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载姜黄素聚维酮碘-聚乙烯醇-聚乙二醇自组装胶束治疗肝纤维化。

Berberine-Loaded PVCL-PVA-PEG Self-Assembled Micelles for the Treatment of Liver Fibrosis.

机构信息

Department of Traditional Chinese Medicine, Anqing Medical College, Anqing, People's Republic of China.

Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, People's Republic of China.

出版信息

Int J Nanomedicine. 2024 Oct 25;19:10857-10872. doi: 10.2147/IJN.S465214. eCollection 2024.

DOI:10.2147/IJN.S465214
PMID:39479175
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11522012/
Abstract

BACKGROUND

Liver fibrosis is a necessary pathological process in many chronic liver diseases. Studies have shown that the progression of chronic liver disease can be slowed by rational intervention in hepatic fibrosis. Berberine (BBR), a natural extract of Phellodendron amurense, inhibits the development of liver fibrosis through several mechanisms. However, the clinical application of BBR is limited due to its low solubility. Drug delivery systems have been developed to improve the solubility of hydrophobic drugs and increase their efficacy in treating the liver fibrosis.

METHODS

In this study, a biocompatible nanomicelle was constructed by thin-film dispersion method using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG) as a carrier to encapsulate BBR (PVCL-PVA-PEG/BBR-MCs) to improve the solubility of BBR and reduce the systemic side effects. The ability to inhibit HSC-T6 cell activation of PVCL-PVA-PEG/BBR-MCs was evaluated in vitro. The anti-hepatic fibrosis effects of PVCL-PVA-PEG/BBR-MCs were investigated in vivo.

RESULTS

PVCL-PVA-PEG/BBR-MCs have a uniform spherical shape with a mean particle size of 60.04 ± 0.027 nm and a potential of 1.49 ± 0.32 mV. It had an encapsulation efficiency of 98.52% ± 0.70 and drug loading content of 6.16% ± 0.04. Compared to free BBR, PVCL-PVA-PEG/BBR-MCs significantly inhibited HSC-T6 cell activation and TGF-β1-induced HSC-T6 cell migration in vitro. In vivo biodistribution experiments showed significantly improved hepatic distribution of PVCL-PVA-PEG/DiD-MCs compared to free DiD, suggesting that PVCL-PVA-PEG micelles enhance the ability of BBR to enter the liver and improve therapeutic efficacy. After treatment, PVCL-PVA-PEG/BBR-MCs significantly improved fibrotic liver structure and reduced collagen deposition in comparison to the CCl-treated group; the treatment outcome was more effective than that of the free BBR group.

CONCLUSION

Our results demonstrate the advantages of encapsulating BBR in PVCL-PVA-PEG micelles and highlight the potential of PVCL-PVA-PEG/BBR-MCs as a therapeutic strategy for the treatment of liver fibrosis.

摘要

背景

肝纤维化是许多慢性肝病的必要病理过程。研究表明，通过合理干预肝纤维化，可以减缓慢性肝病的进展。小檗碱（BBR）是黄皮树的天然提取物，通过多种机制抑制肝纤维化的发展。然而，由于其低溶解度，BBR 的临床应用受到限制。为了提高疏水性药物的溶解度并提高其治疗肝纤维化的疗效，已经开发了药物传递系统。

方法

在这项研究中，通过薄膜分散法用聚己内酯-聚醋酸乙烯酯-聚乙二醇接枝共聚物（PVCL-PVA-PEG）作为载体构建了一种生物相容性的纳米胶束，以包封 BBR（PVCL-PVA-PEG/BBR-MCs），从而提高 BBR 的溶解度并降低其全身副作用。体外评估了 PVCL-PVA-PEG/BBR-MCs 抑制 HSC-T6 细胞激活的能力。体内研究了 PVCL-PVA-PEG/BBR-MCs 的抗肝纤维化作用。

结果

PVCL-PVA-PEG/BBR-MCs 呈均匀的球形，平均粒径为 60.04 ± 0.027nm，电位为 1.49 ± 0.32mV。包封效率为 98.52%±0.70%，载药量为 6.16%±0.04%。与游离 BBR 相比，PVCL-PVA-PEG/BBR-MCs 显著抑制了体外 HSC-T6 细胞的激活和 TGF-β1 诱导的 HSC-T6 细胞迁移。体内生物分布实验表明，与游离 DiD 相比，PVCL-PVA-PEG/DiD-MCs 显著改善了 DiD 在肝脏中的分布，提示 PVCL-PVA-PEG 胶束增强了 BBR 进入肝脏的能力，提高了治疗效果。治疗后，与 CCl 处理组相比，PVCL-PVA-PEG/BBR-MCs 显著改善了纤维化肝脏的结构，减少了胶原沉积；治疗效果优于游离 BBR 组。

结论

我们的结果证明了将 BBR 包封在 PVCL-PVA-PEG 胶束中的优势，并强调了 PVCL-PVA-PEG/BBR-MCs 作为治疗肝纤维化的治疗策略的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/20a9bbe5d968/IJN-19-10857-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/20f49aafe699/IJN-19-10857-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/4a4d0760d38c/IJN-19-10857-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/78ab92fd2f6b/IJN-19-10857-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/8f622efdfbf6/IJN-19-10857-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/236b16ad51b5/IJN-19-10857-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/f74e95e7b761/IJN-19-10857-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/ebeb5d3e73a2/IJN-19-10857-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/098c105c5ca3/IJN-19-10857-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/20a9bbe5d968/IJN-19-10857-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/20f49aafe699/IJN-19-10857-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/4a4d0760d38c/IJN-19-10857-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/78ab92fd2f6b/IJN-19-10857-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/8f622efdfbf6/IJN-19-10857-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/236b16ad51b5/IJN-19-10857-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/f74e95e7b761/IJN-19-10857-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/ebeb5d3e73a2/IJN-19-10857-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/098c105c5ca3/IJN-19-10857-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d0c4/11522012/20a9bbe5d968/IJN-19-10857-g0009.jpg

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