Antibody-drug conjugates for hepato-pancreato-biliary malignancies: "Magic bullets" to the rescue?

Hepato-Pancreato-Biliary (HPB) malignancies constitute a highly aggressive group of cancers that have a dismal prognosis. Patients not amenable to curative intent surgical resection are managed with systemic chemotherapy which, however, confers little survival benefit. Antibody-Drug Conjugates (ADCs) are tripartite compounds that merge the intricate selectivity and specificity of monoclonal antibodies with the cytodestructive potency of attached supertoxic payloads. In view of the unmet need for drugs that will enhance the survival rates of HPB cancer patients, the assessment of ADCs for treating HPB malignancies has become the focus of extensive clinical and preclinical investigation, showing encouraging preliminary results. In the current review, we offer a comprehensive overview of the growing body of evidence on ADC approaches tested for HPB malignancies. Starting from a concise discussion of the functional principles of ADCs, we summarize here all available data from preclinical and clinical studies evaluating ADCs in HPB cancers.

Antibody-Calixarene Drug Conjugate: A General Drug Delivery Platform for Tumor-Targeted Therapy.

Antibody-drug conjugates (ADCs), which combine the precise targeting capabilities of antibodies with the powerful cytotoxicity of small-molecule drugs, have evolved into a promising approach for tumor treatment. However, the traditional covalent coupling method requires the design of a specific linker tailored to the properties of the small-molecule drugs, which greatly limits the development of ADCs and the range of drugs that can be used. Herein, a novel type of antibody-calixarene drug conjugates (ACDCs) that function similarly to ADCs by delivering drugs to their targets using antibodies but without the requirement of covalent conjugation of the drugs with antibodies is presented. By replacement of conventional linkers with supramolecular linkers, the ACDCs can load various chemotherapeutic drugs through host-guest interactions. Furthermore, ACDCs are readily reduced upon reaching the hypoxic microenvironment, resulting in rapid release of the drugs. With this precise drug encapsulation and controlled release mechanism, ACDCs deliver drugs to tumor tissues effectively and achieve a significantly enhanced antitumor effect. Considering that the ACDCs can be easily prepared by combining antibody-calixarene conjugates derived from tumor-targeting antibodies with various small-molecule drugs, ACDCs may provide a promising platform technology to accelerate ADC development and thus improve the therapeutic efficacy of chemotherapy.

Natural-source Payloads used in the conjugated drugs architecture for cancer therapy: Recent advances and future directions.

Drug conjugates are obtained from tumor-located vectors connected to cytotoxic agents via linkers, which are designed to deliver hyper-toxic payloads directly to targeted cancer cells. These drug conjugates include antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), small molecule-drug conjugates (SMDCs), nucleic acid aptamer-drug conjugates (ApDCs), and virus-like drug conjugate (VDCs), which show great therapeutic value in the clinic. Drug conjugates consist of a targeting carrier, a linker, and a payload. Payloads are key therapy components. Cytotoxic molecules and their derivatives derived from natural products are commonly used in the payload portion of conjugates. The ideal payload should have sufficient toxicity, stability, coupling sites, and the ability to be released under specific conditions to kill tumor cells. Microtubule protein inhibitors, DNA damage agents, and RNA inhibitors are common cytotoxic molecules. Among these conjugates, cytotoxic molecules of natural origin are summarized based on their mechanism of action, conformational relationships, and the discovery of new derivatives. This paper also mentions some cytotoxic molecules that have the potential to be payloads. It also summarizes the latest technologies and novel conjugates developed in recent years to overcome the shortcomings of ADCs, PDCs, SMDCs, ApDCs, and VDCs. In addition, this paper summarizes the clinical trials conducted on conjugates of these cytotoxic molecules over the last five years. It provides a reference for designing and developing safer and more efficient conjugates.

Toxicokinetics of 2-ethylhexyl salicylate (EHS) and its seven metabolites in humans after controlled single dermal exposure to EHS.

