AUTHOR=Li Jingtao , Zhang Xiaofeng , Mo Yingying , Huang Tongtong , Rao Huaqing , Tan Zhenyuan , Huang Liuliu , Zeng Decai , Jiang Chunlan , Zhong Yanfen , Cai Yongzhi , Liang Binbin , Wu Ji 

TITLE=Urokinase-loaded cyclic RGD-decorated liposome targeted therapy for in-situ thrombus of pulmonary arteriole of pulmonary hypertension

JOURNAL=Frontiers in Bioengineering and Biotechnology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2022.1038829

DOI=10.3389/fbioe.2022.1038829

ISSN=2296-4185

ABSTRACT=<p><bold>Backgroud:</bold><italic>In-situ</italic> thrombosis is a significant pathophysiological basis for the development of pulmonary hypertension (PH). However, thrombolytic therapy for <italic>in-situ</italic> thrombus in PH was often hampered by the apparent side effects and the low bioavailability of common thrombolytic medications. Nanoscale cyclic RGD (cRGD)-decorated liposomes have received much attention thanks to their thrombus-targeting and biodegradability properties. As a result, we synthesized urokinase-loaded cRGD-decorated liposome (UK-cRGD-Liposome) for therapy of <italic>in-situ</italic> thrombosis as an exploration of pulmonary hypertensive novel therapeutic approaches.</p><p><bold>Purpose:</bold> To evaluate the utilize of UK-cRGD-Liposome for targeted thrombolysis of <italic>in-situ</italic> thrombus in PH and to explore the potential mechanisms of <italic>in-situ</italic> thrombus involved in the development of PH.</p><p><bold>Methods:</bold> UK-cRGD-Liposome nanoscale drug delivery system was prepared using combined methods of thin-film hydration and sonication. Induced PH <italic>via</italic> subcutaneous injection of monocrotaline (MCT). Fibrin staining (modified MSB method) was applied to detect the number of vessels within-situ thrombi in PH. Echocardiography, hematoxylin-eosin (H &amp; E) staining, and Masson’s trichrome staining were used to analyze right ventricular (RV) function, pulmonary vascular remodeling, as well as RV remodeling.</p><p><bold>Results:</bold> The number of vessels with <italic>in-situ</italic> thrombi revealed that UK-cRGD-Liposome could actively target urokinase to <italic>in-situ</italic> thrombi and release its payload in a controlled manner in the <italic>in vivo</italic> environment, thereby enhancing the thrombolytic effect of urokinase. Pulmonary artery hemodynamics and echocardiography indicated a dramatical decrease in pulmonary artery pressure and a significant improvement in RV function post targeted thrombolytic therapy. Moreover, pulmonary vascular remodeling and RV remodeling were significantly restricted post targeted thrombolytic therapy.</p><p><bold>Conclusion:</bold> UK-cRGD-Liposome can restrict the progression of PH and improve RV function by targeting the dissolution of pulmonary hypertensive <italic>in-situ</italic> thrombi, which may provide promising therapeutic approaches for PH.</p>