Temporal SERS Quantification, Chemometric Monitoring of Amikacin Release in Blood Serum from Stimuli-Responsive Drug Carrier: Kinetics Modeling and In-Vitro Pharmacodynamic Evaluation

Abstract

The controlled delivery of antibiotics from stimuli-responsive hydrogel is a promising approach, although controlled release kinetics and pharmacodynamic (PD) outcomes are very challenging to measure accurately. In this research work, surface-enhanced Raman spectroscopy (SERS) is used for the quantification of the Amikacin (AMK) in-vitro release in blood Serum from PVA/AgO hydrogel drug carrier. The silver nanoparticles (AgNPs) are prepared by the chemical reduction method for active SERS substrate. The AMK loaded on the stimuli responsive PVA/AgO hydrogel is released in blood serum and 32 hours release kinetics and in-vitro pharmacodynamics study is carried by the intervals of 4 hours as (0h, 4h, 8h, 12h, 16h, 20h, 24h, 28h and 32h). The chemometric tools, Principal Component Analysis (PCA) is used for the qualitative analysis to study the intensity-based variability while Partial Least Squares Regression (PLSR) is used for the quantification of AMK release kinetics. The release kinetics is additionally validated by UV-Vis spectroscopy quantification compared with AMK released in phosphate buffer solution of pH 7.4 at 37 o C. The in-vitro release kinetics is determined using four kinetic models that included Zero-order, First-order, Higuchi, and Korsmeyer-Peppas. It is shown by mathematical fitting that the release is dominated by Higuchi (R 2 = 0.943 in serum, 0.906 in PBS) and Korsmeyer Peppas models (n = 0.45 which is Fickian diffusion), indicating that the release is diffusion-controlled. Pharmacodynamic potential of released AMK is evaluated systematically by antibacterial activity, Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and biofilm assay against Proteus mirabilis and Enterococcus faecalis. The Cytotoxicity against human liver cancer cell line (HepG2), hemolytic analysis, Time-kill kinetics and in-vitro PK/PD indices are also performed to validate the release kinetics in blood serum.