Category: Formulation and Quality
Purpose: Chronic lung inflammation occurs in patients with a number of diseases such as cystic fibrosis and pulmonary fibrosis. Previously, we reported a solid lipid nanoparticle (SLNs) formulation of TNF-α that downregulates TNF-a expression by macrophages in culture and is effective against chronic inflammation in a mouse model of collagen antibody-induced arthritis. In the present study, we studied the feasibility of pulmonary delivery of the siRNA-solid lipid nanoparticles for potential treatment of lung inflammation.
Methods: The siRNA-solid lipid nanoparticles were engineered by encapsulating TNF-α siRNA complexed with a cationic lipid into solid lipid nanoparticles prepared with lecithin, cholesterol, and a polyethylene glycol (2000)-hydrazone-stearic acid (C18) derivative by nanoprecipitation. The nanoparticles were fluorescently labeled with TopFluor cholesterol. To prepare a dry powder formulation of the siRNA-solid lipid nanoparticles, mannitol was added to the nanoparticles suspension, and the suspension was then freeze-dried. The aerosol performance of the dry powder was examined using a next generation impactor (NGI).
Results: The TNF-a siRNA solid lipid nanoparticles were spherical. Their particle size and polydispersity Index were 118 ± 7 nm and 0.16 ± 0.01. In cell culture, the TNF-a siRNA solid lipid nanoparticles significantly downregulated the expression of TNF-α by J774A.1 mouse macrophage treated with lipopolysaccharide (Figure 1). The NGI data demonstrated the dry powder of the nanoparticles has good aerosol performance with a fine particle fraction (FPF) of 56.9% (Figure 2).
Conclusion: In this study, we report a TNF-a siRNA solid lipid nanoparticle formulation that inhibited TNF-α production by macrophages in culture and alleviated chronic inflammation in mouse model. A dry powder of the nanoparticles showed good aerosol performance for pulmonary delivery.
(1) D’Addio, S. M.; Chan, J. G. Y.; Kwok, P. C. L.; Benson, B. R.; Prud’homme, R. K.; Chan, H.-K. Aerosol Delivery of Nanoparticles in Uniform Mannitol Carriers Formulated by Ultrasonic Spray Freeze Drying. Pharm. Res. 2013, 30 (11), 2891–2901.
(2) Aldayel, A. M.; O’Mary, H. L.; Valdes, S. A.; Li, X.; Thakkar, S. G.; Mustafa, B. E.; Cui, Z. Lipid Nanoparticles with Minimum Burst Release of TNF-α SiRNA Show Strong Activity against Rheumatoid Arthritis Unresponsive to Methotrexate. J. Control. Release 2018, 283 (May), 280–289.
Jie-Liang Wang– Austin, Texas
Haiyue Xu– Graduate Student, UT Austin, Austin, Texas
Hannah O'Mary– Graduate student, University of Texas at Austin, Austin, Texas
Abdulaziz Aldayel– Graduate student, University of Texas at Austin, Austin, Texas
Zhengrong Cui– Professor, University of Texas at Austin, Austin, Texas
Jieliang Wang– The University of Texas at Austin College of Pharmacy-Pharmaceutics, Austin, TX