Liver Targeting Effect Research Articles

Preparation, characterization, and liver targeting evaluation of a novel sustained-release brucine self-assembled micelle mediated by glycyrrhetinic acid.

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 ± 1.09nm, 0.201 ± 0.02 and -24.5 ± 0.19mV 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.

Deconvolving Passive and Active Targeting of Liposomes Bearing LDL Receptor Binding Peptides Using the Zebrafish Embryo Model.

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.

Preliminary Study on Pharmacokinetics and Antitumor Pharmacodynamics of Folic Acid Modified Crebanine Polyethyleneglycol-Polylactic Acid Hydroxyacetic Acid Copolymer Nanoparticles.

Liver cancer is associated significantly with morbidity and mortality. The combination of low-intensity ultrasound with nanomedicine delivery systems holds promise as an alternative for the treatment for liver cancer. This study focuses on the utilization of folic acid (FA) modified nanoparticles, which are loaded with fluorescent dye DiR and liquid fluorocarbon (PFP). These nanoparticles have the potential to enhance liver cancer targeting under ultrasound stimulation and future applications in vivo. The pharmacokinetics and tissue distribution of folic acid-modified Crebanine polyethylene glycol-polylactic acid copolymer nanoparticles (FA-Cre@PEG-PLGA NPs) were investigated. The pharmacokinetic parameters, liver targeting, and in vivo distribution were assessed. Additionally, the inhibitory impacts of FA-Cre@PEG-PLGA NPs in combination with ultrasonic irradiation on the proliferation and acute toxicity of H22 cells of mouse hepatoma were investigated in vitro. The tumor targeting and anti-tumor efficacy of FA-Cre@PEG-PLGA NPs were assessed utilizing a small animal in vivo imaging system and an in situ hepatocellular carcinoma transplantation model, respectively. The pharmacokinetic studies and tissue distribution tests demonstrated that FA-Cre@PEG-PLGA NPs conspicuously prolonged the half-life and retention time of the drug in rats, and the liver targeting effect was pronounced. Additionally, the in vivo acute toxicity test indicated that FA-Cre@PEG-PLGA NPs had minimal adverse reactions and could fulfill the aim of attenuating the drug. The outcomes of the animal experiments further substantiated that FA-Cre@PEG-PLGA NPs had a longer retention time at the tumor site, a superior anti-tumor effect, and less damage to liver and kidney tissue. The integration of FA-Cre@PEG-PLGA NPs with ultrasound irradiation demonstrated exceptional safety and potent anti-tumor efficacy in vivo, presenting a promising therapeutic strategy for the treatment of liver cancer through the combination of ultrasound technology with a nanomedicine delivery system.

Hepatocyte-targeted hyaluronic acid-polyethyleneimine conjugates for acute liver injury therapy by ROS elimination and inflammation modulation

Acute liver injury (ALI) is one of the most important causes of liver failure, and there are no FDA-approved drugs that could therapy late-stage ALI. It has been shown in this study that HA-PEI, a molecule formed by covalently combining HA and PEI, can effectively treat advanced ALI. Through the CD44 receptor, HA-PEI could target the liver actively, with the highest liver-targeting effect confirmed at 1000 K. The underlying mechanism of protection of HA-PEI is by increasing oxygen content, reducing ROS, and maintaining mitochondrial membrane potential. HA-PEI also inhibits the secretion of inflammatory factors and blocks the migration of immune cells to the liver, protecting the hepatocytes not suffer from secondary damage. More importantly, for late-stage ALI, NAC, as the only FDA-approved drug, is completely ineffective, whereas HA-PEI has an excellent therapeutic effect. This work provides a new safe therapeutic agent for ALI, which has a bright application prospect.

