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Tat-functionalized liposomes for the treatment of meningitis: an in vitro study

Authors Bartomeu Garcia C, Shi D, Webster TJ

Received 13 December 2016

Accepted for publication 20 February 2017

Published 12 April 2017 Volume 2017:12 Pages 3009—3021

DOI https://doi.org/10.2147/IJN.S130125

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Thiruganesh Ramasamy

Peer reviewer comments 3

Editor who approved publication: Professor Carlos Rinaldi

Caterina Bartomeu Garcia,1,* Di Shi,2,* Thomas J Webster2

1Department of Chemical Engineering, Universitat Rovira i Virgili, Tarragona, Spain; 2Department of Chemical Engineering, Northeastern University, Boston, MA, USA

*These authors contributed equally to this work

Abstract: Bacterial meningitis has become a global concern, because of the emergence of antibiotic-resistant bacteria. It has been demonstrated that liposomes can enter bacteria, thus providing a possible treatment for numerous infections, including meningitis. Fusogenic liposomes are pH-sensitive with a high capacity to fuse with the bacteria membrane and promote intracellular drug release. Moreover, this ability can be improved by using cell-penetrating peptides (such as Tat47–57, which is a peptide derived from the Tat protein of HIV). The purpose of this in vitro study was to demonstrate for the first time the ability of the presently prepared fusogenic liposomes, which were spherical particles with a diameter of 100 nm loaded with antibiotics and functionalized with-cell penetrating peptides (Tat47–57), to fight the main bacteria that cause meningitis. For this, vancomycin, methicillin, and ampicillin antibiotics were loaded inside fusogenic liposomes to fight Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Antibacterial activity of Tat-functionalized and nonfunctionalized liposomes loaded with antibiotics was tested by determining bacteria colony-forming units and growth-curve assays coupled with live/dead assays using fluorescence microscopy. Results showed a remarkable decrease in antibiotic minimum inhibitory concentration when all of the bacteria were treated with these novel liposomes, especially for the functionalized liposomes loaded with methicillin. With antibiotic concentrations of 1.7–3 µg/mL for Tat-functionalized liposomes loaded with methicillin, the bacteria population was totally eradicated. Cytotoxicity tests with astrocytes and endothelial cells, major cellular components of the blood–brain barrier, were also performed for all of the liposomes, including free antibiotic and the Tat peptide. Results showed much promise for the further study of the presently formulated liposomes to treat meningitis.

Keywords:
fusogenic liposomes, cell-penetrating peptides, minimum inhibitory concentration, MIC, bacteria colony-forming units, fluorescence microscopy, cytotoxicity

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