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-BA12K) 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-BA12K 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-BAP85). RVG29-Nano-BAP85 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-BAP85 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-BAP85 was able to accumulate in brain parenchyma as confirmed by in vivo optical imaging. In addition, RVG29-Nano-BAP85 exhibited high therapeutic efficiencies in both Penicillin-sensitive and -resistant PM mouse models with negligible systemic toxicity. Collectively, RVG29-Nano-BAP85 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.

Antimicrobial peptide-based materials: opportunities and challenges

“…These micelles accumulated in the brain parenchyma and exhibited high therapeutic efficacy in killing Staphylococcus pneumoniae ( S. pneumoniae ) in pneumococcal meningitis mouse model. 158 The enhanced BBB permeability of the micelle was attributed to receptor-mediated endocytosis, reduction in membrane micro-viscosity and exhaustion of ATP. Bacterial infection after CNS surgery is associated with health-related complications and considerable morbidity.…”

Progress in the Application of Nanoparticles and Graphene as Drug Carriers and on the Diagnosis of Brain Infections

“…Optical imaging showed that micelles accumulated in the parenchymal cells of the brain via receptor-mediated transcytosis. The results from the animal studies were promising in the treatment of pneumococcal meningitis [ 57 ]. In another study, nanoscaled micelles were developed to penetrate the endothelial cells of BBB.…”

“…The latest nanotechnology advances have created an unparalleled potential to enhance the diagnosis and early identification of meningitis and other brain diseases [ 8 , 74 , 75 ]. NPs are widely accepted as promising materials for diagnosis of meningitis brain infections because of intrinsically useful features such as elevated surface-to-volume ratio, simplicity of surface modification with preferred ligands, and capacity to cross biological barriers (such as the BBB) [ 57 , 76 ]. Some main nanoparticles for early diagnosis of brain infections and meningitis (Au NPs, Graphene, CNTs, QDs, etc.)…”

Nanovehicles in the improved treatment of infections due to brain-eating amoebae

“…Nanomicelles possess chemical, physical, structural, and biological properties that makes them appropriate carriers for drug delivery across the BBB (Barani et al 2021). Nanomicelles of bacitracin-A was engineered for the treatment of pneumococcal meningitis by adding a brain-targeting peptide and p-glycoprotein inhibitor to the system to produce a mixed micellar system (Hong et al 2018). The system exhibited high BBB permeation and improved uptake in brain capillary endothelial cells, and accumulation of micelles in parenchymal cells of the brain was reported (Hong et al 2018).…”

“…Nanomicelles of bacitracin-A was engineered for the treatment of pneumococcal meningitis by adding a brain-targeting peptide and p-glycoprotein inhibitor to the system to produce a mixed micellar system (Hong et al 2018). The system exhibited high BBB permeation and improved uptake in brain capillary endothelial cells, and accumulation of micelles in parenchymal cells of the brain was reported (Hong et al 2018). In another study, nanomicelles designed with dehydroascorbic acid, a compound that has a high affinity with GLUT1 (provides single direction transport of dehydroascorbic acid from blood to brain) on BBB, were developed to transport itraconazole into endothelial cells of BBB (Shao et al 2015).…”