Intracellular Delivery and Antibacterial Activity of Gentamicin Encapsulated in pH-Sensitive Liposomes
Open accessAbstract
Cell membranes are relatively impermeable to the antibiotic gentamicin, a factor that, along with the toxicity of gentamicin, precludes its use against many important intracellular bacterial infections. Liposomal encapsulation of this drug was used in order to achieve intracellular antibiotic delivery and therefore increase the drug’s therapeutic activity against intracellular pathogens. Gentamicin encapsulation in several dipalmitoylphosphatidylcholine (DPPC) and pH-sensitive dioleoylphosphatidylethanolamine (DOPE)-based carrier systems was characterized. To systematically test the antibacterial efficacies of these formulations, a tissue culture assay system was developed wherein murine macrophage-like J774A.1 cells were infected with bacteria and were then treated with encapsulated drug. Of these formulations, DOPE– N -succinyl-DOPE and DOPE– N -glutaryl-DOPE (70:30;mol:mol) containing small amounts of polyethyleneglycol-ceramide showed appreciable antibacterial activities, killing greater than 75% of intracellular vacuole-resident wild-type Salmonella typhimurium compared to the level of killing of the control formulations. These formulations also efficiently eliminated intracellular infections caused by a recombinant hemolysin-expressing S. typhimurium strain and a Listeria monocytogenes strain, both of which escape the vacuole and reside in the cytoplasm. Control non-pH-sensitive liposomal formulations of gentamicin had poor antibacterial activities. A fluorescence resonance energy transfer assay indicated that the efficacious formulations undergo a pH-dependent lipid mixing and fusion event. Intracellular delivery of the fluorescent molecules encapsulated in these formulations was confirmed by confocal fluorescence microscopy and was shown to be dependent on endosomal acidification. This work shows that encapsulation of membrane-impermeative antibiotics in appropriately designed lipid-based delivery systems can enable their use in treating intracellular infections and details the development of a general assay for testing the intracellular delivery of encapsulated drug formulations.
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In an in vitro model of recombinant S. typhirium infection, gentamicin-loaded pH-sensitive liposomes showed threefold higher activity than the free drug.
“In an in vitro model of recombinant S. typhirium infection, gentamicin-loaded pH-sensitive liposomes showed threefold higher activity than the free drug.”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [65]
Confocal microscopy showed that only pH-sensitive liposomes released the marker intracellularly in murine macrophages.
“Confocal microscopy showed that only pH-sensitive liposomes released the marker intracellularly in murine macrophages.”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [65]
Despite higher cell uptake of pH-insensitive liposomes, they showed inferior activity to the pH-sensitive formulation.
“Despite higher cell uptake of pH-insensitive liposomes, they showed inferior activity to the pH-sensitive formulation.”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [65]
Marker release was abrogated by bafilomycin, an inhibitor of endosome acidification.
“Marker release was abrogated by bafilomycin, an inhibitor of endosome acidification.”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [65]
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References 52 · Cited by 121
Research works printed but not linked: 1
- [23]23. Hope, M. J., R. Nayar, L. D. Mayer, and P. R. Cullis. 1992. Reduction of liposome size and preparation of unilamellar vesicles by extrusion, p. 123139. In G. Gregoriadis (ed.), Liposome technology, vol. 1, 2nd ed. CRC Press, Inc., Boca Raton, Fla.
- Authors
- Lutwyche, P., Cordeiro, C., Wiseman, D. J., St-Louis, M., Uh, M., Hope, M. J., Webb, M. S., & Finlay, B. B.
- Affiliations
- Inimex Pharmaceuticals (Canada) (CA)
- University of British Columbia (CA)
- <!--label omitted: 2-->Biotechnology Laboratory and Departments of Biochemistry & Molecular Biology and Microbiology & Immunology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z32
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1998-10
- Volume
- 42
- Issue
- 10
- Pages
- 2511-2520
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC105873
- OpenAlex
- W2156373483
- Cited by
- 121
- References
- 52
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 9 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 8 · 2014: 10 · 2013: 5 · 2012: 4
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- gentamicin, pH-sensitive liposomes, intracellular drug delivery, intracellular bacterial infection, Salmonella typhimurium, Listeria monocytogenes, macrophages, J774A.1 cells, endosomal acidification, DPPC, liposome encapsulation, antibacterial activity
- MeSH terms
- Animals, Anti-Bacterial Agents, Bacteria, Cell Line, Drug Carriers, Gentamicins, Hydrogen-Ion Concentration, Liposomes, Macrophages, Mice
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