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The purpose of this work was to construct liver-targeted nanoparticles based on the redox response to effectively deliver cannabidiol (CBD) for the prevention of acute liver injury (ALI). CBD-loaded nanoparticles (CBD NPs) with a particle size of 126.5 ± 1.56 nm were prepared using the polymer DA-PP-LA obtained by grafting pullulan polysaccharide with deoxycholic acid (DA) and α-lipoic acid (α-LA). CBD NPs showed typical redox-response release behavior. Interestingly, CBD NPs exhibited admirable liver targeting ability, significantly accumulated in the liver, and effectively promoted the internalization of CBD in liver cells, thus effectively reducing the H2O2-induced oxidative damage of HepG2 cells and avoiding apoptosis. More importantly, CBD NPs effectively prevented CCl4-induced ALI by protecting liver function, ameliorating oxidative stress levels, inhibiting the production of inflammatory factors, and protecting the liver from histological damage. This study provides a promising strategy for achieving targeted delivery of CBD NPs in the liver, thereby effectively preventing ALI.
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Background: Cancer is a serious threat to human life, health and social development. In recent years, nanomicelles, as an emerging drug carrier material, have gradually entered people's field of vision because of their advantages of improving bioavailability, maintaining drug levels, reducing systemic side effects and increasing drug accumulation at target sites. Methods: In this study, B-GPSG nano-micelles were prepared by film dispersion hydration method using brucine as model drug and glycyrrhetinic acid-polyethylene glycol-3-methylene glycol-dithiodipropionic acid-glycerol monostearate polymer as nano-carrier. The preparation process, characterization, drug release in vitro, pharmacokinetics and liver targeting were investigated. Results: The results showed that the range of particle size, polydispersion index and Zeta potential were 102.7 ± 1.09 nm, 0.201 ± 0.02 and -24.5 ± 0.19 mV respectively. The entrapment efficiency and drug loading were 83.79 ± 2.13% and 12.56 ± 0.09%, respectively. The drug release experiments in vitro and pharmacokinetic experiments showed that it had obvious sustained release effect. For pharmacokinetics study, it shows that both the B-GPSG solution group and the B-PSG solution group changed the metabolic kinetic parameters of brucine, but the B-GPSG solution group had a better effect. Compared with the B-PSG solution group, the drug was more prolonged in rats. The half-life in the body and the retention time in the body of B-GPSG are more helpful to improve the bioavailability of the drug and play a long-term effect. The tail vein injection results of mice indicate that B-GPSG can target and accumulate brucine in the liver without affecting other key organs. Cell uptake experiments and tissue distribution experiments in vivo show that glycyrrhetinic acid modified nano-micelles can increase the accumulation of brucine in hepatocytes, has a good liver targeting effect, and can be used as a new preparation for the treatment of liver cancer. Conclusion: The B-SPSG prepared in this experiment can provide a new treatment method and research idea for the treatment of liver cancer.
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Liver fibrosis (LF) is a pathological repair reaction caused by a chronic liver injury that affects the health of millions of people worldwide, progressing to life-threatening cirrhosis and liver cancer without timely intervention. Due to the complexity of LF pathology, multiple etiological characteristics, and the deposited extracellular matrix, traditional drugs cannot reach appropriate targets in a time-space matching way, thus decreasing the therapeutic effect. Nanoparticle drug delivery systems (NDDS) enable multidrug co-therapy and develop multifactor delivery strategies targeting pathological processes, showing great potential in LF therapy. Based on the pathogenesis and the current clinical treatment status of LF, we systematically elucidate the targeting mechanism of NDDS used in the treatment of LF. Subsequently, we focus on the progress of drug delivery applications for LF, including combined delivery for the liver fibrotic pathological environment, overcoming biological barriers, precise intracellular regulation, and intelligent responsive delivery for the liver fibrotic microenvironment. We hope that this review will inspire the rational design of NDDS for LF in the future in order to provide ideas and methods for promoting LF regression and cure.