Construction of a visualized liver-targeting siRNA delivery system

A visualized liver-targeting small-interfering RNA (siRNA) delivery carrier, glycyrrhetinic acid-modified lipid-[poly(aspartate-graft-polyethyleneimine)]-modified superparamagnetic nanoparticles (GLPPS), was prepared for focus on improving the siRNA delivery efficiency and diagnostic capability for hepatocellular carcinoma. Agarose gel electrophoresis, cytotoxicity, and in vitro gene silencing experiments were conducted to determine the optimal carrier formulation. The results showed that the best formulation of the carrier was a weight ratio of LPPS to siRNA of 30:1 and a molar ratio of LPPS to DSPE-PEG-GA of 65:3. Prussian blue staining and in vitro magnetic resonance imaging (MRI) experiments further confirmed that GLPPS had a significant liver-targeting effect. The carrier's biocompatibility was tested both in vitro and in vivo, and the results showed no hemolysis or morphological changes of erythrocytes when the carrier was incubated with rabbit blood cells. Following injection of GLPPS into the tail vein of mice, the hematoxylin and eosin staining of the liver, spleen, and kidney showed normal tissue morphology with no inflammation or injury. Taken together, these results indicated that GLPPS is a safe drug carrier. In vivo MRI showed that GLPPS significantly reduced tumor signal intensity and improved MRI contrast. In conclusion, GLPPS may be a promising liver-targeting siRNA delivery and MRI monitoring carrier.

Mesoporous Hollow Manganese Doped Ceria Nanoparticle for Effectively Prevention of Hepatic Ischemia Reperfusion Injury.

Hepatic ischemia-reperfusion injury (HIRI) is the main reason for liver dysfunction or failure after liver resection and liver transplantation. As excess accumulation of reactive oxygen species (ROS) is the leading factor, ceria nanoparticle, a cyclic reversible antioxidant, is an excellent candidate for HIRI. Manganese doped mesoporous hollow ceria nanoparticles (MnOx-CeO2 NPs) were prepared, and the physicochemical characteristics, such as particle size, morphology, microstructure, etc. were elucidated. The in vivo safety and liver targeting effect were examined after i.v. injection. The anti-HIRI was determined by a mouse HIRI model. MnOx-CeO2 NPs with 0.40% Mn doped exhibited the strongest ROS-scavenging capability, which may due to the increased specific surface area and surface oxygen concentration. The nanoparticles accumulated in the liver after i.v. injection and exhibited good biocompatibility. In the HIRI mice model, MnOx-CeO2 NPs significantly reduced the serum ALT and AST level, decreased the MDA level and increased the SOD level in the liver, prevent pathological damages in the liver. MnOx-CeO2 NPs were successfully prepared and it could significantly inhibit the HIRI after i.v. injection.

Vinegar-baked Radix Bupleuri enhances the liver-targeting effect of rhein on liver injury rats by regulating transporters.

This study aimed to explore whether the liver-targeting enhancing effect of vinegar-baked Radix Bupleuri (VBRB) on rhein was achieved by affecting transporters, metabolism enzymes as well as hepatocyte nuclear factor 1α/4α (HNF1α/HNF4α) in liver injury. The effect of VBRB on the efficacy of rhein was performed with the LPS-induced acute liver injury rat model. Aspartate aminotransferase (AST), alanine transaminase (ALT) and superoxide dismutase (SOD) levels were determined and histopathological examination was taken. Drug concentrations in tissues were determined by high performance liquid chromatography (HPLC). The protein expressions of drug transporters, metabolic enzymes and hepatic nuclear factors were determined by Western blotting and ELISA assays. VBRB improved the liver protecting effect of rhein, which was consistent with its promoting effect on targeted enrichment of rhein in the liver. VBRB or in combination with rhein inhibited P-glycoprotein (Pgp) and multi-resistance related protein 2 (MRP2), while increased organic anion transporting polypeptide 2 (OATP2), which might be the reason why VBRB promoted liver-targeting effect of rhein. VBRB enhances the liver-protecting effect of rhein by down-regulating Pgp, MRP2, and up-regulating OATP2.

