Vancomycin-decorated microbubbles as a theranostic agent for Staphylococcus aureus biofilms

Joop J.P. Kouijzer*, Kirby R. Lattwein, Inés Beekers, Simone A.G. Langeveld, Mariël Leon-Grooters, Jean Marc Strub, Estefania Oliva, Gaëtan L.A. Mislin, Nico de Jong, Antonius F.W. van der Steen, Alexander L. Klibanov, Willem J.B. van Wamel, Klazina Kooiman

*Corresponding author for this work

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Abstract

Bacterial biofilms are a huge burden on our healthcare systems worldwide. The lack of specificity in diagnostic and treatment possibilities result in difficult-to-treat and persistent infections. The aim of this in vitro study was to investigate if microbubbles targeted specifically to bacteria in biofilms could be used both for diagnosis as well for sonobactericide treatment and demonstrate their theranostic potential for biofilm infection management. The antibiotic vancomycin was chemically coupled to the lipid shell of microbubbles and validated using mass spectrometry and high-axial resolution 4Pi confocal microscopy. Theranostic proof-of-principle was investigated by demonstrating the specific binding of vancomycin-decorated microbubbles (vMB) to statically and flow grown Staphylococcus aureus (S. aureus) biofilms under increasing shear stress flow conditions (0–12 dyn/cm2), as well as confirmation of microbubble oscillation and biofilm disruption upon ultrasound exposure (2 MHz, 250 kPa, and 5,000 or 10,000 cycles) during flow shear stress of 5 dyn/cm2 using time-lapse confocal microscopy combined with the Brandaris 128 ultra-high-speed camera. Vancomycin was successfully incorporated into the microbubble lipid shell. vMB bound significantly more often than control microbubbles to biofilms, also in the presence of free vancomycin (up to 1000 µg/mL) and remained bound under increasing shear stress flow conditions (up to 12 dyn/cm2). Upon ultrasound insonification biofilm area was reduced of up to 28%, as confirmed by confocal microscopy. Our results confirm the successful production of vMB and support their potential as a new theranostic tool for S. aureus biofilm infections by allowing for specific bacterial detection and biofilm disruption.

Original languageEnglish
Article number121154
JournalInternational Journal of Pharmaceutics
Volume609
DOIs
Publication statusPublished - 6 Oct 2021

Bibliographical note

Funding Information:
This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [grant agreement 805308)]. Ga?tan Mislin acknowledges the Interdisciplinary Thematic Institute (ITI) InnoVec (Innovative Vectorization of Biomolecules, IdEx, ANR-10-IDEX-0002) and SFRI (ANR-20-SFRI-0012). The authors would like to thank Robert Beurskens, Frits Mastik and Reza Pakdaman Zangabad from the Department of Biomedical Engineering, Michiel Manten from the Department of Experimental Medical Instrumentation, Andi R. Sultan from the Department of Medical Microbiology and Infectious Diseases and Ruud Huisman from the Department of Hospital Pharmacy, all from the Erasmus University Medical Center Rotterdam, for their skillful technical assistance. The authors thank the Optical Imaging Centre of Erasmus MC for the use of their facilities and Gert van Cappellen and Alex Nigg for their help. The authors also thank the members of the Therapeutic Ultrasound Contrast Agent group (Biomedical Engineering Dept.) and the S. aureus working group (Medical Microbiology and Infectious Diseases Dept.) from Erasmus University Medical Center Rotterdam for their useful discussions.

Funding Information:
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program [grant agreement 805308)]. Gaëtan Mislin acknowledges the Interdisciplinary Thematic Institute (ITI) InnoVec (Innovative Vectorization of Biomolecules, IdEx, ANR-10-IDEX-0002) and SFRI (ANR-20-SFRI-0012). The authors would like to thank Robert Beurskens, Frits Mastik and Reza Pakdaman Zangabad from the Department of Biomedical Engineering, Michiel Manten from the Department of Experimental Medical Instrumentation, Andi R. Sultan from the Department of Medical Microbiology and Infectious Diseases and Ruud Huisman from the Department of Hospital Pharmacy, all from the Erasmus University Medical Center Rotterdam, for their skillful technical assistance. The authors thank the Optical Imaging Centre of Erasmus MC for the use of their facilities and Gert van Cappellen and Alex Nigg for their help. The authors also thank the members of the Therapeutic Ultrasound Contrast Agent group (Biomedical Engineering Dept.) and the S. aureus working group (Medical Microbiology and Infectious Diseases Dept.) from Erasmus University Medical Center Rotterdam for their useful discussions.

Publisher Copyright:
© 2021 The Author(s)

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