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Cirrosis Hepática , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Animales , Sistema de Administración de Fármacos con Nanopartículas/química , Sistemas de Liberación de Medicamentos , Nanopartículas/químicaRESUMEN
The formulation of novel delivery protocols for the targeted delivery of genes into hepatocytes by receptor mediation is important for the treatment of liver-specific disorders, including cancer. Non-viral delivery methods have been extensively studied for gene therapy. Gold nanoparticles (AuNPs) have gained attention in nanomedicine due to their biocompatibility. In this study, AuNPs were synthesized and coated with polymers: chitosan (CS), and polyethylene glycol (PEG). The targeting moiety, lactobionic acid (LA), was added for hepatocyte-specific delivery. Physicochemical characterization revealed that all nano-formulations were spherical and monodispersed, with hydrodynamic sizes between 70 and 250 nm. Nanocomplexes with pCMV-Luc DNA (pDNA) confirmed that the NPs could bind, compact, and protect the pDNA from nuclease degradation. Cytotoxicity studies revealed that the AuNPs were well tolerated (cell viabilities > 70%) in human hepatocellular carcinoma (HepG2), embryonic kidney (HEK293), and colorectal adenocarcinoma (Caco-2) cells, with enhanced transgene activity in all cells. The inclusion of LA in the NP formulation was notable in the HepG2 cells, which overexpress the asialoglycoprotein receptor on their cell surface. A five-fold increase in luciferase gene expression was evident for the LA-targeted AuNPs compared to the non-targeted AuNPs. These AuNPs have shown potential as safe and suitable targeted delivery vehicles for liver-directed gene therapy.
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Quitosano , Técnicas de Transferencia de Gen , Oro , Neoplasias Hepáticas , Nanopartículas del Metal , Humanos , Oro/química , Nanopartículas del Metal/química , Células Hep G2 , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/genética , Quitosano/química , Células HEK293 , Receptor de Asialoglicoproteína/metabolismo , Receptor de Asialoglicoproteína/genética , Células CACO-2 , Luciferasas/genética , Luciferasas/metabolismo , Polietilenglicoles/química , Plásmidos/genética , Disacáridos/química , Terapia Genética/métodos , Polímeros/química , Supervivencia Celular/efectos de los fármacosRESUMEN
Activatable near-infrared (NIR) fluorogenic probes offer a potent tool for real-time, in situ detection of hepatic biomarkers, significantly advancing the precision in diagnosing inflammatory liver disease (ILD). However, the limited distribution of small molecule fluorogenic probes in the liver and their rapid clearance impair the accuracy of fluorescence imaging and in ILD diagnosis. In this study, an effective utilization of ionizable lipid nanoparticles (iLNPs) is presented as liver-targeted carriers for efficient delivery of fluorogenic probes, aiming to overcome biodistribution barriers and achieve accurate detection of hepatic biomarkers. Based on this strategy, a liver-targeted NIR fluorogenic nanoprobe hCy-H2O2@iLNP is prepared using hCy-H2O2 as a small molecule reporter for visualizing the over-produced hydrogen peroxide (H2O2) in situ of liver. Notably, iLNPs not only significantly enhance probe accumulation in the liver, but also enable sequence activation of fluorescent nanoprobes. This response is achieved through primary liposome-dissociation release and secondary hCy-H2O2 response with pathological H2O2, enabling high-precision detection of oxidative stress in hepatocytes. These distinctive features facilitate accurate early diagnosis of acetaminophen (APAP)-induced inflammatory liver injury as well as lipopolysaccharide (LPS)-induced hepatitis. Therefore, the organ-targeted nanoprobe design strategy showcasts great potential for early and accurate diagnosis of lesions in situ in different organs.