Synthesis, characterization, and anti-hepatocellular carcinoma effect of glycyrrhizin-coupled bovine serum albumin-loaded luteolin nanoparticles

Background: Luteolin (Lut) is a natural flavonoid with low water solubility. Many studies have revealed that its antitumor effect is more understandable. Objectives: Synthesis of glycyrrhizin-coupled bovine serum albumin-loaded Lut nanoparticles (GL-BSA-Lut-Nps) to progress the water solubility, anticancer effect, liver targeting, cycle arrest, induction apoptosis, and regulating the metabolism of Lut. Materials and Methods: The activity screening of GL-BSA-Lut-Nps on Hepatocellular Carcinoma Bel-7402 cells was spotted by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide (MTT) assay, cell cycle, and apoptosis were measured by flow cytometry. The solubility of GL-BSA-Lut-Nps was evaluated by ultraviolet spectrophotometer. Fluorescein isothiocyanate was employed to label the drug, and the fluorescence intensity of cells after drug uptake was detected under a fluorescence microscope to sense the targeting of GL-BSA-Lut-Nps to tumor cells. The differences of metabolites between Bel-7402 cells treated with GL-BSA-Lut-Nps and the control group were considered by 1 hydrogen-nuclear magnetic resonance metabolomics. Results: The results presented that the GL-BSA-Lut-Nps prepared by solvent removal method had good anti-tumor activity and water solubility in vitro and the No. 4 Lut nanoparticles (GL-BSA-Lut-Nps-4) screened by the MTT method had the best effect. The IC50 of the GL-BSA-Lut-Nps-4 on the Bel-7402 cell inhibition test was 1.999 ± 0.880 mg/mL. The results of cell cycle and apoptosis displayed that the anticancer effect of the prescription is more palpable. The results of the fluorescence original method are proposed to confirm that the experimentally created GL-BSA-Lut-Nps-4 have a liver targeting effect. The study of metabolomics further clarified the metabolic regulation effect of GL-BSA-Lut-Nps-4 on Bel-7402 cells. Conclusion: It delivers a theoretical basis for the development of new high-efficiency and low-toxicity traditional Chinese medicine preparations for liver cancer.

A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity

Although inoculation of COVID-19 vaccines has rolled out globally, there is still a critical need for safe and effective vaccines to ensure fair and equitable supply for all countries. Here, we report on the development of a highly efficacious mRNA vaccine, SW0123 that is composed of sequence-modified mRNA encoding the full-length SARS-CoV-2 Spike protein packaged in core–shell structured lipopolyplex (LPP) nanoparticles. SW0123 is easy to produce using a large-scale microfluidics-based apparatus. The unique core–shell structured nanoparticle facilitates vaccine uptake and demonstrates a high colloidal stability, and a desirable biodistribution pattern with low liver targeting effect upon intramuscular administration. Extensive evaluations in mice and nonhuman primates revealed strong immunogenicity of SW0123, represented by induction of Th1-polarized T cell responses and high levels of antibodies that were capable of neutralizing not only the wild-type SARS-CoV-2, but also a panel of variants including D614G and N501Y variants. In addition, SW0123 conferred effective protection in both mice and non-human primates upon SARS-CoV-2 challenge. Taken together, SW0123 is a promising vaccine candidate that holds prospects for further evaluation in humans.

