Combinatorial Targeted <scp>PLGA</scp> Nanogels for the Enhanced Delivery of Homologous Recombination Inhibitors to Improve Chemotherapeutic Effectiveness

ABSTRACT The present study formulated and evaluated a targeted PEG‐PLGA nanogel focusing on the development of safe and efficient nanomedicines with the potential to inhibit the growth of specific cancer cells and minimize damage to healthy cells. PEG‐PLGA copolymer nanogels offer flexibility in drug encapsulations, extended circulation time, and high bioavailability. We have engineered this nanogel to encapsulate a small‐molecule ATPase inhibitor CB‐5083 and an inhibitory peptide targeting the interaction between RAD51 and BRCA2 proteins, two major players in the Homologous Recombination (HR) DNA repair pathway. The nanogel is surface‐conjugated with a peptide ligand for the epidermal growth factor receptor (EGFR) overexpressed in many tumors. We characterized the nanogel formulation using FT‐IR spectroscopy, Differential Light Scattering (DLS), and Field emission scanning electron microscopy (FE‐SEM). The analyses indicated the successful preparation of nanogels with a size range of 200–500 nm, a polydispersity index of 0.130–0.345, with spherical shape. The cellular uptake of the nanogels was revealed by monitoring the FITC‐labeled peptide in the HeLa cell line by fluorescence microscopy analysis. In addition, increased cytotoxicity in cancer cell lines, cell cycle arrest, and accumulation of chromosomal aberrations demonstrated the successful impact of this combinatorial formulation on the cancer cells through interference in the HR DNA repair process. Through this study, we conclude that this targeted nanogel is a promising system for the targeted delivery of multiple types of inhibitor molecules specifically to cancer cells and thus can boost the efficacy of chemotherapeutics.