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Improving target versus off-target ratio in nanomedicine remains a major challenge for increasing drug bioavailability and reducing toxicity. Active targeting using ligands on nanoparticle surfaces is a key approach but has limited clinical success. A potential issue is the integration of targeting ligands also changes the physicochemical properties of nanoparticles (passive targeting). Direct studies to understand the mechanisms of active targeting and off-targeting in vivo are limited by the lack of suitable tools. Here, the biodistribution of a representative active targeting liposome is analyzed, modified with an apolipoprotein E (ApoE) peptide that binds to the low-density lipoprotein receptor (LDLR), using zebrafish embryos. The ApoE liposomes demonstrated the expected liver targeting effect but also accumulated in the kidney glomerulus. The ldlra-/- zebrafish is developed to explore the LDLR-specificity of ApoE liposomes. Interestingly, liver targeting depends on the LDLR-specific interaction, while glomerular accumulation is independent of LDLR and peptide sequence. It is found that cationic charges of peptides and the size of liposomes govern glomerular targeting. Increasing the size of ApoE liposomes can avoid this off-targeting. Taken together, the study shows the potential of the zebrafish embryo model for understanding active and passive targeting mechanisms, that can be used to optimize the design of nanoparticles.
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Apolipoproteínas E , Liposomas , Péptidos , Receptores de LDL , Pez Cebra , Animales , Liposomas/química , Receptores de LDL/metabolismo , Péptidos/química , Apolipoproteínas E/metabolismo , Embrión no Mamífero/metabolismo , Nanopartículas/químicaRESUMEN
Endocrine therapy is standard for hormone receptor-positive (HR+) breast cancer treatment. However, current strategies targeting estrogen signaling pay little attention to estradiol metabolism in the liver and is usually challenged by treatment failure. In a previous study, we demonstrated that the natural compound naringenin (NAR) inhibited HR+ breast cancer growth by activating estrogen sulfotransferase (EST) expression in the liver. Nevertheless, the poor water solubility, low bio-barrier permeability, and non-specific distribution limited its clinical application, particularly for oral administration. Here, a novel nano endocrine drug NAR-cell penetrating peptide-galactose nanoparticles (NCG) is reported. We demonstrated that NCG presented specific liver targeting and increased intestinal barrier permeability in both cell and zebrafish xenotransplantation models. Furthermore, NCG showed liver targeting and enterohepatic circulation in mouse breast cancer xenografts following oral administration. Notably, the cancer inhibition efficacy of NCG was superior to that of both NAR and the positive control tamoxifen, and was accompanied by increased hepatic EST expression and reduced estradiol levels in the liver, blood, and tumor tissue. Moreover, few side effects were observed after NCG treatment. Our findings reveal NCG as a promising candidate for endocrine therapy and highlight hepatic EST targeting as a novel therapeutic strategy for HR+ breast cancer.
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Neoplasias de la Mama , Flavanonas , Nanopartículas , Humanos , Ratones , Animales , Femenino , Neoplasias de la Mama/patología , Pez Cebra/metabolismo , Receptores de Estrógenos/metabolismo , Estrógenos/metabolismo , Estrógenos/uso terapéutico , Tamoxifeno/farmacología , Estradiol/farmacología , Hígado/metabolismoRESUMEN
Liver diseases are a significant global health burden and are among the most common diseases. Ginssennoside Rg3 (Rg3), which is one of the most abundant ginsenosides, has been found to have significant preventive and therapeutic effects against various types of diseases with minimal side effects. Numerous studies have demonstrated the significant preventive and therapeutic effects of Rg3 on various liver diseases such as viral hepatitis, acute liver injury, nonalcoholic liver diseases (NAFLD), liver fibrosis and hepatocellular carcinoma (HCC). The underlying molecular mechanism behind these effects is attributed to apoptosis, autophagy, antioxidant, anti-inflammatory activities, and the regulation of multiple signaling pathways. This review provides a comprehensive description of the potential molecular mechanisms of Rg3 in the development of liver diseases. The article focuses on the regulation of apoptosis, oxidative stress, autophagy, inflammation, and other related factors. Additionally, the review discusses combination therapy and liver targeting strategy, which can accelerate the translation of Rg3 from bench to bedside. Overall, this article serves as a valuable reference for researchers and clinicians alike.
