Enhancing Quercetin’s Potential: A Nanoliposome Delivery System for High Altitude Pulmonary Edema

Lin Lin,1,2 Baoying Shen,1,2 Jialu Cui,1,2 Yehui Gao,1,2 Libin Wang,3 Tingyu Yang,1,2 Jiading Weng,2,4 Chengcai Lai,2 Xianglin Tang,2 Chengrong Xiao,2 Xin Shen,2 Yue Gao1,2,5 1Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2Beijing Institute of Radiation Medicine, Beijing, People’s Republic of China; 3School of Medicine, Shaanxi Energy Institute, Xianyang, Shaanxi, People’s Republic of China; 4School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 5State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xin Shen, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Haidian District, Beijing, 100850, People’s Republic of China, Tel +86010-66931233, Email [email protected] Yue Gao, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Haidian District, Beijing, 100850, People’s Republic of China, Tel +86010-66931312, Email [email protected]: This study aimed to develop quercetin-loaded nanoliposomes (QUL) to improve the oral bioavailability of quercetin (QU). Furthermore, we comprehensively evaluated the potential of QU for preventing high-altitude pulmonary edema (HAPE) and explored its underlying molecular mechanisms.Methods: Quercetin nanoliposome was created using thin-film hydration method, which was analyzed for morphology, zeta potential, drug loading, encapsulation efficiency, and release in vitro. A simple, sensitive and accurate LC MS/MS method was developed and validated for the simultaneous quantification of QU and QUL in rat plasma using Carbamazepine as internal standard (IS). The efficacy of QU and QUL in preventing HAPE was demonstrated in vitro and in vivo. Various techniques such as Western blotting, and immunofluorescence were employed to elucidate the associated mechanism.Results: Transmission electron microscopy proved that the nanoparticles were evenly distributed. The mean particle size (DLS) was determined to be 157.08± 1.215 nm, with a polydispersity index (PDI) of 0.204± 0.012. After oral administration of QU and QUL, Tmax values were 2.677± 1.033h and 1.167± 0.408h, respectively. Additionally, the Cmax values were 0.37± 0.049ug/mL and 0.585± 0.032ug/mL, respectively, suggesting a faster absorption rate and greater absorption content for QUL. QU and QUL improved lung permeability, reduced mortality, and decreased lung water content in a mouse model. Moreover, they significantly inhibited hypoxia-induced hyperproliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Mechanistic studies indicated that these effects were mediated through the PI3K/AKT/VEGF and ROCK/HIF/TRPC signaling pathways.Conclusion: QU reduces lung water content by modulating the PI3K/AKT/VEGF and ROCK/HIF/TRPC signaling pathways, suggesting its potential for preventing and treating HAPE. Furthermore, quercetin-loaded lipid nanoparticles improve oral bioavailability, thereby enhancing the therapeutic efficacy of quercetin in HAPE management. Keywords: quercetin, nanoliposome, pharmacokinetic, high altitude pulmonary edema, pulmonary artery smooth muscle cells