Nanodelivery of Novel Inhibitors of ERCC1/XPF for sensitizing colorectal cancer cell to platinum drugs

Abstract

This project's long-term goal is to increase the efficacy of genotoxic therapeutics through thesensitization of cells to DNA-damaging therapy ahead of the treatment. The focus of this projectwas on the enhancement of platinum-based chemotherapeutics in colorectal cancer usingcolorectal cancer cell lines as models of the disease. For this purpose e, novel inhibitor of a DNArepair enzyme involved in the repair of DNA caused by platinum-based chemotherapeutics, i.e.,small molecule inhibitors of ERCC1-XPF heterodimerization, namely A4 and pyronaridine wereused. To reduce the systemic effect of ERCC1-XPF inhibitors, that can lead to the sensitization ofnormal cells as well as cancer cells to DNA-damaging chemotherapeutics nano delivery systemsof A4 and pyronaridine were also developed. Inhibition of ERCC1/XPF, a heterodimeric enzymecomplex with endonuclease activity that participates in the repair of DNA inter-and intra-strandcrosslinks, by A4, pyronaridine, and their nano-formulations was hypothesized to make cellssensitive to DNA damage by platinum-based chemotherapeutics. The results of our studies ledto the development of optimum polymer and lipid-based nano-formulations for delivery of A4and pyronaridine, respectively, showing maximum encapsulation efficiency, <50 % drug releasewithin 24 hrs, and average diameter of < 150 nm. Free and particularly encapsulated inhibitorsof ERCC1/XPF were able to sensitize colorectal cancer cells to the cytotoxic effects of platinumbased chemotherapeutics under study at specific dose ratios. The sensitizing effect of ERCC1/XPFinhibitors and their encapsulated counterparts was more noticeable for carboplatin