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OBJECTIVE: To enhance the retention times and therapeutic efficacy of paeoniflorin (PF), a liver-targeted drug delivery system has been developed using glycyrrhetinic acid (GA) as a ligand. SIGNIFICANCE: The development and optimization of GA-modified PF liposomes (GPLs) have shown promising potential for targeted delivery to the liver, opening up new possibilities for liver disease treatment. METHODS: This study aimed to identify the best prescriptions using single-factor experiments and response surface methodology. The formulation morphology was determined using transmission electron microscopy. Tissue distribution was observed through in vivo imaging, and pharmacokinetic studies were conducted. RESULTS: The results indicated that GPLs, prepared using the thin film dispersion method and response surface optimization, exhibited well-dispersed and uniformly sized particles. The in vitro release rate of GPLs was slower compared to PF monomers, suggesting a sustained release effect. The liver-targeting ability of GA resulted in stronger fluorescence signals in the liver for targeted liposomes compared to non-targeted liposomes. Furthermore, pharmacokinetic studies demonstrated that GPLs significantly prolonged the residence time of PF in the bloodstream, thereby contributing to prolonged efficacy. CONCLUSION: These findings suggest that GPLs are more effective than PF monomers in terms of controlling drug release and delivering drugs to specific targets, highlighting the potential of PF as a liver-protective drug.
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Glucósidos , Ácido Glicirretínico , Liposomas , Monoterpenos , Liposomas/farmacología , Ácido Glicirretínico/farmacología , Hígado , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Liver fibrosis is mainly caused by excessive accumulation of extracellular matrix and structural changes in the liver, ultimately leading to cirrhosis if left untreated. Reducing hyaluronan synthesis by inhibiting hyaluronic acid deposition or regulating the expression of hyaluronic synthase can ameliorate liver fibrosis symptoms. In this study, we aimed to improve the bioavailability and liver-targeting capacity of hydroxymethyl coumarin (4-MU) using a newly developed phospholipid complex chitosan nanoparticle (4-MU PC/CNP) optimized using the Box-Behnken design. The composite nanocarrier delivery system was formulated using solvent evaporation technology, and formulation and process parameters were evaluated. Furthermore, 4-MU PC/CNPs and their pharmacokinetics were characterized. The established 4-MU PC/CNPs had an average particle size of 153.07 ± 0.29 nm, a polydispersity index value of 0.383, and a positive zeta potential of â¼35.4 mV. Compared with 4-MUs, 4-MU PC/CNPs exhibited significantly improved water solubility, faster plasma clearance and tissue distribution, and better liver targeting. Pharmacokinetic analysis showed that the oral bioavailability of 4-MU in 4-MU PC/CNPs was significantly higher than that of simple 4-MU. In conclusion, 4-MU PC improved drug lipid (oil-water distribution coefficient of 1.31 ± 0.03) and water solubilities (2.05 times the drug substance). 4-MU PC/CNPs significantly improved 4-MU oral bioavailability, representing a promising approach for enhancing drug solubility. This study demonstrates that the targeting parameters of 4-MU PC/CNPs in the liver were all greater than 1, indicating that they specifically targeted the liver, thereby potentially alleviating liver fibrosis.