In vitro and in vivo antitumor effects of lupeol-loaded galactosylated liposomes

Lupeol liposomes, modified with Gal-PEG-DSPE, were developed following a thin-film dispersion method. Then, the morphology, physicochemical properties, and in vitro release properties of those liposomes were investigated. The scanning electron microscopic images showed that most of the liposomes were spherical particles; they were similar in size and uniformly dispersed. Both lupeol liposomes and Gal-lupeol liposomes exhibited an average particle size of about 100 nm. The encapsulation efficiency was greater than 85%. The encapsulation efficiency of lupeol liposome and Gal-lupeol liposome, stored with 15% sucrose as glycoprotein for 6 months, was higher than 80%; although the particle size increased, they remained within 200 nm. The cell-uptake study demonstrated that the Gal-lupeol-liposome uptake efficiency was the highest in HepG2 cells. The HepG2 cells treated with the Gal-lupeol liposomes had higher apoptotic efficiency than the lupeol liposome and free lupeol. After HepG2 cells were treated with Gal-lupeol liposome, the expressions of AKT/mTOR-related proteins (p-AKT308 and p-AKT473) were also significantly reduced than the lupeol-liposome and free lupeol group. The in vivo targeting studies showed that Gal-NR-L exhibited liver-targeting effects on FVB mice. The pharmacodynamic study was performed by transfecting AKT and c-MET via the high-pressure tail vein of FVB mice. After Gal-lupeol-L administration, the liver index and liver weight of mice were less than those non-targeted group. The histopathological study showed that the lobular structure in the mice liver was clearer, the vacuoles were more obvious, and the cytoplasm was more abundant after Gal-lupeol-L administration. Also, the qRT-PCR study showed that AFP, GPC3, and EpCAM mRNA expression levels were significantly lower than those non-targeted lupeol-liposomes.

Targeted delivery of hyaluronic acid nanomicelles to hepatic stellate cells in hepatic fibrosis rats

Hepatic fibrosis is one kind of liver diseases with a high mortality rate and incidence. The activation and proliferation of hepatic stellate cells (HSCs) is the most fundamental reason of hepatic fibrosis. There are no specific and effective drug delivery carriers for the treatment of hepatic fibrosis at present. We found that when hepatic fibrosis occurs, the expression of CD44 receptors on the surface of HSCs is significantly increased. Based on this finding, we designed silibinin-loaded hyaluronic acid (SLB-HA) micelles to achieve the treatment of hepatic fibrosis. Meanwhile, we constructed liver fibrosis rat model using Sprague–Dawley rats. We demonstrated that HA micelles had specific uptake to HSCs in vitro while avoiding the distribution in normal liver cells and the phagocytosis of macrophages. Importantly, HA micelles showed a significant liver targeting effect in vivo, especially in fibrotic liver which highly expressed CD44 receptors. In addition, SLB-HA micelles could selectively kill activated HSCs, having an excellent anti-hepatic fibrosis effect in vivo and a significant sustained release effect, and also had a good biological safety and biocompatibility. Overall, HA micelles represented a novel nanomicelle system which showed great potentiality in anti-hepatic fibrosis drugs delivery.

Pharmacokinetics and liver uptake of three Schisandra lignans in rats after oral administration of liposome encapsulating β-cyclodextrin inclusion compound of Schisandra extract

Schisandra chinensis fructus (SCF) is widely used traditional Chinese medicine, which possesses hepato-protective potential. Schisandrin (SD), schisantherin (ST), and γ-schizandrin (SZ) are the major bioactive lignans. The main problem associated with the major bioactive lignans oral administration is low oral bioavailability due to the lignans’ poor aqueous solubility and taste. The aim of the present research work was to develop liposome (SCL) encapsulated β-cyclodextrin (β-CD) inclusion complex loaded with SCF extract (SCF-E). The SD, ST, and SZ were selected as effective candidates to perform comparisons of liver targeting among the solution (SES), β-cyclodextrin inclusion compound (SCF-E-β-CD), liposome (SEL), and SCL of SCF-E to characterize the pharmacokinetic behaviors and liver targeting in rats. The β-CD inclusion complex (SCF-E-β-CD) was used to improve the solubility. The concentrations were determined using high-performance liquid chromatography (HPLC) and analyzed by DAS3.0. The pharmacokinetic results indicate that the plasma concentration-time courses were fitted well to the one-compartment model with the first weighing factor. The half-life period (t1/2) and area under the concentration-time curve (AUC) of the three components in SCL were the largest. The SCL exhibit a relatively high liver targeting effect. The results would be helpful for guiding the clinical application of this herbal medicine.

