Temporal SERS quantification and the chemometric monitoring of amikacin release in blood serum from a stimuli-responsive drug carrier: kinetics modeling and in-vitro pharmacodynamic evaluation

Abstract

The controlled delivery of antibiotics from stimuli-responsive hydrogels is a promising approach, although controlled release kinetics and pharmacodynamic (PD) outcomes are very challenging to measure accurately. In this research, surface-enhanced Raman spectroscopy (SERS) is used for the quantification of the in-vitro release of amikacin (AMK) in blood serum from a PVA/AgO hydrogel drug carrier. The silver nanoparticles (AgNPs) are prepared by the chemical reduction method for an active SERS substrate. AMK loaded onto the stimuli-responsive PVA/AgO hydrogel is released in blood serum, and a 32-hour release kinetics study and in-vitro pharmacodynamics study are carried out in intervals of 4 hours (4, 8, 12, 16, 20, 24, 28 and 32 hours). The chemometric tools as principal component analysis (PCA) is used for the qualitative study of intensity-based variability and partial least squares regression (PLSR) is used for the quantification of AMK release kinetics. The release kinetics is additionally validated by UV-Vis spectroscopy by comparing the spectra of AMK released in blood serum and a phosphate buffer solution of pH 7.4 at 37 °C. The in-vitro release kinetics is determined using four kinetic models: zero-order, first-order, Higuchi, and Korsmeyer–Peppas models. Mathematical fittings reveal that the release is dominated by Higuchi (R² = 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. The pharmacodynamic potential of the released AMK is evaluated systematically by antibacterial activity analysis, minimum inhibitory concentration (MIC) analysis, minimum bactericidal concentration (MBC) analysis and biofilm assay against Proteus mirabilis and Enterococcus faecalis. Cytotoxicity against human liver cancer cell line (HepG2), hemolytic analysis, time–kill kinetics and in-vitro PK/PD indices are also evaluated to validate the release kinetics of AMK in blood serum.