PEGylated Silk Fibroin Nanoparticles for Oral Antibiotic Delivery: Insights into Drug–Carrier Interactions and Process Greenness

Insights into antibiotic-carrier interactions in the silk-fibroin-based nanoparticles and considerations on the formulation process greenness are limited. Hence, this work developed and characterized polyethylene glycol-functionalized silk fibroin nanoparticles for oral delivery of cefotaxime (PEG/SFPs-CTX), with a focus on the <i>in silico</i> simulations and process greenness. The particles were formulated by the two methods of co-condensation and adsorption. Dependent on the processes, the particles possessed spherical shape, smooth/rough surfaces, nanosize (170-650 nm), negative charge (-23 to -30 mV), and drug entrapment efficiency of ∼50%. The system rapidly absorbed the drug within 30 min, followed second-order kinetics, and significantly controlled the drug release rate in the simulated gastrointestinal system, which could bypass the stomach acidic pH. Interestingly, <i>in silico</i> docking revealed that CTX mostly bound strongly and noncovalently with fibroin, particularly at glutamic acid, via hydrogen bonds, van der Waals forces, and π-π interactions, while PEG enhanced the stability of the system. Molecular dynamics simulations confirmed the complex's stability under physiological conditions. Lastly, life cycle assessment analysis showed that both formulation methods were environmental friendly, with limited impacts on the ecosystem, and the adsorption method was "greener" than the co-condensation method.