Engineering a multi-component nanocarrier for Olaparib: A chemo-physical and network pharmacology approach

Breast cancer treatment remains challenging, prompting innovative therapeutic strategies. In the study, network analysis was performed to evaluate the degree of interaction and to explore the synergistic potential for Olaparib, Hyaluronic Acid, and Graphene Quantum Dots. This was followed by molecular docking studies to assess the binding affinity and interaction of compounds with their target proteins. Finally, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted to pinpoint the biological processes and pathways that are most affected. A total of 910 breast cancer–related targets were identified from the GeneCards database, while 366 compound-associated targets were obtained from DIGEP-Pred, SuperPred, and SwissTargetPrediction databases. By overlapping these datasets, 90 common targets were identified, representing the potential intersection between disease-related and compound-related genes. Network pharmacology analysis revealed HA had the highest target interaction (degree = 31), followed by GQD (27) and Olaparib (18). These agents influenced key breast cancer targets (MAPK1, PIK3CA, AKT1, EGFR) and critical pathways like PI3K-Akt and MAPK signalling. Molecular docking showed strong binding affinities for GQD to EGFR and HA to Carbonic Anhydrase II. GO and KEGG analyses further highlighted the involvement of PI3K-Akt, MAPK, and JAK-STAT pathways in tumour progression and chemoresistance. Physicochemical characterization of the nanoformulation confirmed spherical morphology (173 nm particle size, PDI 0.28, zeta potential -30.5 mV). Cytotoxicity assays on MDA-MB-231 cells demonstrated the nanoformulation superior anticancer efficacy, reducing Olaparib's IC₅₀ from 512.07 µg/mL to 243.63 µg/mL.Network pharmacology provided crucial insights which highlighted potential synergies and targets in breast cancer by improving cellular uptake of nanoformulation. Importantly, the blank nanoparticles exhibited no significant toxicity, with an IC50 value 948.3 µg/mL.These findings underscore the promising nanocarrier-based system for enhancing Olaparib's therapeutic index, warranting further in vitro and in vivo validation for clinical translation.