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Quitosano , Nanopartículas , Humanos , Fosfolípidos/química , Quitosano/química , Agua , Nanopartículas/química , Cirrosis HepáticaRESUMEN
The 3-succinate-30-stearyl glycyrrhetinic acid(18-GA-Suc) was inserted into glycyrrhetinic acid(GA)-tanshinone â ¡_A(TSN)-salvianolic acid B(Sal B) liposome(GTS-lip) to prepare liver targeting compound liposome(Suc-GTS-lip) mediated by GA receptors. Next, pharmacokinetics and tissue distribution of Suc-GTS-lip and GTS-lip were compared by UPLC, and in vivo imaging tracking of Suc-GTS-lip was conducted. The authors investigated the effect of Suc-GTS-lip on the proliferation inhibition of hepatic stellate cells(HSC) and explored their molecular mechanism of improving liver fibrosis. Pharmacokinetic results showed that the AUC_(Sal B) decreased from(636.06±27.73) µg·h·mL~(-1) to(550.39±12.34) µg·h·mL~(-1), and the AUC_(TSN) decreased from(1.08±0.72) µg·h·mL~(-1) to(0.65±0.04) µg·h·mL~(-1), but the AUC_(GA) increased from(43.64±3.10) µg·h·mL~(-1) to(96.21±3.75) µg·h·mL~(-1). The results of tissue distribution showed that the AUC_(Sal B) and C_(max) of Sal B in the liver of the Suc-GTS-lip group were 10.21 and 4.44 times those of the GTS-lip group, respectively. The liver targeting efficiency of Sal B, TSN, and GA in the Suc-GTS-lip group was 40.66%, 3.06%, and 22.08%, respectively. In vivo imaging studies showed that the modified liposomes tended to accumulate in the liver. MTT results showed that Suc-GTS-lip could significantly inhibit the proliferation of HSC, and RT-PCR results showed that the expression of MMP-1 was significantly increased in all groups, but that of TIMP-1 and TIMP-2 was significantly decreased. The mRNA expressions of collagen-I and collagen-â ¢ were significantly decreased in all groups. The experimental results showed that Suc-GTS-lip had liver targeting, and it could inhibit the proliferation of HSC and induce their apoptosis, which provided the experimental basis for the targeted treatment of liver fibrosis by Suc-GTS-lip.
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Ácido Glicirretínico , Liposomas , Humanos , Células Estrelladas Hepáticas , Ácido Glicirretínico/farmacología , Hígado , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/genética , Colágeno/farmacologíaRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is caused by an accumulation of excess fat in the liver leading to oxidative stress and liver cell injury, as well as overproduction of inflammatory cytokines. CD44 has been identified as a potential therapeutic target in the development of NAFLD to nonalcoholic steatohepatitis. Here, chondroitin sulfate (CS) is selected to construct a CD44-targeted delivery system for the treatment of NAFLD. Specifically, two CS-derived amphiphilic materials including CS conjugated with either 4-aminophenylboronic acid pinacol ester (CS-PBE) or phenformin (CS-PFM) were synthesized, respectively. The presence of PBE moieties on CS-PBE rendered the vehicle with enhanced loading capacity and scavenging potential against reactive oxygen species, while the presence of guanidine moieties on CS-PFM enhanced the internalization of vehicles in the differentiated hepatocytes. Next, celastrol (CLT) was encapsulated in the hybrid micelle to afford CS-Hybrid/CLT, which demonstrates sufficient stability, enhanced cellular uptake efficiencies in differentiated HepG2 cells, and therapeutic potential to alleviate lipid accumulation in differentiated HepG2 cells. In a high-fat-diet-induced NAFLD rat model, CS-Hybrid/CLT micelles demonstrated the capacity to dramatically decrease hepatic lipid accumulation and free fatty acid levels with greatly improved pathologic liver histology and downregulated hepatic inflammation levels. These results suggest that CS-based amphiphilic micelles may offer a promising strategy to effectively deliver therapeutic cargos to the liver for the treatment of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Ratas , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Micelas , Sulfatos de Condroitina , LípidosRESUMEN
Sorafenib is an oral treatment for hepatocellular carcinoma (HCC). However, poor water solubility, harsh gastrointestinal environment and off-target effects contribute to the low bioavailability of oral sorafenib. Plant-derived extracellular vesicles (PDEVs) are biological nanovesicles with various bioactive functions that offer significant advantages in the field of oral drug delivery: protection from degradation by gastrointestinal fluids; crossing the intestinal epithelial barrier; specific targeting; safety; and abundant yield. However, there are fewer studies applying PDEVs for anti-tumor drug delivery to extra-digestive tissues. In this study, kiwifruit-derived extracellular vesicles (KEVs) were isolated and purified from kiwifruit, and their natural hepatic accumulation properties were exploited for targeted delivery of sorafenib (KEVs-SFB). Evidence showed that encapsulation of KEVs reduced the leakage of sorafenib in the gastrointestinal environment and enhanced the ability to cross the intestinal epithelium; KEVs-SFB was able to achieve liver accumulation and was predominantly taken up by HepG2 cells; KEVs-SFB was effective in inhibiting 4T1 cell proliferation; in the orthotopic liver cancer model, oral administration of KEVs-SFB inhibited tumor growth and improved the side effects of SFB. This PDEVs-based oral drug delivery platform is important for improving oral bioavailability and reducing drug side effects.
