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Technetium-99m labeled DNL-PE effectively crossed blood–brain barrier and showed a time dependant accumulation in rat brain.

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pH-responsive drug delivery systems are yielding opportunities to directly deliver antibiotics to the site of infection. Therefore, this study aimed to develop and evaluate novel pH-responsive lipid−dendrimer hybrid nanoparticles (LDH-NPs) for the delivery of vancomycin (VCM) to the site of infection, by intracellular bacterial pathogens. The LDH-NPs were formulated using the emulsification solvent evaporation method and were characterized by various in vitro and molecular dynamic (MD) simulation techniques. LDH-NPs were 124.4 ± 2.01 nm in size, with a zeta-potential of −7.15 ± 2.98 mV and drug entrapment efficiency of 82.70 ± 4.09%, which exhibited pH-responsive behavior by shifting the surface charge from negative at physiological pH to positive in acidic pHs, with a size increase from 124.4 ± 2.01 to 173.9 ± 13.38 nm, and 252.7 ± 3.98 nm at pHs of 7.4, 6.0, and 4.5, respectively. Results indicated that the in vitro drug release of VCM from LDH-NPs occurred faster at pH 6.0 than at pH 7.4. The antibacterial activity of LDH-NPs against methicillin-resistance Staphylococcus aureus (MRSA) showed 8-fold lower MICs at pH 6.0 and 7.4, compared to treatment with VCM only. A bacterial cell viability study showed LDH-NPs had an 84.19% killing of MRSA, compared to VCM (49.26%) at the same MIC, further confirming its efficacy. Cell uptake studies showed that LDH-NPs intracellularly accumulated in HEK 293 cells, confirming significant clearance (p < 0.0001) of intracellular bacteria. MD simulation showed that interaction between the dendrimer and oleylamine was predominantly governed by van der Waals (VdW) interactions; whereas the interaction between the dendrimer and VCM was governed by both VdW and electrostatic interactions. Therefore, this study concludes that the pH-responsive release of VCM enhanced antibacterial efficacy against MRSA and intracellular delivery of an antibiotic. Thus, LDH-NPs is a promising nanocarrier system for antibiotics with the potential to improve the treatment outcomes of bacterial infections in patients with antibiotic resistant strains.