Promising positive liver targeting delivery system based on arabinogalactan-anchored polymeric micelles of norcantharidin

Liver cancer is the third most common cause of global cancer-related deaths. This study focused on newly developed drug delivery systems with hepatocyte asialoglycoprotein receptor binding targeting the liver. Although norcantharidin (NCTD) is effective in primary liver cancer treatment, its toxicity in the urinary system remains. Positive liver-targeting effect could be achieved by preparing polymer micelles by arabinogalactan on the surface of N-(4-methylimidazole)-hydroxyethyl-chitosan (MHC). HepG2 cells were used to analyze the cytotoxicity, invasion, apoptosis and uptake of NCTD-loaded micelles. The in vivo antitumor efficacy of NCTD-M was evaluated using tumor-bearing nude mice. Successful preparation of NCTD-M was shown. In vivo imaging showed that micelles significantly increased positive liver drug targeting. Laser confocal microscopy showed increased cellular uptake of micelles. NCTD-M also enhanced cell invasion and the proportion of apoptotic cells. Compared with the other groups, the micelles showed better antitumor effects in vivo. Therefore, the positive liver-targeting NCTD-M, which can enhance antitumor efficacy and reduce toxicity, could be a promising and effective therapeutic agent for liver cancer treatment.

Liver-targeted delivery of liposome-encapsulated curcumol using galactosylated-stearate.

Liver-targeted drug delivery improves the efficacy of anti-liver cancer agents and reduces systemic toxicity by limiting the bioavailability of these drugs to within tumors. Liver targeting reagents with galactose residues, which selectively combine to asialoglyco protein receptors, have previously been used to improve liposome-encapsulated drug accumulation within liver cells. They lead to a reduction in liver cancer cell growth and have been used to cure certain hepatic diseases. In the present study, curcumol, which is the primary active component of Chinese traditional medicine Rhizoma zedoariae, was encapsulated in galactosylated-liposomes to enhance its anti-liver cancer efficacy. Galactosylated-liposomes and normal liposomes were labeled with propidium iodide. Galactosylated-liposomes with increasing concentrations of galactosylated-stearate (Gal-s) had a notably increased level of uptake in HepG2 cells (hepatoblastoma) compared with SGC-7901 (gastric cancer) and A549 (non-small cell lung cancer) cells. When the percentage of Gal-s reached 20%, liposome uptake plateaued. In the in vitro anti-liver cancer experiment, the anti-liver cancer efficacy of galactosylated-curcumol-liposomes increased significantly more compared with normal curcumol liposomes and free curcumol as indicated by cell survival rate and lactate dehydrogenase release rate. Collectively, these results demonstrate that galactosylated-liposomes are able to enhance the in vitro liver-targeting effect and anti-liver cancer efficacy of curcumol.

Recent progress in nanomedicine for hepatocellular carcinoma therapy

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with insidious onset, insensitive to chemotherapy and poor prognosis, which make its clinical treatment face an enormous challenge. In recent years, with the rapid development of nanotechnology, increasing kinds of nanomedicine come to the forefront in biomedical fields. Through rational design, nanomedicine can be prepared in suitable size and modified with specific liver targeting ligands. Moreover, various therapeutic agents of different mechanisms can be co-loaded into the same nanosystem, thus achieving the synergistic therapeutic effects towards HCC. Nanomedicine is able to enhance drug bioavailability and liver-targeting effect as well as reduce the side effects to normal tissues, which provide a great potential in HCC therapy. This review summarizes the recent progress in the application of nanomedicine for HCC therapy from two aspects: their liver-targeting design strategies and the recent progress in combination therapy of HCC.