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Antineoplásicos , Carcinoma Hepatocelular , Vesículas Extracelulares , Neoplasias Hepáticas , Humanos , Sorafenib , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patología , Línea Celular TumoralRESUMEN
Optimization of metabolic regulation is a promising solution for many pathologies, including obesity, dyslipidemia, type 2 diabetes, and inflammatory liver disease. Synthetic thyroid hormone mimics-based regulation of metabolic balance in the liver showed promise but was hampered by the low biocompatibility and harmful effects on the extrahepatic axis. In this work, we show that specifically directing the thyromimetic to the liver utilizing a nanogel-based carrier substantially increased therapeutic efficacy in a diet-induced obesity mouse model, evidenced by the near-complete reversal of body weight gain, liver weight and inflammation, and cholesterol levels with no alteration in the thyroxine (T4) / thyroid stimulating hormone (TSH) axis. Mechanistically, the drug acts by binding to thyroid hormone receptor ß (TRß), a ligand-inducible transcription factor that interacts with thyroid hormone response elements and modulates target gene expression. The reverse cholesterol transport (RCT) pathway is specifically implicated in the observed therapeutic effect. Overall, the study demonstrates a unique approach to restoring metabolic regulation impacting obesity and related metabolic dysfunctions.
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OBJECTIVE: Arsenic trioxide (ATO) exerts therapeutic effects on various solid tumors, and artesunate (ART) synergizes with antitumor drugs. We herein combined ART and an ATO prodrug (ATOP) in pH-responsive and liver-targeting liposomes to improve targeted hepatocellular carcinoma (HCC) treatment. METHODS: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-hydrazone (HYD)-polyethylene glycol (PEG)-glycyrrhetinic acid (GA) (DSPE-HYD-PEG-GA) was synthesized and characterized. The optimal ratio of ART and ATOP was selected. Calcium arsenate nanoparticles (CaAs NPs) and DSPE-HYD-PEG-GA@ART/CaAs NPs liposomes were prepared and their physicochemical properties were characterized. Their intracellular uptake, intracellular localization, uptake pathway identification, cytotoxicity, proapoptotic effects, and relevant mechanisms were studied. RESULTS: The DSPE-HYD-PEG-GA was successfully synthesized. The best ratio of ART and ATOP was 7:1. The particle size of CaAs NPs under transmission electron microscopy was 142.39 ± 21.50 nm. Arsenic (As), calcium, and oxygen elements were uniformly distributed in CaAs NPs, and the drug loading and encapsulation efficiency of As are 37.28% and 51.40%, respectively. The liposomes were elliptical, and the particle size was 100.91 ± 39.31 nm. The liposome cell intake was significantly increased in Huh-7 cells. The liposomes entered the cell through macropinocytosis and caveolin-mediated endocytosis and were predominantly distributed in the cytoplasm. They exerted an excellent inhibitory effect on Huh-7 cells and promoted tumor cell apoptosis through lipid peroxidation, mitochondrial membrane potential reduction, and cell-cycle blockage. CONCLUSIONS: The pH-responsive and liver-targeting drug delivery system for the combination delivery of ART with ATOP showed promising effects on hepatocellular carcinoma (HCC).
