PMID- 35286915 OWN - NLM STAT- MEDLINE DCOM- 20220510 LR - 20220510 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 107 DP - 2022 Jun TI - NGR-modified PEG-PLGA micelles containing Shikonin enhance targeting of dendritic cells for therapy of allergic rhinitis. PG - 108649 LID - S1567-5769(22)00133-3 [pii] LID - 10.1016/j.intimp.2022.108649 [doi] AB - BACKGROUND: Allergic rhinitis (AR) is a disease in the nasal mucosa related with Th2 lymphocyte inflammatory action. Dendritic cells (DCs) have been proved that they played a significant role in the development and maintenance of AR. However, there is still a lack of specific therapies for DCs in clinical practice. Shikonin (SHI) is a natural naphthoquinone compound isolated from the Chinese herb Radix Arnebiae. It is reported that SHI can interference the phenotype and function of dendritic cells, so we speculate that SHI may be an effective drug for the treatment of AR. However, the clinical usage of SHI has been limited by the bioactive properties of poor solubility, short retention time and low bioavailability. Therefore, in order to better exert the anti-inflammatory effect of SHI, an efficient SHI delivery system is urgently needed. METHODS: We prepared and characterized SHI-PM and NGR-SHI-PM with the thin-film hydration method. We used retrodialysis method to explore the release behavior. We took immunofluorescence to investigate the expression of CD13 in vitro. Then we tested BM-DCs mature cell detection by flow cytometry. An allergic rhinosinusitis murine model, hematoxylin and eosin stain and flow cytometry were established to test the efficiency of anti-inflammation in vivo. At last, western blot analysis and plasmid construction and transfection assay were taken to reveal the molecular mechanisms. RESULTS: In the present study, we revealed that NGR-modifified could strengthen the intracellular uptake of PM (p < 0.001) and CD13 was high expressed on mature BM-DCs (p < 0.001). NGR-modified could enhance the inhibition of SHI in vitro (p < 0.05). NGR-modifified could increase the distribution of PM in vivo by DiI fluorescently (p < 0.01). NGR-modified could enhance SHI anti-allergic activity in OVA-sensitized mice and enhance the inhibition of SHI on DC maturation in lymph node (p < 0.001). Our findings also suggest that SHI may have the inhibitory effect on AR through NF-kappaB pathway by targeting PARP. CONCLUSIONS: In summary, we have shown that NGR-PM-SHI could be a novel strategy for targeted treating allergic rhinitis through the NF-kappaB pathway by targeting PARP. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Liu, Chengcheng AU - Liu C AD - Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Weiqi Road, Jinan, Shandong, China. FAU - Qi, Wenwen AU - Qi W AD - Department of Otolaryngology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China; Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. FAU - Teng, Zhenxiao AU - Teng Z AD - Department of Otolaryngology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China; Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. FAU - Xu, Runtong AU - Xu R AD - Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. FAU - Xi, Yue AU - Xi Y AD - Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. FAU - Qin, Yiming AU - Qin Y AD - College of Chemical Engineering and Materials Science, Shandong Normal University, 250014 Jinan, China. FAU - Xu, Fenglei AU - Xu F AD - Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. FAU - Shi, Lei AU - Shi L AD - Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. Electronic address: 617976718@qq.com. FAU - Zhao, Miaoqing AU - Zhao M AD - Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. Electronic address: zhaomqsd@163.com. FAU - Xia, Ming AU - Xia M AD - Department of Otolaryngology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China; Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwuweiqi Road, 250021 Jinan, Shandong Province, China. Electronic address: xiamingsdu@sohu.com. LA - eng PT - Journal Article DEP - 20220311 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Micelles) RN - 0 (NF-kappa B) RN - 0 (Naphthoquinones) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 0 (Polyesters) RN - 0 (polyethylene glycol-poly(lactide-co-glycolide)) RN - 3IK6592UBW (shikonin) RN - 3WJQ0SDW1A (Polyethylene Glycols) RN - 9006-59-1 (Ovalbumin) SB - IM MH - Animals MH - Dendritic Cells MH - Disease Models, Animal MH - Mice MH - Mice, Inbred BALB C MH - Micelles MH - NF-kappa B/metabolism MH - *Naphthoquinones/pharmacology/therapeutic use MH - Nasal Mucosa/metabolism MH - Ovalbumin/metabolism MH - Poly(ADP-ribose) Polymerase Inhibitors/metabolism/pharmacology/therapeutic use MH - Polyesters MH - Polyethylene Glycols MH - *Rhinitis, Allergic/drug therapy/metabolism OTO - NOTNLM OT - Allergic rhinitis OT - Dendritic cells OT - Immunology OT - NGR-PEG OT - Shikonin EDAT- 2022/03/15 06:00 MHDA- 2022/05/11 06:00 CRDT- 2022/03/14 20:10 PHST- 2021/12/20 00:00 [received] PHST- 2022/01/26 00:00 [revised] PHST- 2022/02/20 00:00 [accepted] PHST- 2022/03/15 06:00 [pubmed] PHST- 2022/05/11 06:00 [medline] PHST- 2022/03/14 20:10 [entrez] AID - S1567-5769(22)00133-3 [pii] AID - 10.1016/j.intimp.2022.108649 [doi] PST - ppublish SO - Int Immunopharmacol. 2022 Jun;107:108649. doi: 10.1016/j.intimp.2022.108649. Epub 2022 Mar 11.