The chemical UV filter 2-ethylhexyl salicylate (EHS) is used in various personal-care products. The dermal and oral metabolism of EHS have already been targeted by different studies. However, toxicokinetic data after a single dermal exposure to EHS was missing. In our study, three volunteers were dermally exposed to a commercial EHS-containing sunscreen for 9 h with an application dose of 2 mg sunscreen per cm2 body surface area. The exposure was performed indoors, and sunscreen was applied on about 75% of the total skin area. Complete urine voids were collected over 72 h and eight blood samples were drawn from each subject. Urine samples were analyzed for EHS and seven known metabolites (5OH-EHS, 4OH-EHS, 2OH-EHS, 6OH-EHS, 4oxo-EHS, 5oxo-EHS, and 5cx-EPS) by online-SPE UPLC MS/MS. The peaks of urinary elimination occurred 10-11 h after application. The elimination half-lives (Phase 1) were between 6.6 and 9.7 h. The dominant urinary biomarkers were EHS itself, followed by 5OH-EHS, 5cx-EPS, 5oxo-EHS, and 4OH-EHS. 2OH-EHS, 6OH-EHS, and 4oxo-EHS were detected only in minor amounts. An enhanced analysis of conjugation species revealed marginal amounts of unconjugated metabolites and up to 40% share of sulfate conjugates for 5OH-EHS, 5oxo-EHS, and 5cx-EPS. The results demonstrated a delayed systemic resorption of EHS via the dermal route. Despite an extensive metabolism, the parent compound occurred as main urinary parameter. The delayed dermal resorption as well as the slow elimination of EHS indicate an accumulation up to toxicological relevant doses during daily repeated dermal application to large skin areas.

Single-Domain Antibodies as Antibody-Drug Conjugates: From Promise to Practice-A Systematic Review.

BACKGROUND: Antibody-drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due to acquired resistance and potential side effects. OBJECTIVES: This study focuses on advances in various ADC components to improve both the efficacy and safety of these agents, and includes the analysis of several novel ADC formats. This work assesses whether the unique features of VHHs-such as their small size, enhanced tissue penetration, stability, and cost-effectiveness-make them a viable alternative to conventional antibodies for ADCs and reviews their current status in ADC development. METHODS: Following PRISMA guidelines, this study focused on VHHs as components of ADCs, examining advancements and prospects from 1 January 2014 to 30 June 2024. Searches were conducted in PubMed, Cochrane Library, ScienceDirect and LILACS using specific terms related to ADCs and single-domain antibodies. Retrieved articles were rigorously evaluated, excluding duplicates and non-qualifying studies. The selected peer-reviewed articles were analyzed for quality and synthesized to highlight advancements, methods, payloads, and future directions in ADC research. RESULTS: VHHs offer significant advantages for drug conjugation over conventional antibodies due to their smaller size and structure, which enhance tissue penetration and enable access to previously inaccessible epitopes. Their superior stability, solubility, and manufacturability facilitate cost-effective production and expand the range of targetable antigens. Additionally, some VHHs can naturally cross the blood-brain barrier or be easily modified to favor their penetration, making them promising for targeting brain tumors and metastases. Although no VHH-drug conjugates (nADC or nanoADC) are currently in the clinical arena, preclinical studies have explored various conjugation methods and linkers. CONCLUSIONS: While ADCs are transforming cancer treatment, their unique mechanisms and associated toxicities challenge traditional views on bioavailability and vary with different tumor types. Severe toxicities, often linked to compound instability, off-target effects, and nonspecific blood cell interactions, highlight the need for better understanding. Conversely, the rapid distribution, tumor penetration, and clearance of VHHs could be advantageous, potentially reducing toxicity by minimizing prolonged exposure. These attributes make single-domain antibodies strong candidates for the next generation of ADCs, potentially enhancing both efficacy and safety.

Novel antibody-drug conjugates based on DXd-ADC technology.

In recent years, antibody-drug conjugate (ADC) technology, which uses monoclonal antibodies (mAbs) to specifically deliver effective cytotoxic payloads to tumor cells, has become a promising method of tumor targeted therapy. ADCs are a powerful class of biopharmaceuticals that link antibodies targeting specific antigens and small molecule drugs with potent cytotoxicity via a linker, thus enabling selective destruction of cancer cells while minimizing systemic toxicity. DXd is a topoisomerase I inhibitor that induces DNA damage leading to cell cycle arrest, making it an option for ADC payloads. The DXd-ADC technology, developed by Daiichi Sankyo, is a cutting-edge platform that produces a new generation of ADCs with improved therapeutic metrics and has shown significant therapeutic potential in various types of cancer. This review provides a comprehensive assessment of drugs developed with DXd-ADC technology, with a focus on mechanisms of action, pharmacokinetics studies, preclinical data, and clinical outcomes for DS-8201a, U3-1402, DS-1062a, DS-7300a, DS-6157a, and DS-6000a. By integrating existing data, we aim to provide valuable insights into the current therapeutic status and future prospects of these novel agents.

Rapid identification of the aging time of Liupao tea using AI-multimodal fusion sensing technology combined with analysis of tea polysaccharide conjugates.

