Effect of the Ratio of Betamethasone to TNF-α siRNA Coencapsulated in Solid Lipid Nanoparticles on the Acute Proinflammatory Activity of the Nanoparticles

Hannah L. O'Mary, Mahmoud S. Hanafy, Abdulaziz M. Aldayel, Solange A. Valdes, Riyad F. Alzhrani, Stephanie Hufnagel, John J. Koleng, Zhengrong Cui

Research output: Contribution to journalArticle

Abstract

There is evidence that encapsulating glucocorticoids into nucleic acid-containing nanoparticles reduces the inflammatory toxicities of the nanoparticles. Herein, using betamethasone acetate (BA), a glucocorticoid, and a solid lipid nanoparticle formulation of siRNA, we confirmed that coencapsulating BA into the siRNA solid lipid nanoparticles significantly reduced the proinflammatory activity of the siRNA nanoparticles in a mouse model. Using TNF-α siRNA, we then showed that the BA and TNF-α siRNA coencapsulated into the solid lipid nanoparticles acted as a dual anti-inflammatory and synergistically reduced TNF-α release by mouse macrophages in culture following stimulation with lipopolysaccharide, as compared to solid lipid nanoparticles encapsulated with TNF-α siRNA or BA alone. Importantly, upon studying the effect of the ratio of BA and TNF-α siRNA on the proinflammatory activity of the resultant nanoparticles, we identified that BA and TNF-α siRNA coencapsulated solid lipid nanoparticles prepared with a BA to TNF-α siRNA weight ratio of 2:1 induced the lowest proinflammatory cytokine production by macrophages in culture. This result was in comparison to nanoparticles prepared with BA to TNF-α siRNA ratios both higher and lower than 2:1 (i.e., 4:1, 1:1, and 0.5:1) and is likely due to differences in molecular interactions among the various components in the BA and TNF-α-siRNA coencapsulated solid lipid nanoparticles at these ratios. Encapsulating glucocorticoids into siRNA-nanoparticles represents a viable strategy to reduce the proinflammatory activity of the nanoparticles; however, the ratio of the glucocorticoid to siRNA in the nanoparticles requires optimization.

Original languageEnglish (US)
Pages (from-to)4496-4506
Number of pages11
JournalMolecular Pharmaceutics
Volume16
Issue number11
DOIs
StatePublished - Jun 6 2019

Fingerprint

Betamethasone
Nanoparticles
Small Interfering RNA
Lipids
Glucocorticoids
Macrophages
betamethasone acetate
Nucleic Acids

Keywords

  • TNF-α
  • acute inflammation
  • glucocorticoid
  • nanoparticles
  • siRNA

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Effect of the Ratio of Betamethasone to TNF-α siRNA Coencapsulated in Solid Lipid Nanoparticles on the Acute Proinflammatory Activity of the Nanoparticles. / O'Mary, Hannah L.; Hanafy, Mahmoud S.; Aldayel, Abdulaziz M.; Valdes, Solange A.; Alzhrani, Riyad F.; Hufnagel, Stephanie; Koleng, John J.; Cui, Zhengrong.

In: Molecular Pharmaceutics, Vol. 16, No. 11, 06.06.2019, p. 4496-4506.

Research output: Contribution to journalArticle

O'Mary, Hannah L. ; Hanafy, Mahmoud S. ; Aldayel, Abdulaziz M. ; Valdes, Solange A. ; Alzhrani, Riyad F. ; Hufnagel, Stephanie ; Koleng, John J. ; Cui, Zhengrong. / Effect of the Ratio of Betamethasone to TNF-α siRNA Coencapsulated in Solid Lipid Nanoparticles on the Acute Proinflammatory Activity of the Nanoparticles. In: Molecular Pharmaceutics. 2019 ; Vol. 16, No. 11. pp. 4496-4506.
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AU - Hanafy, Mahmoud S.

AU - Aldayel, Abdulaziz M.

AU - Valdes, Solange A.

AU - Alzhrani, Riyad F.

AU - Hufnagel, Stephanie

AU - Koleng, John J.

AU - Cui, Zhengrong

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AB - There is evidence that encapsulating glucocorticoids into nucleic acid-containing nanoparticles reduces the inflammatory toxicities of the nanoparticles. Herein, using betamethasone acetate (BA), a glucocorticoid, and a solid lipid nanoparticle formulation of siRNA, we confirmed that coencapsulating BA into the siRNA solid lipid nanoparticles significantly reduced the proinflammatory activity of the siRNA nanoparticles in a mouse model. Using TNF-α siRNA, we then showed that the BA and TNF-α siRNA coencapsulated into the solid lipid nanoparticles acted as a dual anti-inflammatory and synergistically reduced TNF-α release by mouse macrophages in culture following stimulation with lipopolysaccharide, as compared to solid lipid nanoparticles encapsulated with TNF-α siRNA or BA alone. Importantly, upon studying the effect of the ratio of BA and TNF-α siRNA on the proinflammatory activity of the resultant nanoparticles, we identified that BA and TNF-α siRNA coencapsulated solid lipid nanoparticles prepared with a BA to TNF-α siRNA weight ratio of 2:1 induced the lowest proinflammatory cytokine production by macrophages in culture. This result was in comparison to nanoparticles prepared with BA to TNF-α siRNA ratios both higher and lower than 2:1 (i.e., 4:1, 1:1, and 0.5:1) and is likely due to differences in molecular interactions among the various components in the BA and TNF-α-siRNA coencapsulated solid lipid nanoparticles at these ratios. Encapsulating glucocorticoids into siRNA-nanoparticles represents a viable strategy to reduce the proinflammatory activity of the nanoparticles; however, the ratio of the glucocorticoid to siRNA in the nanoparticles requires optimization.

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