咪喹莫特的肝细胞靶向递送可降低乙型肝炎病毒表面抗原

StephenW

咪喹莫特的肝细胞靶向递送可降低乙型肝炎病毒表面抗原
Nojoud A L Fayez 1 , Elham Rouhollahi 1 , Chun Yat Ong 1 , Jiamin Wu 1 , Anne Nguyen 1 , Roland Böttger 1 , Pieter R Cullis 2 , Dominik Witzigmann 2 , Shyh-Dar Li 3
隶属关系
隶属关系

    1
    不列颠哥伦比亚大学药学院，温哥华，不列颠哥伦比亚省 V6T 1Z3，加拿大。
    2
    不列颠哥伦比亚大学生物化学与分子生物学系，温哥华，不列颠哥伦比亚省 V6T 1Z3，加拿大；纳米药物创新网络 (NMIN)。
    3
    不列颠哥伦比亚大学药学院，温哥华，不列颠哥伦比亚省 V6T 1Z3，加拿大；纳米药物创新网络 (NMIN)。电子地址：[email protected]。

    PMID：36058352 DOI：10.1016/j.jconrel.2022.08.058

抽象的

乙型肝炎病毒（HBV）传播后可在肝细胞内迅速复制，导致慢性肝炎、肝硬化，最终导致肝细胞癌。干扰素-α (IFN-α) 包含在慢性乙型肝炎 (CHB) 的标准治疗中。然而，这种疗法会导致严重的副作用。选择性地将 IFN-α 递送至肝脏可提高其疗效和安全性。咪喹莫特 (IMQ) 是一种 Toll 样受体 (TLR) 7 激动剂，可刺激具有有效抗病毒活性的 IFN-α 的释放。然而，IMQ较差的溶解性和组织选择性限制了其临床应用。在这里，我们展示了使用基于脂质的纳米颗粒 (LNP) 来传递 IMQ 并增加肝脏中 IFN-α 的产生。我们将 IMQ 封装在两种针对肝脏的 LNP 制剂中：分别针对肝细胞和枯否细胞的无磷脂小单层囊泡 (PFSUV) 和 DSPG 脂质体。对这两种制剂的体外药物释放/保留、体内药代动力学、肝内分布、IFN-α 产生和血清 HBV 表面抗原 (HBsAg) 的抑制进行了评估和比较。 PFSUV 在 1/20 (w/w) 的药物与脂质比 (D/L) 下为 IMQ 提供 >95% 的封装效率，并在血清存在下显示出稳定的药物保留。 DSPG-IMQ 在 1/20 (D/L) 处显示 79% 的 IMQ 包封，并在与血清一起孵育时表现出约 30% 的突释。在肝脏内，PFSUVs 对肝细胞表现出高选择性，而 DSPG 脂质体靶向 Kupffer 细胞。最后，在实验性 HBV 小鼠模型中，与对照组、IFN-α 和 DSPG-IMQ 组相比，PFSUV 显着降低了 HBsAg 的血清水平 12 倍、6.3 倍和 2.2 倍。结果表明，载有 IMQ 的肝细胞靶向 PFSUV 表现出增强 CHB 治疗的显着潜力。

关键词：慢性乙型肝炎（CHB）；乙型肝炎表面抗原（HBsAg）；乙型肝炎病毒（HBV）；咪喹莫特（IMQ）；干扰素-α（干扰素-α）；无磷脂小单层囊泡 (PFSUV)。

版权所有 © 2022。Elsevier B.V. 出版

StephenW

Hepatocyte-targeted delivery of imiquimod reduces hepatitis B virus surface antigen
Nojoud A L Fayez  1 , Elham Rouhollahi  1 , Chun Yat Ong  1 , Jiamin Wu  1 , Anne Nguyen  1 , Roland Böttger  1 , Pieter R Cullis  2 , Dominik Witzigmann  2 , Shyh-Dar Li  3
Affiliations
Affiliations

    1
    Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
    2
    Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; NanoMedicines Innovation Network (NMIN).
    3
    Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; NanoMedicines Innovation Network (NMIN). Electronic address: [email protected].

    PMID: 36058352 DOI: 10.1016/j.jconrel.2022.08.058

Abstract

Hepatitis B virus (HBV) can rapidly replicate in the hepatocytes after transmission, leading to chronic hepatitis, liver cirrhosis and eventually hepatocellular carcinoma. Interferon-α (IFN-α) is included in the standard treatment for chronic hepatitis B (CHB). However, this therapy causes serious side effects. Delivering IFN-α selectively to the liver may enhance its efficacy and safety. Imiquimod (IMQ), a Toll-Like Receptor (TLR) 7 agonist, stimulates the release of IFN-α that exhibits potent antiviral activity. However, the poor solubility and tissue selectivity of IMQ limits its clinical use. Here, we demonstrated the use of lipid-based nanoparticles (LNPs) to deliver IMQ and increase the production of IFN-α in the liver. We encapsulated IMQ in two liver-targeted LNP formulations: phospholipid-free small unilamellar vesicles (PFSUVs) and DSPG-liposomes targeting the hepatocytes and the Kupffer cells, respectively. In vitro drug release/retention, in vivo pharmacokinetics, intrahepatic distribution, IFN-α production, and suppression of serum HBV surface antigen (HBsAg) were evaluated and compared for these two formulations. PFSUVs provided >95% encapsulation efficiency for IMQ at a drug-to-lipid ratio (D/L) of 1/20 (w/w) and displayed stable drug retention in the presence of serum. DSPG-IMQ showed 79% encapsulation of IMQ at 1/20 (D/L) and exhibited ~30% burst release when incubated with serum. Within the liver, PFSUVs showed high selectivity for the hepatocytes while DSPG-liposomes targeted the Kupffer cells. Finally, in an experimental HBV mouse model, PFSUVs significantly reduced serum levels of HBsAg by 12-, 6.3- and 2.2-fold compared to the control, IFN-α, and DSPG-IMQ groups, respectively. The results suggest that the hepatocyte-targeted PFSUVs loaded with IMQ exhibit significant potential for enhancing therapy of CHB.

Keywords: Chronic hepatitis B (CHB); Hepatitis B surface antigen (HBsAg); Hepatitis B virus (HBV); Imiquimod (IMQ); Interferon-α (IFN-α); Phospholipid-free small unilamellar vesicles (PFSUVs).

Copyright © 2022. Published by Elsevier B.V.