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Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P.?aeruginosa Biofilm Infections |
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| Authors: | Dr Duy-Khiet Ho Dr Xabier Murgia Dr Chiara De Rossi Rebekka Christmann Dr Antonio G Hüfner de Mello Martins Dr Marcus Koch Anastasia Andreas Dr Jennifer Herrmann Prof?Dr Rolf Müller Dr Martin Empting Prof?Dr Rolf W Hartmann Dr Didier Desmaele Dr Brigitta Loretz Prof?Dr Patrick Couvreur Prof?Dr Claus-Michael Lehr |
| Institution: | 1. Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, 66123 Saarbrücken, Germany;2. Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, 66123 Saarbrücken, Germany
Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany Current address: Kusudama Therapeutics, Parque Científico y Tecnológico de Gipuzkoa, 20014 Donostia-San Sebastián, Spain;3. Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, 66123 Saarbrücken, Germany Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany;4. INM—Leibniz Institute for New Materials, 66123 Saarbrücken, Germany;5. Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, 66123 Saarbrücken, Germany German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 66123 Saarbrücken, Germany;6. Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, 66123 Saarbrücken, Germany German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 66123 Saarbrücken, Germany Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany;7. Faculté de Pharmacie, Institut Galien Paris Sud, Université Paris-Saclay, UMR CNRS 8612, 92296 Châtenay-Malabry, France |
| Abstract: | Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self-assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug-loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16-fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use. |
| Keywords: | biofilms drug delivery Pseudomonas aeruginosa quorum sensing inhibitors tobramycin |