Aminocellulose-Grafted Polymeric Nanoparticles for Selective Targeting of CHEK2-Deficient Colorectal Cancer.

We report the formulation of aminocellulose-grafted polymeric nanoparticles containing LCS-1 for synthetic lethal targeting of checkpoint kinase 2 (CHEK2)-deficient HCT116 colon cancer (CRC) cells to surpass the limitations associated with the solubility of LCS-1 (a superoxide dismutase inhibitor). Aminocellulose (AC), a highly biocompatible and biodegradable hydrophilic polymer, was grafted over polycaprolactone (PCL), and a nanoprecipitation method was employed for formulating nanoparticles containing LCS-1. In this study, we exploited the synthetic lethal interaction between SOD1 and CHEK2 for the specific inhibition of CHEK2-deficient HCT116 CRC cells using LCS-1-loaded PCL-AC NPs. Furthermore, the effects of formation of protein corona on PCL-AC nanoparticles were also assessed in terms of size, cellular uptake, and cell viability. LCS-1-loaded NPs were evaluated for their size, zeta potential, and polydispersity index using a zetasizer, and their morphological characteristics were assessed by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy analyses. Cellular internalization using confocal microscopy exhibited that nanoparticles were uptaken by HCT116 cells. Also, nanoparticles were cytocompatible as they did not induce cytotoxicity in hTERT and HEK-293 cells. The LCS-1-loaded PCL-AC NPs were quite hemocompatible and were 240 times more selective in killing CHEK2-deficient cells as compared to CHEK2-proficient CRC cells. Moreover, PCL-AC NPs exhibited that the protein corona-coated nanoparticles were incubated in the human and fetal bovine sera as visualized by SDS-PAGE. A slight increment in hydrodynamic diameter was observed for corona-coated PCL-AC nanoparticles, and size increment was further confirmed by TEM. Corona-coated PCL-AC NPs also exhibited cellular uptake as demonstrated by flow cytometric analysis and did not cause cytotoxic effects on hTERT cells. The nanoformulation was developed to enhance therapeutic potential of the drug LCS-1 for enhanced lethality of colorectal cancer cells with CHEK2 deficiency.