Clofazimine functionalized polymeric nanoparticles for brain delivery in the tuberculosis treatment

• Published in: International journal of pharmaceutics 2021-06, Vol.602, p.120655, Article 120655
• Main Authors: de Castro, Renata Ribeiro, do Carmo, Flavia Almada, Martins, Cláudia, Simon, Alice, de Sousa, Valeria Pereira, Rodrigues, Carlos Rangel, Cabral, Lucio Mendes, Sarmento, Bruno
• Format: Article
• Language: English
• Subjects: Brain delivery; Clofazimine; Targeted nanoparticles; Transferrin-receptor; Tuberculosis treatment
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2021.120655

[Display omitted] •Clofazimine-loaded PLGA-PEG nanoparticles (NP-CFZ) were produced by nanoprecipitation.•NP-CFZ were functionalized with a peptide (NP-CFZ-Pep) that binds transferrin receptor.•NP-CFZ-Pep reduced drug toxicity and enhanced drug permeability across hCMEC/D3 cell.•NP-CFZ-Pep can be administered by intravenous route and drive the drug to the brain.•The NP-CFZ-Pep is promising to central nervous system tuberculosis treatment. Central nervous system tuberculosis (CNS-TB) is the most severe form of the disease especially due to the inability of therapeutics to cross the blood–brain barrier (BBB). Clofazimine (CFZ) stands out for presenting high in vitro activity against multi-drug resistant strains of Mycobacterium tuberculosis, however, CFZ physicochemical and pharmacokinetics properties limit drug penetration into the CNS and, consequently, its clinical use. The aim of this work was to develop polymeric nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) loaded with CFZ and functionalized with a transferrin receptor (TfR)-binding peptide, aiming brain drug delivery for CNS-TB treatment by the intravenous route. The poor water solubility and high lipophilicity of CFZ was overcome through its entrapment into PLGA-PEG NPs manufactured by both conventional and microfluidic techniques using the nanoprecipitation principle. In vitro studies in brain endothelial hCMEC/D3 cells demonstrated that CFZ incorporation into the NPs was advantageous to reduce drug cytotoxicity. The TfR-binding peptide-functionalized NPs showed superior cell interaction and higher CFZ permeability across hCMEC/D3 cell monolayers compared to the non-functionalized NP control, thus indicating the efficacy of the functionalization strategy on providing CFZ transport through the BBB in vitro. The functionalized NPs demonstrate suitability for CFZ biological administration, suggested with low plasma protein binding, off-target biodistribution and precise delivery of CFZ towards the brain parenchyma.