Identifying the aging time of Liu-Pao Tea (LPT) presents a persistent challenge. We utilized an AI-Multimodal fusion method combining FTIR, E-nose, and E-tongue to discern LPT's aging years. Compared to single-source and two-source fusion methods, the three-source fusion significantly enhanced identifying accuracy across all four machine learning algorithms (Decision tree, Random forest, K-nearest neighbor, and Partial least squares Discriminant Analysis), achieving optimal accuracy of 98-100 %. Physicochemical analysis revealed monotonic variations in tea polysaccharide (TPS) conjugates with aging, observed through SEM imaging as a transition from lamellar to granular TPS conjugate structures. These quality changes were reflected in FTIR spectral characteristics. Two-dimensional correlation spectroscopy (2D-COS) identified sensitive wavelength regions of FTIR from LPT and TPS conjugates, indicating a high similarity in spectral changes between TPS conjugates and LPT with aging years, highlighting the significant role of TPS conjugates variation in LPT quality. Additionally, we established an index for evaluating quality of aging, which is sum of three fingerprint peaks (1029 cm-1, 1635 cm-1, 2920 cm-1) intensities. The index could effectively signify the changes in aging years on macro-scale (R2 = 0.94) and micro-scale (R2 = 0.88). These findings demonstrate FTIR's effectiveness in identifying aging time, providing robust evidence for quality assessment.

Unraveling molecular aberrations and pioneering therapeutic strategies in osteosarcoma.

Osteosarcoma, a rare primary bone cancer, presents diverse molecular aberrations that underscore its complexity. Despite the persistent endeavors by researchers, the limited amelioration in the five-year survival rate indicates that current therapeutic strategies prove inadequate in addressing the clinical necessities. Advancements in molecular profiling have facilitated an enhanced comprehension of the biology of osteosarcoma, offering a promising outlook for treatment. There is an urgent need to develop innovative approaches to address the complex challenges of osteosarcoma, ultimately contributing to enhanced patient outcomes. This review explores the nexus between osteosarcoma and cancer predisposition syndromes, intricacies in its somatic genome, and clinically actionable alterations. This review covers treatment strategies, including surgery, chemotherapy, immune checkpoint inhibitors (ICIs), and tyrosine kinase inhibitors (TKIs). Innovative treatment modalities targeting diverse pathways, including multi-target tyrosine kinases, cell cycle, PI3K/mTOR pathway, and DNA damage repair (DDR), offer promising interventions. This review also covers promising avenues, including antibody-drug conjugates (ADCs) and immunotherapy strategies, such as cytokines, adoptive cellular therapy (ACT), ICIs, and cancer vaccines. This comprehensive exploration contributes to a holistic understanding, offering guidance for clinical applications to advance the management of osteosarcoma.

Advances in analytical technologies for emerging drug modalities and their separation challenges in LC-MS systems.

The last few years have seen a rise in the identification and development of bio-therapeutics through the use of cutting-edge delivery methods or bio-formulations, which has created bio-analytical difficulties. Every year, new bio-pharmaceutical product innovations come out, but the analytical development of these products is challenging. Quantifying the products and components of conjugated molecular structures is essential for preclinical and clinical research in order to guide therapeutic development, given their intrinsic complexity. Furthermore, a significant amount of information is needed for the measurement of these unique modalities by LC-MS techniques. Numerous LC-MS based methods have been developed, including AEX-HPLC-MS, RP-IP-LCMS, HILIC-MS, LCHRMS, Microflow-LC-MS, ASMS, Hybrid LBA/LC-MS, and more. However, these methods continue to face problems, prompting the development of alternative approaches. Therefore, developing bio-molecules that are this complicated and, low in concentration requires a skilled LC-MS based approach and knowledgeable personnel. This review covers general novel modalities classifications, sample preparation techniques, current status and bio-analytical strategies for analyzing various novel modalities, including gene bio-therapeutics, oligonucleotides, antibody-drug conjugates, monoclonal antibodies and PROTACs. It also covers how these strategies have been used in the past and how they are being used now to address challenges in the development of LC-MS based methods, as well as improvement strategies, current advancements and recent developed methods. We additionally covered on the benefits and drawbacks of different LC-MS based techniques for the examination of bio-pharmaceutical products and the future perspectives.

Double Agents in Immunotherapy: Unmasking the Role of Antibody Drug Conjugates in Immune Checkpoint Targeting.

