Evaluation of a Novel PLGA-HA-Based Drug Delivery System Targeting the cell cycle and PI3K/AKT/mTOR Pathway in HCT116 Colorectal Carcinoma Cells with Differing P53 Statuses

Colorectal carcinoma (CRC) is a very important health problem all over the world, and the P53 gene plays an important role in tumor development and in treatment response. The strategy of developing novel DDS that could target specific tumor pathways is one of the most promising approaches to improve therapeutic efficacy. The aim of this study was to evaluate the performance of a newly synthesized PLGA-HA-based DDS encapsulating the mTOR inhibitor Dactolisib on HCT116 CRC cells with differing P53 statuses; P53 positive and P53 negative. The previously synthesized and characterized DDS was tested on HCT-116 P53 positive and negative cell lines. Assessments included: cell cycle distribution analysis by flow cytometry; gene expression profiling of key components of the PI3K/AKT/mTOR pathway by using qPCR, and proteomic via Western blotting. DDS induced a differential effect on the cell cycle progress, which arrested the cell cycle at the G0/G1 phase in a statistically significant way in P53 positive cells, while in P53 negative cells, it resulted in an increase in the S phase. The gene expression analysis revealed downregulation of PIK3CA, AKT1, and MTOR in both cell lines; however, the inhibition seemed more potent in P53-positive cells. The proteomic analysis confirmed reduced p-AKT and p-mTOR with increased levels of P53 protein in P53-positive cells. The new PLGA-HA-based DDS exhibits promising anti-cancer activity against CRC cells, which have different influences related to P53 status. These observations suggest an application for personalized cancer therapy, particularly in the case of tumors with functional P53.