Brain-targeted delivery of PEGylated nano-bacitracin A against Penicillin-sensitive and -resistant Pneumococcal meningitis: formulated with RVG₂₉ and Pluronic^® P85 unimers

Abstract

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, RVG₂₉) and a P-glycoprotein inhibitor (Pluronic^® P85 unimers) to construct a mixed micellar system (RVG₂₉-Nano-BA_P85). RVG₂₉-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. RVG₂₉-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 RVG₂₉ and P85 unimers through receptor-mediated transcytosis, exhaustion of ATP, and reduction in membrane microviscosity. In vivo results further demonstrated that RVG₂₉-Nano-BA_P85 was able to accumulate in brain parenchyma as confirmed by in vivo optical imaging. In addition, RVG₂₉-Nano-BA_P85 exhibited high therapeutic efficiencies in both Penicillin-sensitive and -resistant PM mouse models with negligible systemic toxicity. Collectively, RVG₂₉-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.

Keywords:

• Pneumococcal meningitis
• blood-brain barrier
• rabies virus glycoprotein
• Pluronic^® P85 unimers
• RVG₂₉-Nano-BA_P85

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This article has been republished with minor changes. These changes do not impact the academic content of the article.

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No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors are grateful for the financial support by the National Key Research and Development Program of China (Grant No. 2016YFD0501309), the National Science Foundation for Young Scientists of China (Grant No. 31602108), the PhD Start-up Fund of Natural Science Foundation of Liaoning Province (Grant No. 201601101), and the Key Laboratory of Zoonosis of Liaoning Province.