Multifunctional Hybrid Nano-Platform for Co-Delivery of Erlotinib and Silibinin: A Nanotherapeutic Strategy Against Triple-Negative Breast Cancer

<title>Abstract</title> <p>Triple-negative breast cancer (TNBC) is associated with high mortality due to the lack of hormonal receptors necessary for targeted therapies. However, the prevalent overexpression of basal biomarkers, such as EGFR, provides an opportunity to explore alternative treatment options. In this research investigation, we designed and fabricated erlotinib (ERL), an EGFR tyrosine kinase inhibitor, alongside silibinin (SLB), a phytoconstituent known for its additional anticancer as well as its antioxidant, anti-inflammatory, and antimetastatic effects. These agents were encapsulated in lecithin-PLGA hybrid nanoparticles (ERL-SLB-LPHN) to enhance therapeutic outcomes in TNBC. The fabrication of ERL-SLB-LPHN was optimized using the Box-Behnken design, resulting in a formulation with a particle size of 160.13 ± 0.90 nm, a PDI of 0.13 ± 0.03, and percent encapsulation rates of ERL at 63.18 ± 8.2% and SLB at 98.21 ± 0.12%, respectively. The in vitro release study showed controlled release behaviour of both drugs from the nanoparticles, and the stability data indicated that the ERL-SLB-LPHN is stable at 2–8°C. Further hemocompatibility studies of the formulation were conducted, indicating good biocompatibility. Furthermore, an in vitro cell culture study found that ERL-SLB-LPHN had an IC of 7.99 µg/ml and exhibited higher cellular uptake than the free ERL and SLB. MMP, Apoptosis, and DCFDA staining analysis revealed that, as compared to the free drug, ERL-SLB-LPHN showed higher apoptosis and ROS production. An pharmacokinetic study revealed 1.49- fold and 1.35-fold enhancement in AUC with ERL-LPHN and SLB-LPHN, compared to free ERL and SLB, respectively. The toxicological study suggested that ERL-SLB-LPHN exhibits a safe toxicological profile. To summarize, the hybrid nanoparticle enhanced the drug's therapeutic potential and anticancer efficacy.</p>