Antibody-drug conjugates (ADCs) have high specificity with lesser off-target effects, thus providing improved efficacy over traditional chemotherapies. A total of 14 ADCs have been approved for use against cancer by the US Food and Drug Administration (FDA), with more than 100 ADCs currently in clinical trials. Of particular interest ADCs targeting immune antigens PD-L1, B7-H3, B7-H4 and integrins. Specifically, we describe ADCs in development along with the gene and protein expression of these immune checkpoints across a wide range of cancer types. let url = window.clickTag || window.clickTag1 || window.clickTag2 || window.clickTag3 || window.clickTag4 || window.bsClickTAG || window.bsClickTAG1 || window.bsClickTAG2 || window.url || ''; if(typeof url == 'string'){ document.body.dataset['perxceptAdRedirectUrl'] = url;}.

A Targeted Click-to-Release Activation of the Last-Resort Antibiotic Colistin Reduces its Renal Cell Toxicity.

The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically-triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click-to-release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse-electron-demand Diels-Alder reaction between trans-cyclooctenes (TCO) and the amine-functionalized tetrazine Tz7. The antibiotic activity of colistin against Escherichia coli was masked by TCO units, but restored upon reaction with d-Ubi-Tz, a tetrazine functionalised with the bacterial binding peptide d-Ubi29-41. While standard TCO did not improve toxicity against human proximal tubular kidney HK-2 cells, the installation of an aspartic acid-modified TCO masking group reduced the overall charge of the peptide and entry to the kidney cells, thereby dramatically lowering its toxicity. The analog Col-(TCO-Asp)1 had favourable pharmacokinetic properties in mice and was successfully activated locally in the lung by d-Ubi-Tz in an in vivo infection model, whereas it remained inactive and non-harmful without the chemical trigger. This study constitutes the first example of a systemically acting two-component antibiotic with improved drug tolerability.

Development of amphipathic derivatives of thymol and carvacrol as potent broad-spectrum antibacterial agents.

In the current study, to discover novel antibacterial agents, we designed and synthesized 72 carvacrol and thymol derivatives by biomimicking the structure and function of cationic antimicrobial peptides (AMPs). Many of the derivatives showed good antibacterial activity, and compound thy2I exhibited the most potent antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.5 µg/mL to 8 µg/mL. Compound thy2I could kill both gram-positive and gram-negative bacteria via a membrane-targeting mechanism of action with a low frequency of resistance. In addition, thy2I had the advantages of good membrane selectivity, low toxicity in vitro and in vivo, and good plasma stability. The in vivo activity results revealed that thy2I exhibited a positive therapeutic effect in a mouse skin abscess model induced by Staphylococcus aureus ATCC29213. After thy2I treatment (10 mg/kg), the bacterial load of the S. aureus-infected abscesses was reduced by approximately 99.65 %. Our study suggests that thy2I may serve as an antibacterial lead for further clinical evaluation.

Advanced Application of Polymer Nanocarriers in Delivery of Active Ingredients from Traditional Chinese Medicines.

Active ingredients from Traditional Chinese Medicines (TCMs) have been a cornerstone of healthcare for millennia, offering a rich source of bioactive compounds with therapeutic potential. However, the clinical application of TCMs is often limited by challenges such as poor solubility, low bioavailability, and variable pharmacokinetics. To address these issues, the development of advanced polymer nanocarriers has emerged as a promising strategy for the delivery of TCMs. This review focuses on the introduction of common active ingredients from TCMs and the recent advancements in the design and application of polymer nanocarriers for enhancing the efficacy and safety of TCMs. We begin by discussing the unique properties of TCMs and the inherent challenges associated with their delivery. We then delve into the types of polymeric nanocarriers, including polymer micelles, polymer vesicles, polymer hydrogels, and polymer drug conjugates, highlighting their application in the delivery of active ingredients from TCMs. The main body of the review presents a comprehensive analysis of the state-of-the-art nanocarrier systems and introduces the impact of these nanocarriers on the solubility, stability, and bioavailability of TCM components. On the basis of this, we provide an outlook on the future directions of polymer nanocarriers in TCM delivery. This review underscores the transformative potential of polymer nanocarriers in revolutionizing TCM delivery, offering a pathway to harness the full therapeutic potential of TCMs while ensuring safety and efficacy in a modern medical context.

Kinetic models towards an enhanced understanding of diverse ADC conjugation reactions.

