Blood Compatibility of Drug–Inorganic Hybrid in Human Blood: Red Blood Cell Hitchhiking and Soft Protein Corona

A drug-delivery system consisting of an inorganic host—layered double hydroxide (LDH)—and an anticancer drug—methotrexate (MTX)—was prepared via the intercalation route (MTX-LDH), and its hematocompatibility was investigated. Hemolysis, a red blood cell counting assay, and optical microscopy revealed that the MTX-LDH had no harmful toxic effect on blood cells. Both scanning electron microscopy and atomic force microscopy exhibited that the MTX-LDH particles softly landed on the concave part inred blood cells without serious morphological changes of the cells. The time-dependent change in the surface charge and hydrodynamic radius of MTX-LDH in the plasma condition demonstrated that the proteins can be gently adsorbed on the MTX-LDH particles, possibly through protein corona, giving rise to good colloidal stability. The fluorescence quenching assay was carried out to monitor the interaction between MTX-LDH and plasma protein, and the result showed that the MTX-LDH had less dynamic interaction with protein compared with MTX alone, due to the capsule moiety of the LDH host. It was verified by a quartz crystal microbalance assay that the surface interaction between MTX-LDH and protein was reversible and reproducible, and the type of protein corona was a soft one, having flexibility toward the biological environment.