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Lung Tissue Delivery of Virus-Like Particles Mediated by Macrolide Antibiotics
Stephen N Crooke1, Jiri Schimer1,2, Idris Raji1
1School of Chemistry and Biochemistry , ∥School of Biological Sciences , and §Parker H. Petit Institute for Bioengineering and Bioscience , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.
Abstract:
Macrophage cells are present in high abundance in the lung to intercept invading microorganisms that gain access through airway mucosal surfaces. Several bacterial pathogens have evolved the capacity to evade the innate immune response by establishing infections within pulmonary macrophages upon phagocytosis, leading to prolonged disease. Macrolide antibiotics such as azithromycin and clarithromycin accumulate in phagocytic cells and have been shown to preferentially distribute in tissues where populations of these cells reside. We employed this class of molecules as targeting ligands to direct virus-like particles (VLPs) to lung-resident macrophages. VLP-macrolide conjugates showed enhanced uptake into RAW 264.7 macrophage cells in culture, with azithromycin displaying the greatest effect; distinct differences were also observed for different macrocycle structures and orientations on the particle surface. Activation of macrophage cells was stimulated by particle uptake toward an intermediate activation state, in contrast to previous reports using macrolide-functionalized gold nanorods that stimulated a cytotoxic macrophage response. Attached azithromycin was also able to direct VLPs to the lungs in mice, with significant accumulation within 2 h of systemic injection. These results suggest that this new class of bioconjugate could serve as an effective platform for intracellular drug delivery in the context of pulmonary infections.
Insights
This study developed macrolide-antibiotic-linked virus-like particles (VLPs) for targeted drug delivery to lung macrophages. Azithromycin-conjugated VLPs showed enhanced uptake and lung accumulation, offering a promising platform for pulmonary infection treatments.
Area of Science:
- Immunology
- Nanotechnology
- Pharmacology
Background:
- Pulmonary macrophages are crucial for lung immunity but can harbor bacterial pathogens.
- Bacterial infections within macrophages lead to persistent lung diseases.
- Macrolide antibiotics accumulate in phagocytic cells, targeting lung tissues.
Purpose of the Study:
- To develop virus-like particles (VLPs) targeted to lung macrophages using macrolide antibiotics as ligands.
- To evaluate the efficacy of macrolide-VLP conjugates for intracellular drug delivery in pulmonary infections.
Main Methods:
- Conjugation of macrolide antibiotics (azithromycin, clarithromycin) to virus-like particles (VLPs).
- Assessing VLP-macrolide conjugate uptake in RAW 264.7 macrophage cell cultures.
- Evaluating VLP biodistribution in mouse lungs following systemic injection.
Main Results:
- VLP-macrolide conjugates demonstrated enhanced uptake in macrophage cells, with azithromycin showing the most significant effect.
- Particle uptake induced an intermediate macrophage activation state, avoiding cytotoxicity.
- In vivo studies showed significant VLP accumulation in mouse lungs within 2 hours of injection.
Conclusions:
- Macrolide-functionalized VLPs represent a novel platform for targeted intracellular drug delivery to lung macrophages.
- This approach shows potential for treating pulmonary infections by enhancing drug accumulation in infected tissues.
- Azithromycin-conjugated VLPs are particularly effective for targeting lung-resident macrophages.
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