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.