Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

Abstract

BackgroundNanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin.MethodsOvarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects.ResultsWe show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model.ConclusionThus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2206-4) contains supplementary material, which is available to authorized users.

Folate‐appended cyclodextrin carrier targets ovarian cancer cells expressing the proton‐coupled folate transporter

“…Because the cytotoxicity of PTX/Fol‐c 1 ‐β‐CyD was decreased by knockdown of PCFT, but not FRα, in A2780 cells, it is likely that PTX/Fol‐c 1 ‐β‐CyD uptake in A2780 cells is mediated primarily through PCFT (Figure 3C). Aside from in this study, A2780 and SK‐OV‐3 cells are frequently used as target cells in studies of FRα‐targeting drugs for ovarian cancer 16,36‐40. Some studies have compared expression levels of FRα between A2780 and SK‐OV‐3 cells, and in all of the studies, consistent with our results, A2780 cells expressed lower levels of FRα than SK‐OV‐3 cells 16,37,39.…”

Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

“…They also found that angiogenesis in the tumors was reduced in treated mice as indicated by less CD31-positive staining. The same group also reported that surface functionalization of CeO 2 nanoparticle with folic acid and its co-delivery with cisplatin further decreased the tumor burden and angiogenesis [157]. In other studies, CeO 2 nanoparticle administration to carbon-tetrachloride (CCl 4 )-induced liver fibrosis mice was shown to inhibit oxidative [158], [159] and endoplasmic reticulum stress signaling pathways as well as reduction in inflammatory cytokines such as TNF-α and IL-1β [158].…”

Variable in Vivo and in Vitro Biological Effects of Cerium Oxide Nanoparticle Formulations

“…Nanoparticle coating or stabilization is typically utilized to achieve reduced reticuloendothelial uptake (Murugan et al, 2015), direct the nanoparticle to a particular tissue target (Cimini et al, 2012;Hijaz et al, 2016), or to provide a functional property such as reduced angiogenesis (Lord et al, 2013). Minor changes to surface chemistry, for example by varying the density of polyethylene glycol coating, yield distinct profiles of corona proteins and differing macrophage uptake patterns (Walkey et al, 2012).…”