Enhanced delivery of doxorubicin to the liver through self-assembled nanoparticles formed via conjugation of glycyrrhetinic acid to the hydroxyl group of hyaluronic acid

Liver-targeted nanoparticles is highly desired for better therapy of liver cancer. In this study, enhanced delivery of doxorubicin (DOX) to the liver cells through self-assembled nanoparticles formed via conjugation of glycyrrhetinic acid (GA) to the hydroxyl group of hyaluronic acid (HA) was investigated. The DOX loaded hyaluronic acid-glycyrrhetinic acid succinate (HSG) conjugates based nanoparticles (HSG/DOX nanoparticles) were sub-spherical in shape with particle size in the range of 180–280 nm, the drug loading was drug-to-carrier ratio and GA graft ratio dependent. In vitro release study suggested that the release of DOX from HSG nanoparticles was sustained and the release rate was pH and GA graft ratio dependent. MTT assay indicated the HSG/DOX nanoparticles presented a GA-dependent cytotoxicity to HepG2 cells. Pharmacokinetics study demonstrated the HSG/DOX nanoparticles could prolong blood circulation time of DOX and had a higher AUC value than that of DOX solution. Furthermore, tissue distribution study revealed the HSG/DOX nanoparticles significantly increased the accumulation of DOX in the liver and meanwhile decreased the cardiotoxicity and nephrotoxicity of DOX. Moreover, the liver targeting enhancing capacity was HSG conjugate structure dependent. The accumulation of HSG-20/DOX, HSG-12/DOX, and HSG-6/DOX nanoparticles in the liver was 4.0-, 3.1-, and 2.6-fold higher than that of DOX solution. In vivo imaging analysis further demonstrated HSG nanoparticles not only had better liver targeting effect, but also presented superior tumor targeting efficiency, and the tumor targeting capacity was also GA-dependent. These results indicated that HSG conjugates prepared via modifying the hydroxyl groups of HA have promising potential as a liver-targeting nanocarrier for the delivery of hydrophobic anti-tumor drugs.

Enhanced liver-targeting via coadministration of 10-Hydroxycamptothecin polymeric micelles with vinegar baked Radix Bupleuri

BackgroundVinegar baked Radix Bupleuri (VBRB) is a wildly used traditional Chinese medicine, it could be used as a meridian guided drug to enhance liver targeting efficiency of the delivered drug in addition to its therapeutic effect. PurposeTo investigate the liver targeting effect induced by VBRB via coadministration with 10-Hydroxycamptothecin loaded polymeric micelles. MethodsFirst of all, the inhibitory effect of VBRB on the activity of glutathione S-transferase (GST) was investigated in vitro to select the most effective extract. After oral administration of 10-Hydroxycamptothecin (HCPT) polymeric micelles with low, medium and high doses of VBRB, pharmacokinetic parameters, including the ratio of Cmax in the liver (Ce) and the relative uptake efficiency (RUE), were employed to assess the liver targeting efficiency. ResultsIt was found that VBRB extract BC1 has the strongest inhibition effect on GST activity in the five extracts. By coadministration of HCPT loaded micelles with three doses of BC1, the AUC0-t of HCPT in the liver raised by 42.5%, 23.0%, −0.2%, with RUE 1.45, 1.23, 1.02 for low, medium and high dose groups, respectively, indicating that low and medium dose of BC1 presented better liver-targeting enhancing effect than that of the high dose, which corresponded to the commonly used dose of VBRB in traditional Chinese medicine formulae. ConclusionsVBRB could effectively enhance the liver-targeting efficiency of HCPT loaded polymeric micelles after oral coadministration. Such a simple but effective strategy may enlighten on the potential use of meridian guided drug together with modern drug delivery system to achieve better active drug targeting.

Characterization and Oral Delivery of Proinsulin-Transferrin Fusion Protein Expressed Using ExpressTec.

