Liver-Targeted Delivery Based on Prodrug: Passive and Active Approaches

Background: The liver, a central organ in human metabolism, is often the primary target for drugs. However, conditions such as viral hepatitis, cirrhosis, non-alcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC) present substantial health challenges worldwide. Existing treatments, which suffer from the non-specific distribution of drugs, frequently fail to achieve desired efficacy and safety, risking unnecessary liver harm and systemic side effects. Purpose: The aim of this review is to synthesize the latest progress in the design of liver-targeted prodrugs, with a focus on passive and active targeting strategies, providing new insights into the development of liver-targeted therapeutic approaches. Methods: This study conducted an extensive literature search through databases like Google Scholar, PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI), systematically collecting and selecting recent research on liver-targeted prodrugs. The focus was on targeting mechanisms, including the Enhanced Permeability and Retention (EPR) effect, the unique microenvironment of liver cancer, and active targeting through specific transporters and receptors. Results: Active targeting strategies achieve precise drug delivery by binding specific ligands to liver surface receptors. Passive targeting takes advantage of the EPR effect and tumor characteristics to enrich drugs in liver tumors. The review details successful cases of using small molecule ligands, peptides, antibodies and nanoparticles as drug carriers. Conclusion: Liver-targeted prodrug strategies show great potential in enhancing the efficacy of drug treatment and reducing side effects for liver diseases. Future research should balance the advantages and limitations of both targeting strategies, focusing on optimizing drug design and targeting efficiency, especially for clinical application. In-depth research on liver-specific receptors and the development of innovative targeting molecules are crucial for advancing the field of liver-targeted prodrugs.

背景：肝脏是人体代谢的核心器官，亦是药物作用的主要靶标之一。然而病毒性肝炎、肝硬化、非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）以及肝细胞癌（hepatocellular carcinoma, HCC）等病症在全球范围内均构成严峻的健康挑战。现有治疗方案普遍存在药物分布非特异性的缺陷，往往难以达到预期的疗效与安全性，不仅可能造成不必要的肝脏损伤，还会诱发全身性不良反应。目的：本综述旨在系统总结肝脏靶向前药（prodrug）设计领域的最新研究进展，重点围绕被动靶向与主动靶向策略展开阐述，以期为肝脏靶向治疗手段的开发提供全新的研究视角。方法：本研究通过Google Scholar、PubMed、Web of Science以及中国知网（China National Knowledge Infrastructure, CNKI）等数据库开展了全面的文献检索，系统性收集并筛选了近年来有关肝脏靶向前药的相关研究。本次综述重点关注的靶向机制包括：实体瘤的高通透性和滞留效应（Enhanced Permeability and Retention effect, EPR效应）、肝癌独特的微环境，以及通过特异性转运体与受体介导的主动靶向策略。结果：主动靶向策略通过将特异性配体与肝脏表面受体相结合，实现精准的药物递送；被动靶向策略则借助EPR效应与肿瘤生物学特性，使药物在肝脏肿瘤组织中富集。本综述详细介绍了以小分子配体、多肽、抗体及纳米颗粒作为药物载体的成功应用案例。结论：肝脏靶向前药策略在提升肝脏疾病药物治疗疗效、降低治疗不良反应方面展现出巨大的应用潜力。未来的研究应兼顾两类靶向策略的优势与局限性，重点优化药物设计与靶向效率，以推动其临床转化应用。针对肝脏特异性受体的深入研究以及新型靶向分子的开发，对于推动肝脏靶向前药领域的发展至关重要。