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Profármacos , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Trióxido de Arsénico/farmacología , Trióxido de Arsénico/uso terapéutico , Profármacos/farmacología , Liposomas , Artesunato/farmacología , Artesunato/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Sistemas de Liberación de Medicamentos , Polietilenglicoles/química , Concentración de Iones de Hidrógeno , Línea Celular TumoralRESUMEN
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and it poses a significant risk to patients health and longevity due to its high morbidity and fatality rates. Surgical ablation, radiotherapy, chemotherapy, and, most recently, immunotherapy have all been investigated for HCC, but none have yielded the desired outcomes. Several unique nanocarrier drug delivery techniques have been studied for their potential therapeutic implications in the treatment of HCC. Nanoparticle-based imaging could be effective for more accurate HCC diagnosis. Since its inception, nanomedicine has significantly transformed the approach to both the treatment and diagnostics of liver cancer. Nanoparticles (NPs) are being studied as a potential treatment for liver cancer because of their ability to carry small substances, such as treatment with chemotherapy, microRNA, and therapeutic genes. The primary focus of this study is on the most current discoveries and practical uses of nanomedicine-based diagnostic and therapeutic techniques for liver cancer. In this section, we had gone over what we know about metabolic dysfunction in HCC and the treatment options that attempt to fix it by targeting metabolic pathways. Furthermore, we propose a multi-target metabolic strategy as a viable HCC treatment option. Based on the findings given here, the scientists believe that smart nanomaterials have great promise for improving cancer theranostics and opening up new avenues for tumor diagnosis and treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Nanopartículas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , MicroARNs/genética , Inmunoterapia , Nanopartículas/uso terapéuticoRESUMEN
Background: Alveolar echinococcosis (AE) is a lethal parasitic disease caused by infection with the metacestode of the dog/fox tapeworm Echinococcus multilocularis, which primarily affects the liver. Although continued efforts have been made to find new drugs against this orphan and neglected disease, the current treatment options remain limited, with drug delivery considered a likely barrier for successful treatment. Methods: Nanoparticles (NPs) have gained much attention in the field of drug delivery due to their potential to improve delivery efficiency and targetability. In this study, biocompatible PLGA nanoparticles encapsulating a novel carbazole aminoalcohol anti-AE agent (H1402) were prepared to promote the delivery of the parent drug to liver tissue for treating hepatic AE. Results: H1402-loaded nanoparticles (H1402-NPs) had a uniform spherical shape and a mean particle size of 55 nm. Compound H1402 was efficiently encapsulated into PLGA NPs with a maximal encapsulation efficiency of 82.1% and drug loading content of 8.2%. An in vitro uptake assay demonstrated that H1402-NPs rapidly penetrated the in vitro cultured pre-cyst wall and extensively accumulated in the pre-cysts of E. multilocularis within only 1 h. The biodistribution profile of H1402-NPs determined through ex vivo fluorescence imaging revealed significantly enhanced liver distribution compared to unencapsulated H1402, which translated to improved therapeutic efficacy and reduced systemic toxicity (especially hepatotoxicity and cytotoxicity) in a hepatic AE murine model. Following a 30-day oral regimen (100 mg/kg/day), H1402-NPs significantly reduced the parasitic burden in both the parasite mass (liver and metacestode total weight, 8.8%) and average metacestode size (89.9%) compared to unmedicated infected mice (both p-values < 0.05); the treatment outcome was more effective than those of albendazole- and free H1402-treated individuals. Conclusion: Our findings demonstrate the advantages of encapsulating H1402 into PLGA nanoparticles and highlight the potential of H1402-NPs as a promising liver-targeting therapeutic strategy for hepatic AE.
