Biomimetic pH/lipase dual responsive vitamin-based solid lipid nanoparticles for on-demand delivery of vancomycin.

Abstract In this study, ascorbyl tocopherol succinate (ATS) was designed, synthesized and characterized via FT-IR, HR-MS, H1 NMR and C13 NMR, to simultaneously confer biomimetic and dual responsive properties of an antibiotic nanosystem to enhance their antibacterial efficacy and reduce antimicrobial resistance. Therefore, an in silico-aided design (to mimic the natural substrate of bacterial lipase) was employed to demonstrate the binding potential of ATS to lipase (−32.93 kcal/mol binding free energy (ΔGbind) and bacterial efflux pumps blocking potential (NorA ΔGbind: −37.10 kcal/mol, NorB ΔGbind: −34.46 kcal/mol). ATS bound stronger to lipase than the natural substrate (35 times lower Kd value). The vancomycin loaded solid lipid nanoparticles (VM-ATS-SLN) had a hydrodynamic diameter, zeta potential, polydispersity index and entrapment efficiency of 106.9 ± 1.4 nm, −16.5 ± 0.93 mV, 0.11 ± 0.012 and 61.9 ± 1.31%, respectively. In vitro biocompatibility studies revealed VM-ATS-SLN biosafety and non-haemolytic activity. Significant enhancement in VM release was achieved in response to acidified pH and lipase enzyme, compared to controls. VM-ATS-SLN showed enhanced sustained in vitro antibacterial activity for 5 days, 2-fold greater MRSA biofilm growth inhibition and 3.44-fold reduction in bacterial burden in skin infected mice model compared to bare VM. Therefore, ATS shows potential as a novel multifunctional adjuvant for effective and targeted delivery of antibiotics.