capable of suppressing the ascites volume significantly (p < 0.05) and reducing the number of ascites cells. The expression of VEGF and SPARC was also reduced, which indicates the underlying therapeutic mechanism of the ABZ.ConclusionOur data suggest that the BSA-ABZ may hold promise for the treatment and control of progression of ovarian cancer with ascites. However further studies are required to examine the efficacy of both the formulations in aggressive models of recurrent ovarian cancer with respect to particle size and dosing parameters.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-015-0082-8) contains supplementary material, which is available to authorized users.
Highlights
The poor prognosis of patients with drug resistant ovarian cancer and the lack of targeted therapy have raised the need for alternative treatments
The nanoparticles were spherical in shape and possessed a smooth surface morphology as shown by transmission electron microscope (TEM) (Figure 1B and C)
There was no significant difference in release behaviour between the two formulations (Figure 2). 50% and 37% of the drug was released from Bovine Serum Albumin Albendazole (BSA-ABZ) 10 nm and Nano albumin formulation of albendazole (Nab-ABZ) 200 nm respectively in the first 6 hours at pH 7.4
Summary
The poor prognosis of patients with drug resistant ovarian cancer and the lack of targeted therapy have raised the need for alternative treatments. We hypothesized that ABZ could be repurposed as a potential anti-angiogenic drug due to its potent inhibition of vascular endothelial growth factor (VEGF) in ovarian cancer with ascites. We further examined the anticancer effects of ABZ carrying nanoparticles in ovarian cancer cells, in both in vitro and in vivo models. Albendazole (ABZ), Methyl [5-(Propylthio)-1-H-Benzimidazol-2Yl] Carbamate, is an anti-anthelminthic drug and has been explored as a potential inhibitor of VEGF [11], hypoxia inducible factor 1-α [12] and tumor angiogenesis [13] over the past few years. ABZ shows superior anti-VEGF activity in a xenograft model of ovarian cancer [16]. In light of its anticancer properties coupled with VEGF inhibition, we hypothesized that ABZ could be repurposed as a new treatment of ovarian cancer
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