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雷公藤甲素通过包裹于聚乙二醇化TRX - 20修饰脂质体实现肾脏靶向递送。

Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes.

作者信息

Yuan Zhi-Xiang, Jia Lu, Lim Lee Yong, Lin Ju-Chun, Shu Gang, Zhao Ling, Ye Gang, Liang Xiao-Xia, Ji Hongming, Fu Hua-Lin

机构信息

Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan.

Department of Neurosurgery, Shanxi Provincial People' Hospital, Taiyuan, China.

出版信息

Int J Nanomedicine. 2017 Aug 8;12:5673-5686. doi: 10.2147/IJN.S141095. eCollection 2017.

DOI:10.2147/IJN.S141095
PMID:28848346
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5557620/
Abstract

Previously, 3,5-dipentadecyloxybenzamidine hydrochloride (TRX-20)-modified liposomes were reported to specifically target mesangial cells (MCs) in glomeruli. To further gain a better understanding of the characteristics and potential application for glomerular diseases of TRX-20-modified liposomes, we synthesized TRX-20 and prepared TRX-20-modified liposomes (TRX-LPs) with different molar ratios - 6% (6%-TRX-LP), 11% (11%-TRX-LP), and 14% (14%-TRX-LP) - of TRX-20 to total lipid in the present study. All TRX-LPs exhibited concentration-dependent toxicity against the MCs at a lipid concentration ranging from 0.01 to 1.0 mg/mL with IC values of 3.45, 1.13, and 0.55 mg/mL, respectively. Comparison of the cell viability of TRX-LPs indicated that high levels of TRX-20 caused severe cell mortality, with 11%-TRX-LP showing the higher cytoplasmic accumulation in the MCs. Triptolide (TP) as a model drug was first loaded into 11%-TRX-LP and the liposomes were further modified with PEG (PEG-TRX-TP-LP) in an attempt to prolong their circulation in blood and enhance TP-mediated immune suppression. Due to specific binding to MCs, PEG-TRX-TP-LP undoubtedly showed better anti-inflammatory action in vitro, evidenced by the inhibition of release of nitric oxide (NO) and tumor necrosis factor-α from lipopolysaccharide-stimulated MCs, compared with free TP at the same dose. In vivo, the PEG-TRX-TP-LP effectively attenuated the symptoms of membranous nephropathic (MN) rats and improved biochemical markers including proteinuria, serum cholesterol, and albumin. Therefore, it can be concluded that the TRX-modified liposome is an effective platform to target the delivery of TP to glomeruli for the treatment of MN.

摘要

此前有报道称，3,5-二十五烷氧基苯甲脒盐酸盐（TRX-20）修饰的脂质体可特异性靶向肾小球系膜细胞（MCs）。为了进一步深入了解TRX-20修饰脂质体的特性及其在肾小球疾病中的潜在应用，在本研究中，我们合成了TRX-20，并制备了TRX-20与总脂质摩尔比分别为6%（6%-TRX-LP）、11%（11%-TRX-LP）和14%（14%-TRX-LP）的TRX-20修饰脂质体（TRX-LPs）。在脂质浓度为0.01至1.0 mg/mL范围内，所有TRX-LPs对MCs均表现出浓度依赖性毒性，其IC值分别为3.45、1.13和0.55 mg/mL。TRX-LPs细胞活力的比较表明，高水平的TRX-20会导致严重的细胞死亡，11%-TRX-LP在MCs中显示出较高的细胞质蓄积。雷公藤甲素（TP）作为模型药物首先被载入11%-TRX-LP中，然后用聚乙二醇（PEG）对脂质体进行进一步修饰（PEG-TRX-TP-LP），以延长其在血液中的循环时间并增强TP介导的免疫抑制作用。由于与MCs的特异性结合，与相同剂量的游离TP相比，PEG-TRX-TP-LP在体外无疑表现出更好的抗炎作用，这可通过抑制脂多糖刺激的MCs释放一氧化氮（NO）和肿瘤坏死因子-α得到证明。在体内，PEG-TRX-TP-LP有效减轻了膜性肾病（MN）大鼠的症状，并改善了包括蛋白尿、血清胆固醇和白蛋白在内的生化指标。因此，可以得出结论，TRX修饰的脂质体是将TP靶向递送至肾小球以治疗MN的有效平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/1775bb955f35/ijn-12-5673Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/a3431f6b7808/ijn-12-5673Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/fa0f17b96482/ijn-12-5673Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/86fa8bf08c3f/ijn-12-5673Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/47cda877770e/ijn-12-5673Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/0ffd9d80804b/ijn-12-5673Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/1775bb955f35/ijn-12-5673Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/a3431f6b7808/ijn-12-5673Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/fa0f17b96482/ijn-12-5673Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/86fa8bf08c3f/ijn-12-5673Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/47cda877770e/ijn-12-5673Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/0ffd9d80804b/ijn-12-5673Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b48a/5557620/1775bb955f35/ijn-12-5673Fig6.jpg

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