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Anti-angiogenesis by dual action of R5K peptide conjugated itraconazole nanoparticles

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Neovascular age-related macular degeneration (AMD) is a leading cause of central vision loss and irreversible blindness. Vascular endothelial growth factor (VEGF) plays an important role in neovascularization under the retina and macula by promoting endothelial cell proliferation, migration, and angiogenesis. Although anti-VEGF drugs have shown their efficacy in visual improvement, long-term use of these drugs leads to ocular and systemic complications due to the non-selectivity of the drug. In this study, the dual-mode anti-angiogenic drug delivery system, which potentially inhibited VEGF in two different ways, was developed. The itraconazole encapsulated nanoparticles, conjugated with R5K peptide, were fabricated to allow multivalent binding interactions with VEGF. The R5K peptide blocked VEGF binding to its receptor, while itraconazole altered the signaling pathway of VEGF stimulation. The dual action of this novel drug delivery system aimed to enhance the anti-angiogenic effects of individual drugs. R5K-ITZ-NPs demonstrated potent, cell-type specific, and dose-dependent inhibition of vascular endothelial cell proliferation, migration, and tube formation in response to VEGF stimulation. The physical stability study showed that R5K-ITZ-NPs were stable when stored at 4 °C. However, the drug remaining in R5K-ITZ-NPs when stored at 4 °C for 28 days were only 17.2%. The chemical stability test revealed that the degradation of R5K-ITZ-NPs followed second-order kinetics. The release profile showed the burst release of ITZ followed by sustained release of the drug This novel drug delivery system may be an option for neovascular AMD patients who are resistant to ITZ and may represent a novel therapy for AMD.

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The authors gratefully acknowledge the use of the facility of the Research Center for Drug Discovery and Development, Srinakharinwirot University.


This work was supported by the Office of the Higher Education Commission and the Thailand Research Fund (MRG6180064).

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Correspondence to Chuda Chittasupho.

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Chittasupho, C., Kengtrong, K., Chalermnithiwong, S. et al. Anti-angiogenesis by dual action of R5K peptide conjugated itraconazole nanoparticles. AAPS PharmSciTech 21, 74 (2020). https://doi.org/10.1208/s12249-019-1568-8

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  • angiogenesis
  • R5K
  • itraconazole
  • PLGA