Brain-targeted delivery of PEGylated nano-bacitracin A against Penicillin-sensitive and -resistant Pneumococcal meningitis: formulated with RVG(29) and Pluronic(®) P85 unimers

Pneumococcal meningitis (PM), caused by Streptococcus pneumonia, remains a high-burden disease in developing countries. Antibiotic therapy has been limited due to the inefficiency of drug transport across the blood-brain barrier (BBB) and the emergence of drug-resistant strains. In our preliminary study, PEGylated nano-self-assemblies of bacitracin A (PEGylated Nano-BA(12K)) demonstrated a strong antibacterial potency against S. pneumonia. In this study, the potential application of this micelle for the treatment of both Penicillin-sensitive and -resistant PM was studied. To address BBB-targeting and -crossing issues, PEGylated Nano-BA(12K) was formulated with a specific brain-targeting peptide (rabies virus glycopeptide-29, RVG(29)) and a P-glycoprotein inhibitor (Pluronic(®) P85 unimers) to construct a mixed micellar system (RVG(29)-Nano-BA(P85)). RVG(29)-Nano-BA(P85) demonstrated a strong antibacterial potency against 13 clinical isolates of S. pneumonia, even higher than that of Penicillin G, a conventional anti-PM agent. RVG(29)-Nano-BA(P85) had more cellular uptake in brain capillary endothelial cells (BCECs) and higher BBB-crossing efficiency than single formulated Nano-BAs as shown in an in vitro BBB model. The enhanced BBB-permeability was attributed to the synergetic effect of RVG(29) and P85 unimers through receptor-mediated transcytosis, exhaustion of ATP, and reduction in membrane microviscosity. In vivo results further demonstrated that RVG(29)-Nano-BA(P85) was able to accumulate in brain parenchyma as confirmed by in vivo optical imaging. In addition, RVG(29)-Nano-BA(P85) exhibited high therapeutic efficiencies in both Penicillin-sensitive and -resistant PM mouse models with negligible systemic toxicity. Collectively, RVG(29)-Nano-BA(P85) could effectively overcome BBB barriers and suppressed the growth of both drug-sensitive and -resistant S. pneumonia in the brain tissues, which demonstrated its potential for the treatment of PM.