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A2984 - Surfactant Protein-A Nanobody-Conjugated Liposomes Loaded with Methylprednisolone Demonstrate High Lung Targeting and Therapeutic Effect for Acute Lung Injury
Author Block: D. Weng1, L. Huiping2; 1Respiratory Medicine, Shanghai Pulmonary Hospital, Shanghai, China, 2Shanghai Pulmonary, Shanghai, China.
Objective: The present study aimed to develop a lung-targeting glucocorticoid nanoparticle that could deliver the active primarily to the lung tissues, thereby reducing the toxic systemic side effects.Methods: Methylprednisolone (MPS), the treatment drug, was loaded into -sterically stabilized unilameraller liposomes (NSSLs) delivery vehicles forming MPS-NSSLs particles. Specific tissue targeting was introduced to the MPS-NSSLs particles through conjugation ofnanobodies of surfactant protein A (SPANb) to make MPS-NSSLs-SPANb. The physico-chemical characteristics of MPS-NSSLs-SPANb particles were evaluated. Prticle size was measured using dynamic light scattering, the particle morphology was determined through cryo-transmission electron microscopy (cryo-TEM). The encapsulation efficiency and the ratio between the drug and the lipids were assessed by high-performance liquid chromatograph (HPLC). Small animal imaging was performed in nude mice to analyze the distribution of MPS-NSSLs-SPANb in vivo. The MPS levels in the different organs of rats was measured at different time points to assess the lung-targeting property of MPS-NSSLs-SPANb. Finally, the safety and therapeutic effects of MPS-NSSLs-SPANb were evaluated in rats with bleomycin-induced lung injury.Results: 1) The diameter of MPS-NSSLs-SPANb particles was 106 ± 1 nm, the encapsulation efficiency of NSSLs-SPANb to MPS was 92.5 ± 0.3%, and the drug:lipid ratio was approximately 0.40. MPS-NSSLs-SPANb nanoparticles could be stored at 4 °C for no less than 12 weeks. Cryo-TEM observation showed MPS-NSSLs-SPANb particles were unilamellar and well disperses with no observable aggregation. 2) ELISA showed that MPS-NSSLs-SPANb could actively bind with SP-A antigen. Small animal imaging and pharmacokinetic study of MPS-NSSLs-SPANb in rats showed that the peak value of MPS in lung after MPS-NSSLs-SPANb injection was 4.6-fold (Ce = 4.6) of that after MPS injection, and the AUC0-12h after MPS-NSSLs-SPANb injection was 178-fold (Re = 17.8) of that after MPS injection, indicating that MPS-NSSLs-SPANb had good lung-targeting properties. 3) In rats with bleomycin-induced lung injury, MPS-NSSLs-SPANb significantly reduced the level of TNF-α, IL-8, and TGF-β1 in rat bronchoalveolar lavage fluid (BALF) and the expression of NK-κB in the lung tissues, thereby alleviating the injuries of the lung and increasing the survival proportion of rats after lung damage. Conclusion: These particles are the first specific lung-targeting nanoparticles specifically developed for \glucocorticoid delivery (MPS-NSSLs-SPANb). We deomsntrate that using SP-A nanobody as the lung-targeting moleculewas more effective in treating rats with bleomycin-induced lung injury.