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Equinococosis Hepática , Equinococosis , Perros , Animales , Ratones , Equinococosis Hepática/tratamiento farmacológico , Distribución TisularRESUMEN
Commercial gadolinium (Gd)-based contrast agents (GBCAs) play important role in clinical diagnostic of hepatocellular carcinoma, but their diagnostic efficacy remained improved. As small molecules, the imaging contrast and window of GBCAs is limited by low liver targeting and retention. Herein, we developed a liver-targeting gadolinium (â ¢) chelated macromolecular MRI contrast agent based on galactose functionalized o-carboxymethyl chitosan, namely, CS-Ga-(Gd-DTPA)n, to improve hepatocyte uptake and liver retention. Compared to Gd-DTPA and non-specific macromolecular agent CS-(Gd-DTPA)n, CS-Ga-(Gd-DTPA)n showed higher hepatocyte uptake, excellent cell and blood biocompatibility in vitro. Furthermore, CS-Ga-(Gd-DTPA)n also exhibited higher relaxivity in vitro, prolonged retention and better T1-weighted signal enhancement in liver. At 10 days post-injection of CS-Ga-(Gd-DTPA)n at a dose of 0.03 mM Gd/Kg, Gd had a little accumulation in liver with no liver function damage. The good performance of CS-Ga-(Gd-DTPA)n gives great confidence in developing liver-specifc MRI contrast agents for clinical translation.
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A bifunctional hepatocyte-mitochondrion targeting nanosystem was prepared for astaxanthin by conjugating lactobionic acid (LA) and triphenylphosphonium-modified 2-hydroxypropyl-ß-cyclodextrin onto sodium alginate. Hepatocyte-targeting evaluation indicated that the fluorescence intensity of HepaRG cells treated with the bifunctional nanosystem increased 90.3%, which was greater than that (38.7%) of the LA-only targeted nanosystem. The Rcoloc was 0.81 for the bifunctional nanosystem in mitochondrion-targeting analysis, which was greater than that (0.62) of the LA-only targeted nanosystem. The reactive oxygen species (ROS) level of the astaxanthin bifunctional nanosystem treated group significantly reduced to 62.20%, lower than that of free astaxanthin (84.01%) and LA-only targeted group (73.83%). Mitochondrial membrane potential recovered 97.35% in the astaxanthin bifunctional nanosystem treated group while the LA-only targeted group recovered 77.45%. The accumulation of bifunctional nanosystem in liver increased by 31.01% compared to the control. These findings indicated that the bifunctional nanosystem was beneficial for astaxanthin delivery in the liver precision nutrition intervention.
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Hepatocitos , Hígado , Especies Reactivas de Oxígeno , MitocondriasRESUMEN
BACKGROUND & AIMS: A single hepatitis B virus (HBV) particle is sufficient to establish chronic infection of the liver after intravenous injection, suggesting that the virus targets hepatocytes via a highly efficient transport pathway. We therefore investigated whether HBV uses a physiological liver-directed pathway that supports specific host-cell targeting in vivo. METHODS: We established the ex vivo perfusion of intact human liver tissue that recapitulates the liver physiology to investigate HBV liver targeting. This model allowed us to investigate virus-host cell interactions in a cellular microenvironment mimicking the in vivo situation. RESULTS: HBV was rapidly sequestered by liver macrophages within 1 hour after a virus pulse perfusion but was detected in hepatocytes only after 16 hours. We found that HBV associates with lipoproteins in serum and within machrophages. Electron and immunofluorescence microscopy corroborated a co-localization in recycling endosomes within peripheral and liver macrophages. Recycling endosomes accumulated HBV and cholesterol, followed by transport of HBV back to the cell surface along the cholesterol efflux pathway. To reach hepatocytes as final target cells, HBV was able to utilize the hepatocyte-directed cholesterol transport machinery of macrophages. CONCLUSIONS: Our results propose that by binding to liver targeted lipoproteins and using the reverse cholesterol transport pathway of macrophages, HBV hijacks the physiological lipid transport pathways to the liver to most efficiently reach its target organ. This may involve transinfection of liver macrophages and result in deposition of HBV in the perisinusoidal space from where HBV can bind its receptor on hepatocytes.