Department of Pharmacology, Drug and Molecular Medicine Laboratory (The Blue Lab), Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), No.162, PH Road, Chennai, Tamil Nadu, 600 077, India.
Eur J Pharmacol. 2021 Feb 15;893:173832. doi: 10.1016/j.ejphar.2020.173832. Epub 2021 Jan 1.
Chronic liver diseases (CLD) are responsible for significant morbidity and mortality worldwide. CLD patients are at a high risk of developing progressive liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and subsequent liver failure. To date, there is no specific and effective therapies exist for patients with various forms of CLD. The application of nanotechnology has emerged as a rapidly developing area of interest for the safe and target-specific delivery of poorly aqueous soluble hepatoprotective agents and nucleic acids (siRNA/miRNAs) in CLD. The nanoparticle combination improves bioavailability and plasma stability of drugs with poor aqueous solubility. However, the extent of successful functional delivery of nanoparticles into hepatocytes is often surprisingly low. High Kupffer cells interaction reduces the nanomedicine efficacy. During fibrosis, the extracellular matrix accumulation in the perisinusoidal space restricts nanoparticle delivery to hepatocytes. The availability and uptake of nanoparticles exposure to different cells in the liver microenvironment is as Kupffer cells > sinusoidal endothelial cells > HSCs > hepatocytes. The most widely used strategy to reduce nanoparticles and macrophages interaction is to coat the particle surface with polyethylene glycol. The cationic charged nanoparticles have increased hepatocyte delivery by increased cellular interaction by disrupting the endosomal system via their pH buffering capacity. The immune clearance and toxicity of nanoparticles are mainly unpredictable. Therefore, more elaborate knowledge on exact cellular uptake and intracellular accumulation, trafficking, and endosomal sorting of nanoparticle is the need of the hour to improve the rational carrier design.
慢性肝脏疾病（CLD）在全球范围内导致了相当高的发病率和死亡率。CLD 患者发生进行性肝纤维化、肝硬化、肝细胞癌（HCC）和随后的肝功能衰竭的风险很高。迄今为止，各种形式的 CLD 患者尚无特异性和有效的治疗方法。纳米技术的应用已成为安全靶向递送水溶性差的肝保护剂和核酸（siRNA/miRNAs）的新兴研究领域。纳米颗粒的组合提高了水溶性差药物的生物利用度和血浆稳定性。然而，纳米颗粒进入肝细胞的有效功能递送程度往往出人意料地低。高库普弗细胞相互作用降低了纳米医学的疗效。在纤维化过程中，细胞外基质在窦周间隙中的积累限制了纳米颗粒向肝细胞的传递。纳米颗粒在肝微环境中不同细胞中的暴露可用性和摄取率为库普弗细胞＞窦状内皮细胞＞HSCs＞肝细胞。减少纳米颗粒与巨噬细胞相互作用的最广泛应用的策略是在颗粒表面涂覆聚乙二醇。带正电荷的纳米颗粒通过破坏其 pH 缓冲能力来增加细胞内的相互作用，从而增加了对肝细胞的递送。纳米颗粒的免疫清除和毒性主要是不可预测的。因此，更详细地了解纳米颗粒的确切细胞摄取和细胞内积累、运输和内体分拣，是改进合理载体设计的当务之急。
