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

In this study, ascorbyl tocopherol succinate (ATS) was designed, synthesized and characterized via FT-IR, HR-MS, H-1 NMR and C-13 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 silicoaided 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 (Delta G(bind)) and bacterial efflux pumps blocking potential (NorA Delta G(bind): -37.10 kcal/mol, NorB Delta G(bind): -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 VMATS-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.

Automated summary

In this study, a novel antibiotic nanosystem ATS was designed to enhance antibacterial efficacy and combat antimicrobial resistance. Experimental results demonstrated that ATS could serve as a potential multifunctional adjuvant for effective and targeted delivery of antibiotics.