Proinsulin-transferrin fusion protein (ProINS-Tf) has been designed and successfully expressed from the mammalian HEK293 cells (HEK-ProINS-Tf). It was found that HEK-ProINS-Tf could be converted into an activated form in the liver. Furthermore, HEK-ProINS-Tf was demonstrated as an extra-long acting insulin analogue with liver-specific insulin action in streptozotocin (STZ)-induced type 1 diabetic mice. However, due to the low production yield from transfected HEK293 cells, there are other interesting features, including the oral bioavailability, which have not been fully explored and characterized. To improve the protein production yield, an alternative protein expression system, ExpressTec using transgenic rice (Oryza sativa L.), was used. The intact and active rice-derived ProINS-Tf (ExpressTec-ProINS-Tf) was successfully expressed from the transgenic rice expression system. Our results suggested that, although the insulin-like bioactivity of ExpressTec-ProINS-Tf was slightly lower in vitro, its potency of in vivo blood glucose control was considerably stronger than that of HEK-ProINS-Tf. The oral delivery studies in type 1 diabetic mice demonstrated a prolonged control of blood glucose to near-normal levels after oral administration of ExpressTec-ProINS-Tf. Results in this report suggest that ExpressTec-ProINS-Tf is a promising insulin analog with advantages including low cost, prolonged and liver targeting effects, and most importantly, oral bioactivity.

Saikosaponins A, C and D enhance liver-targeting effects of anticancer drugs by modulating drug transporters.

Vinegar-baked Radix Bupleuri (VBRB) is clinically used to enhance the pharmacological activity of drugs used to treat liver diseases. Our previous study demonstrated that this effect is dependent on increased drug accumulation in the liver; however, the underlying mechanism remains unclear. We hypothesize that VBRB mediated its effects by altering drug transporters. Thus, the present study was designed to determine the effects of VBRB's main components, saikosaponin A, C, and D, on drug transporters. Transporter activity was determined by measuring the intracellular concentration of transporter substrates. Protein and mRNA levels were measured by Western blot and qPCR, respectively. Colchicine was used as the substrate for P-glycoprotein (Pgp) and multidrug resistance protein (MRP) 1, cisplatin was used as the substrate for Mrp2 and organic cation transporters 2 (Oct2), and verapamil and MK571 were used as inhibitors of Pgp and MRP1, respectively. Saikosaponin A, C, and D differentially affected transporter activity. All of the saikosaponins inhibited Pgp activity in Pgp over-expressing HEK293 cells and increased substrate uptake of OCT2 in OCT2 over-expressing HEK293. Saikosaponin C and D inhibited MRP2 activity in HEK293 cells and BRL 3A cell with high MRP2 expression; saikosaponin A increased colchicine accumulation in GSH-stimulated HEK293 cells, but decreased colchicine uptake in HEK293 cells. Saikosaponin D inhibited MRP1 activity in GSH-stimulated HEK293 cells, but marginally affected the uptake of colchicine in HEK293 cells. In conclusion, saikosaponins play a role in VBRB's induced liver targeting effect through affecting drug transporters with a transporter expression amount depending manner.

Preparation and in vivo study of liposomes mediated by glycyrrhetinic acid derivative ligand 18-GA-Gly

Based on the research of active liver targeting liposomes mediated by glycyrrhetinic acid ligand at home and abroad, this paper focuses on the liver targeting effect of liposomes mediated with 18-GA-Gly, a kind of glycyrrhetinic acid ligand. salvianolic acid B(Sal B)-tanshinone ⅡA (TSN)liposomes mediated by 18-GA-Gly as well as the liposomes with unmodified ligands were prepared by film dispersion-high pressure homogenization method, and then the particle size, potential, encapsulation efficiency and ligand binding rate were detected. Plasma samples of the heart, liver, spleen, lung and kidney tissues were taken at different time points after tail vein injections. The contents of Sal B and TSN in each sample were determined with UPLC methods and the liver targeting effect of 18-GA-Gly ligands was evaluated. The results showed that the particle size, potential, encapsulation efficiency and ligand binding rate met the basic requirements; in vivo targeting investigation results showed no difference between GLY-TS-Lip group and TS-Lip group. The liposomes mediated by glycyrrhetinic acid derivative ligand 18-GA-Gly can increase the peak concentration of Sal B and TSN in liver, but showed no significant liver targeting effect.