Nano-delivery of a novel inhibitor of ERCC1-XPF for targeted sensitization of colorectal cancer to platinum-based chemotherapeutics.

Abstract

In this study, a novel inhibitor of ERCC1/XPF heterodimerization, A4, was used as an inhibitor of repair for DNA damage by platinum-based chemotherapeutics. Nano-formulations of A4 were developed, using self-assembly of the following block copolymers: methoxy-poly(ethylene oxide)-block-poly(α-benzyl carboxylate-ε-caprolactone) (PEO-b-PBCL), methoxy-poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL), or methoxy-poly(ethylene oxide)-block-poly (D, L, lactide) (PEO-b-PDLA 50-50). The nano-formulations were characterized for their average diameter, polydispersity, morphology, A4 encapsulation and in vitro release. The activity of A4 and its nano-formulation on the inhibition of ERCC1/XPF dimerization was investigated. The cytotoxicity of carboplatin and oxaliplatin in colorectal cancer (CRC) cell lines, without or with pre-treatment with A4 or its nanoparticle formulation was assessed by conducting colony forming as well as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Among the three nano-formulations of A4 under study, optimum properties were achieved with PEO-b-PBCL nanocarriers, showing an encapsulation efficiency of 83.1 ± 5.83%, loading content of 11.5 ± 0.37 w/w %, < 50% drug release within 24 hs, and an average diameter of < 150 nm. The chemo sensitizing effect of A4 and its nano-encapsulated counterparts were more noticeable when A4 was combined with carboplatin versus oxaliplatin. The results of cytotoxicity studies in HCT116 XPF^-/- cells confirmed the specificity of A4 through an XPF-dependent mechanism in the sensitization of these cells to carboplatin at concentrations below 0.5 μM. The result of the study shows great potential for A4 and its PEO-b-PBCL nano-formulation in sensitization of CRC to platinum-based chemotherapeutics.