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Development and in vitro characterization of poly(lactide-co-glycolide) microspheres loaded with an antibacterial natural drug for the treatment of long-term bacterial infections

Authors Reinbold J, Hierlemann T, Hinkel H, Müller I, Maier M, Weindl T, Schlensak C, Wendel H, Krajewski S

Received 29 January 2016

Accepted for publication 17 May 2016

Published 7 September 2016 Volume 2016:10 Pages 2823—2832

DOI https://doi.org/10.2147/DDDT.S105367

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Wei Duan


Jochen Reinbold,1 Teresa Hierlemann,1 Helena Hinkel,1 Ingrid Müller,2 Martin E Maier,3 Tobias Weindl,4 Christian Schlensak,1 Hans Peter Wendel,1 Stefanie Krajewski1

1Department of Thoracic, Cardiac and Vascular Surgery, University Hospital Tuebingen, Tuebingen, 2Department of Pharmaceutical Engineering, Albstadt-Sigmaringen University, Sigmaringen, 3Institute of Organic Chemistry, University Tuebingen, Tuebingen, 4Aimecs GmbH, Pfarrkirchen, Germany

Abstract: Biodegradable polymers, especially poly(lactide-co-glycolide) (PLGA), have good biocompatibility and toxicological properties. In combination with active ingredients, a specialized drug delivery system can be generated. The aim of the present study was to develop a drug delivery system consisting of PLGA microspheres loaded with the natural active ingredient totarol, which has several antimicrobial mechanisms. Totarol, isolated from the Podocarpus totara tree, was purified using column chromatography, and the eluate was checked for purity using thin layer chromatography. The spherically shaped microspheres with mean diameters of 147.21±3.45 µm and 131.14±3.69 µm (totarol-loaded and -unloaded microspheres, respectively) were created using the single emulsion evaporation method. Furthermore, the encapsulation efficiency, in a range of 84.72%±6.68% to 92.36%±0.99%, was measured via UV/vis spectroscopy. In a 90-day in vitro drug release study, the release of totarol was investigated by UV/vis spectroscopy as well, showing a release of 53.76%. The toxicity on cells was determined using BJ fibroblasts or Human Embryonic Kidney cells and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, which showed no influence on the cell growth. The minimal inhibitory concentration was ascertained. A totarol concentration between 64 µg/mL and 128 µg/mL was necessary to inhibit the bacterial growth over a period of 24 hours. Biofilm formation on the surface of totarol-loaded microspheres was determined using transmission electron microscopy. No biofilm formation could be detected, even if the totarol concentration was below the minimal inhibitory concentration. The hemocompatibility investigations on various markers with fresh heparinized blood (1.5 IU/mL) showed that totarol and totarol-loaded microspheres have no influence on different blood parameters. The PLGA microspheres characterized by slow release of totarol and great entrapment efficiency represent a novel drug delivery system, which may be highly beneficial for the long-term therapy of bacterial infections.

Keywords: totarol, drug delivery system, Staphylococcus aureus, antibacterial, cytotoxicity

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