The conjugation reaction is the central step in the manufacturing process of antibody-drug conjugates (ADCs). This reaction generates a heterogeneous and complex mixture of differently conjugated sub-species depending on the chosen conjugation chemistry. The parametrization of the conjugation reaction through mechanistic kinetic models offers a chance to enhance valuable reaction knowledge and ensure process robustness. This study introduces a versatile modeling framework for the conjugation reaction of cysteine-conjugated ADC modalities-site-specific and interchain disulfide conjugation. Various conjugation kinetics involving different maleimide-functionalized payloads were performed, while controlled gradual payload feeding was employed to decelerate the conjugation, facilitating a more detailed investigation of the reaction mechanism. The kinetic data were analyzed with a reducing reversed phase (RP) chromatography method, that can readily be implemented for the accurate characterization of ADCs with diverse drug-to-antibody ratios, providing the conjugation trajectories of the single chains of the monoclonal antibody (mAb). Possible kinetic models for the conjugation mechanism were then developed and selected based on multiple criteria. When calibrating the established model to kinetics involving different payloads, conjugation rates were determined to be payload-specific. Further conclusions regarding the kinetic comparability across the two modalities could also be derived. One calibrated model was used for an exemplary in silico screening of the initial concentrations offering valuable insights for profound understanding of the conjugation process in ADC development.

Antibody-drug conjugates in cancer therapy: mechanisms and clinical studies.

Antibody-drug conjugates (ADCs) consist of monoclonal antibodies that target tumor cells and cytotoxic drugs linked through linkers. By leveraging antibodies' targeting properties, ADCs deliver cytotoxic drugs into tumor cells via endocytosis after identifying the tumor antigen. This precise method aims to kill tumor cells selectively while minimizing harm to normal cells, offering safe and effective therapeutic benefits. Recent years have seen significant progress in antitumor treatment with ADC development, providing patients with new and potent treatment options. With over 300 ADCs explored for various tumor indications and some already approved for clinical use, challenges such as resistance due to factors like antigen expression, ADC processing, and payload have emerged. This review aims to outline the history of ADC development, their structure, mechanism of action, recent composition advancements, target selection, completed and ongoing clinical trials, resistance mechanisms, and intervention strategies. Additionally, it will delve into the potential of ADCs with novel markers, linkers, payloads, and innovative action mechanisms to enhance cancer treatment options. The evolution of ADCs has also led to the emergence of combination therapy as a new therapeutic approach to improve drug efficacy.

Receptor tyrosine kinase-like orphan receptor serves as a potential target in cancer immunotherapy.

Receptor tyrosine kinase-like orphan receptor (ROR), consisting of ROR1 and ROR2, is a conserved family of receptor tyrosine kinase superfamily that plays crucial roles during embryonic development with limited expression in adult normal tissues. However, it is overexpressed in a range of hematological malignancies and solid tumors and functions in cellular processes including cell survival, polarity, and migration, serving as a potential target in cancer immunotherapy. This review summarizes the expression and structure of ROR in developmental morphogenesis and its function in cancers associated with Wnt5a signaling and highlights the cancer immunotherapy strategies targeting ROR.

Antibody-drug conjugates combinations in cancer treatment.

Antibody-drug conjugates (ADCs) have emerged as a promising class of anticancer agents. Currently, the Food and Drug Administration has granted approval to 12 compounds, with 2 later undergoing withdrawal. Moreover, several other compounds are currently under clinical development at different stages. Despite substantial antitumoral activity observed among different tumor types, adverse events and the development of resistance represent significant challenges in their use. Over the last years, an increasing number of clinical trials have been testing these drugs in different combinations with other anticancer agents, such as traditional chemotherapy, immune checkpoint inhibitors, monoclonal antibodies, and small targeted agents, reporting promising results based on possible synergistic effects and a potential for improved treatment outcomes among different tumor types. Here we will review combinations of ADCs with other antitumor agents aiming at describing the current state of the art and future directions.

Soy protein-polyphenols conjugates interaction mechanism, characterization, techno-functional and biological properties: An updated review.

Soy protein is a promising nutritional source with improved functionality and bioactivities due to conjugation with polyphenols (PP)-the conjugates between soy protein and PP held by covalent and noncovalent bonds. Different approaches, including thermodynamics, spectroscopy, and molecular docking simulations, can demonstrate the outcomes and mechanism of these conjugates. The soy protein, PP structure, matrix properties (temperature, pH), and interaction mechanism alter the ζ-potential, secondary structure, thermal stability, and surface hydrophobicity of proteins and also improve the techno-functional properties such as gelling ability, solubility, emulsifying, and foaming properties. Soy protein-PP conjugates also reveal enhanced in vitro digestibility, anti-allergic, antioxidant, anticancer, anti-inflammatory, and antimicrobial activities. Thus, these conjugates may be employed as edible film additives, antioxidant emulsifiers, hydrogels, and nanoparticles in the food industry. Future research is needed to specify the structure-function associations of soy protein-PP conjugates that may affect their functionality and application in the food industry.

Exploring membranous NECTIN-4 expression patterns and enfortumab vedotin response in prostate cancer.

Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130-150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.

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 synthesise 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 tumour characteristics to enrich drugs in liver tumours. 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 optimising 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.