Dual Delivery of Tetramethylpyrazine and miR-194-5p Using Soft Mesoporous Organosilica Nanoparticles for Acute Lung Injury Therapy

Abstract

Simin Min,1,2 Weiting Tao,1 Yuchen Miao,3 Yan Li,4 Tianyu Wu,5 Xiaoyu He,6 Yijing Zhang,7 Bangye Liu,7 Zixin Meng,7 Ke Han,1 Saisai Liu,1 Li Li,1 Jie Chen,1 Shidi Zhao,1 Junjie Zhang,3 Xiaonan Zhang1 1Bengbu Medical College Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 2Suzhou Hospital of Anhui Medical University, Suzhou, Anhui, 234000, People’s Republic of China; 3Department of Chemistry, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 4School of Medicine and Health Engineering, Changzhou University, Changzhou, Jiangsu, 213164, People’s Republic of China; 5School of Public Health, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 6Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 7School of Clinical Medicine, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of ChinaCorrespondence: Xiaonan Zhang, Department of Pathophysiology, Bengbu Medical College, 2600 Donghai Avinue, Longzihu District, Bengbu, Anhui, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected] Junjie Zhang, Department of Chemistry, Bengbu Medical College, 2600 Donghai Avinue, Longzihu District, Bengbu, Anhui, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]: The respiratory system is intensely damaged by acute lung injury (ALI). The anti-inflammatory effects of tetramethylpyrazine (TMP) against ALI have been confirmed, but it exhibits a short half-life. miR-194-5p could directly target Rac1, but the internalization rate of miRNA cells was low.Purpose: To explore the potential of the soft mesoporous organic silica nanoplatform (NPs) as carriers for delivery of TMP and miR-194-5p through the tail vein.Methods: NPs@TMP and NPs@PEI@miR-194-5p were added to the HUVEC cell-lines, in vitro, to observe the cell uptake and cytotoxic effects. In vivo experiments were conducted by injecting fluorescently labeled NPs through the tail vein and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically.Results: In vitro study exhibited that NPs have no toxic effect on HUVECs within the experimental parameters and have excellent cellular uptake. The IVIS Spectrum Imaging System shows that NPs accumulate mainly in the lungs. NPs@TMP treatment can improved oxidative stress and inflammation levels in ALI mice and inhibited the TLR4/NLRP3/caspase 1 pathway. NPs@PEI@miR-194-5p can inhibit the Rac1/ZO-1/occludin pathway and improved endothelial cell permeability in ALI mice. The co-treatment of NPs@TMP and NPs@PEI@miR-194-5p can significantly improved the survival rates of the mice, reduced pulmonary capillary permeability and improved pathological injury in ALI mice.Innovation: This study combined traditional Chinese medicine, bioinformatics, cellular molecular biology and nanobiomedicine to study the pathogenesis and treatment of ALI. The rate of cellular internalization was improved by changing the shape and hardness of nanoparticles. NPs@TMP and NPs@PEI@miR-194-5p combined application can significantly improve the survival condition and pathological injury of mice.Conclusion: NPs loaded with TMP and miR-194-5p showed a greater therapeutic effect in ALI mice. Keywords: NPs@TMP, NPs@PEI@miR-194-5p, tight junction, pulmonary capillary, endothelial cells, inflammation, acute lung injury

Keywords

• nps@tmp
• nps@pei@mir-194-5p
• tight junction
• pulmonary capillary
• endothelial cells
• inflammation
• acute lung injury