PMID- 36332825 OWN - NLM STAT- MEDLINE DCOM- 20221214 LR - 20221221 IS - 1879-0720 (Electronic) IS - 0928-0987 (Linking) VI - 180 DP - 2023 Jan 1 TI - Ultrasound-induced destruction of heparin-loaded microbubbles attenuates L-arginine-induced acute pancreatitis. PG - 106318 LID - S0928-0987(22)00203-2 [pii] LID - 10.1016/j.ejps.2022.106318 [doi] AB - PURPOSE: Acute pancreatitis (AP) involves sudden inflammation caused by abnormal activation of pancreatic enzymes. The mechanisms underlying AP include oxidative stress, high levels of inflammatory mediators and inflammatory cell infiltration. Heparin, a key therapeutic drug, exerts anti-inflammatory, antioxidative, and anticoagulative effects. However, safe and effective drug delivery remains an obstacle. This study is the first to investigate the therapeutic effects of heparin-loaded microbubbles (HPMB) combined with ultrasound (UHPMB) and the role of heparin in acoustic cavitation. METHODS: The characteristics of the microbubbles, including particle size, concentration, release, stability, and development, were studied. Heparin concentration in the HPMB was measured, and heparin-induced anticoagulation was evaluated. Drug safety was explored using hemolysis and cell viability assessments. The ability of HPMB to alleviate oxidative stress and inflammation were investigated in vitro. L-arginine induces AP in vivo. UHPMB was used for AP treatment. Serum amylase levels were measured and pancreatic architecture and pathological features were evaluated to determine AP severity. In vivo efficacy was evaluated, and the underlying mechanism of heparin action during acoustic cavitation was explored. RESULTS: HPMB was spherical and presented as an emulsion-like solution without aggregation. HPMB was visible and stable and effectively released the drug under ultrasound (US). HPMB and UHPMB led to lower AP severity than in the untreated group. US-targeted microbubble destruction (UTMD) enhanced the therapeutic effect by decreasing oxidative stress and inflammation in AP models without injuring vital organs. UHPMB regulated VEGF/Flt-1 and SOD-1 expression. HPMB can also mitigate oxidative stress and inflammation in H(2)O(2)-pretreated cells. CONCLUSION: UHPMB exhibits a strong ability not only to selectively target pancreatic lesions and release heparin but also to provide efficient protection by inhibiting oxidative stress and inflammation. CI - Copyright (c) 2022. Published by Elsevier B.V. FAU - Lin, Lili AU - Lin L AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Xie, Saili AU - Xie S AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Zhao, Yingzheng AU - Zhao Y AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. FAU - Liang, Zenghui AU - Liang Z AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Wu, Qilong AU - Wu Q AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Fang, Mingling AU - Fang M AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Teng, Xiaolu AU - Teng X AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Shi, Binbin AU - Shi B AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Yang, Yunjun AU - Yang Y AD - Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: yyjunjim@163.com. FAU - Chen, Bin AU - Chen B AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Department of Ultrasound, First Affiliated Hospital of Shenzhen University, Second People's Hospital of Shenzhen, Shenzhen, China. Electronic address: doctorchbe@126.com. LA - eng PT - Journal Article DEP - 20221101 PL - Netherlands TA - Eur J Pharm Sci JT - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JID - 9317982 RN - 9005-49-6 (Heparin) RN - BBX060AN9V (Hydrogen Peroxide) RN - 94ZLA3W45F (Arginine) SB - IM MH - Humans MH - *Pancreatitis/chemically induced/drug therapy/metabolism MH - Heparin/therapeutic use MH - Acute Disease MH - Hydrogen Peroxide MH - Arginine/therapeutic use MH - Inflammation OTO - NOTNLM OT - Acute pancreatitis OT - Destruction OT - Heparin OT - Inflammation OT - Oxidative stress OT - Ultrasound-targeted microbubbles COIS- Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/11/05 06:00 MHDA- 2022/12/15 06:00 CRDT- 2022/11/04 20:29 PHST- 2022/08/30 00:00 [received] PHST- 2022/10/28 00:00 [revised] PHST- 2022/10/29 00:00 [accepted] PHST- 2022/11/05 06:00 [pubmed] PHST- 2022/12/15 06:00 [medline] PHST- 2022/11/04 20:29 [entrez] AID - S0928-0987(22)00203-2 [pii] AID - 10.1016/j.ejps.2022.106318 [doi] PST - ppublish SO - Eur J Pharm Sci. 2023 Jan 1;180:106318. doi: 10.1016/j.ejps.2022.106318. Epub 2022 Nov 1.