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

Abstract

We report the formulation of aminocellulosegrafted 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.

Superior Photophysical and Photosensitizing Properties of Nanoaggregates of Weakly Emissive Dyes for Use in Bioimaging and Photodynamic Therapy

“…However, the cells treated with 1NPs ⊂ PF-127 exhibited significant fluorescence, as observed under the flow cytometry experiments. Further, the quantification of fluorescence intensity was performed by comparing the fluorescence intensities of untreated group, free form of 1 compound-treated group, and 1NPs ⊂ PF-127-treated group, and results were found to be in corroboration with previous studies. , HCT116 cells treated with 1NPs ⊂ PF-127 demonstrated significantly (* p ≤ 0.001) higher fluorescence intensity as compared to both untreated or free form of compound-treated cells.…”

Recent advances in nanomedicine preparative methods and their therapeutic potential for colorectal cancer: a critical review

“…There was also cell uptake and no harmful effects on hTERT cells when PCL-AC NPs were coated with a coronal layer. By developing a nano formulation of LCS-1, researchers hoped to increase its ability to kill colorectal cancer cells with CHEK2 lack ( 71 ).…”

Applications of Bioengineered Polymer in the Field of Nano-Based Drug Delivery

“…Also, nanoparticles were cytocompatible as they did not induce cytotoxicity in hTERT and HEK-293 cells. 102 Diabetes. Diabetes is a chronic disease that affects millions of people worldwide.…”

“…Confocal imaging demonstrated cellular internalization and uptake of nanoparticles by HCT116 cells. Also, nanoparticles were cytocompatible as they did not induce cytotoxicity in hTERT and HEK-293 cells …”