The liver is the largest vital organ responsible for functions including metabolism, immunity, digestion, detoxification and endocrine regulation. Its multifaceted role, unique anatomical features and specialized blood supply—receiving blood directly from the GI tract and heart—render it an indispensable target for therapeutic interventions aimed at addressing liver diseases and improving overall health outcomes.
Normally, drugs accumulate in the liver due to the concentration of transporters and receptors, which are responsible for the uptake, detoxification, metabolism and excretion of xenobiotics. However, this also makes the liver vulnerable to drug-induced damage.
Drugs are primarily metabolized and concentrated in the liver and subsequently excreted through urine or bile. The first step of drug metabolism, phase I reaction, is mediated by hepatic cytochrome p450 system enzymes. Toxic intermediate products generated in this step may interact with cellular organelles, leading to hepatocyte dysfunction and cell death. These products are then inactivated through phase II reactions. If phase II reactions fail, toxic metabolites accumulate, leading to liver damage, as seen in alcohol and acetaminophen abuse.
Drug-induced liver injury
Drug-induced liver injury (DILI) is a common issue, as almost all medication classes can cause liver disease. DILI can result from direct drug toxicity, their metabolites, or immune-mediated mechanisms, which may be interconnected. Mitochondrial dysfunction is often the initial event, causing increased ROS and energy depletion, leading to hepatocyte death. Immune-mediated injury, involving liver immune components and cytokines/ROS, also contributes to liver injury.
Addressing DILI requires effective liver-specific drug delivery, which is challenging due to the liver's complex anatomy and the distinct functions and entry mechanisms of different cell types. Drug molecules must navigate a complex network of blood vessels and anatomical barriers to reach their intended target. The liver's elevated metabolic and elimination processes compound this challenge, causing drugs to potentially accumulate in unintended tissues and lead to side effects such as toxicity and non-specific biodistribution.
In recent years, advancements in drug delivery platforms have enhanced drug efficacy and reduced liver toxicity, leading to better therapeutic outcomes. The aim is to develop drug delivery systems that selectively target specific liver cell types and maintain intracellular drug levels for longer. Nanoparticles, such as liposomes, exosomes, micelles, and polymeric/inorganic nanoparticles, have gained significant attention due to their ability to enhance drug efficacy, reduce liver toxicity, and selectively target specific liver cell receptors.
For instance, hyaluronated and PEGylated liposomes encapsulating therapeutic agents have demonstrated potential for targeted delivery to the liver, particularly in treating hepatitis and liver cancer. Due to their low immunogenicity and high biocompatibility, exosomes are being studied for their potential hepatoprotective, antioxidant and drug-sensitizing effects on liver diseases. Studies also show that MSC-derived exosomes can be manipulated to facilitate liver regeneration, regulate inflammation and fibrosis, or inhibit tumor growth and metastasis.
Ligand-based targeting is another promising strategy for liver-specific drug delivery. Various ligands, such as carbohydrates, peptides, and antibodies, have been investigated for their potential to enhance the selectivity and uptake of drug-loaded carriers by hepatocytes. For instance, the asialoglycoprotein receptor (ASGP-R) can be targeted using carbohydrate- or lipoprotein-decorated delivery systems. Scavenging receptors can target non-parenchymal liver cells like Kupffer and endothelial cells, while colloidal carriers coupled with vitamin A can target stellate cells involved in liver fibrosis.
Stem cell-based carriers deliver therapeutic agents to the liver due to their tropism for injured tissues, while macrophage-based carriers use their phagocytic capacity and ability to migrate to inflammation sites for efficient liver-targeted drug delivery. Combination therapy using multiple drugs can improve efficacy and safety, but simultaneous delivery may cause unintended side effects. Sequential drug delivery can mitigate these effects and enhance synergistic efficacy, particularly in liver-targeted treatments.
Optimizing pharmacokinetics is critical for developing effective liver-targeted drug delivery systems. Key factors include minimizing release at non-target sites, efficient delivery to target sites, and maintaining adequate concentration for therapeutic effects. Additionally, it's important to minimize the elimination of drug-carrier conjugates and to rapidly eliminate free drugs from the body to reduce toxicity. The liver is mainly responsible for removing drug conjugates from circulation, as they are too large to be eliminated through the kidneys.