Zhenbao Li

Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation.

Stealth active targeting nanoparticles (NPs) usually include two types of ligand sites: ligand anchored on distal ends of the polyethylene glycol (PEG) and ligand buried under pegylated layer. The latter typical case is hyaluronic acid (HA)-based NPs; however, there is little information available for the latter NPs about effect of the optimal density of surface PEG coating on the blood circulation time, cellular uptake and in vivo anticancer activity. Thus, in this study, in order to optimize the anticancer effects of HA-based NPs, we focus on how uncovalent pegylation degree modulates blood circulation time and cellular uptake of HA-based NPs. We firstly designed a new double-hydrophilic copolymer by conjugating HP-β-cyclodextrin with HA, and this carrier was further pegylated with adamantyl-peg (ADA-PEG) to form inclusion complex HA-HPCD/ADA-PEG, termed as HCPs. The supramolecular nanoassemblies were fabricated by host-guest and polar interactions between HCPs and doxorubicin (Dox), with vitamin E succinate (VES) being a nanobridge. Despite the active recognition between HA and CD44 receptor, the cellular uptake and targeting efficiency of HA-NPs decreased with the increasing peg density, demonstrating HA was partly buried by high density peg coating. However, the high density of peg coating was beneficial to long circulation time, tumor biodistribution and anticancer activity in vivo. NPs with 5% peg coating had the optimal cellular targeting efficiency in vitro and anticancer effects in vivo. The findings suggest that balancing long circulation property and cellular uptake is important to achieve the optimal antitumor efficacy for pegylated HA-based NPs, and that PEG coating densities cannot be extended beyond a certain density for shielding effect without compromising the efficacy of hyaluronic acid targeted delivery.

Triterpenoids from the husks of Xanthoceras sorbifolia Bunge

A new triterpenoid saponin, 3-O-[(3-O-α-l-arabinofuranosyl-2-O-β-d-galactopyranosyl)-β-d-glucuronopyranosyl]-21,22-di-O-angeloyl-R1-barrigenol (1), together with four known triterpenoids, have been isolated from the husks of Xanthoceras sorbifolia Bunge. Their structures were elucidated based on chemical and spectral analysis. Among them, 1 was found to have activity of inhibiting the proliferation of six human tumour cell lines (IC50 10–40 μg/ml).

Critical determinant of intestinal permeability and oral bioavailability of pegylated all trans-retinoic acid prodrug-based nanomicelles: Chain length of poly (ethylene glycol) corona

Pegylation method is widely used to prolong the blood circulation time of proteins and nanoparticles after intravenous administration, but the effect of surface poly (ethylene glycol) (PEG) chain length on oral absorption of the pegylated nanoparticles is poorly reported. The aim of our study was to investigate the influence of PEG corona chain length on membrane permeability and oral bioavailability of the amphiphilic pegylated prodrug-based nanomicelles, taking all trans-retinoic acid (ATRA) as a model drug. The amphiphilic ATRA-PEG conjugates were synthesized by esterification reaction between all trans-retinoic acid and mPEGs (mPEG500, mPEG1000, mPEG2000, and mPEG5000). The conjugates could self-assemble in aqueous medium to form nanomicelles by emulsion-solvent evaporation method. The resultant nanomicelles were in spherical shape with an average diameter of 13-20 nm. The drug loading efficiency of ATRA-PEG500, ATRA-PEG1000, ATRA-PEG2000, and ATRA-PEG5000 was about 38.4, 26.6, 13.1, and 5.68 wt%, respectively. With PEG chain length ranging from 500 to 5000, ATRA-PEG nanomicelles exhibited a bell shape of chemical stability in different pH buffers, intestinal homogenate and plasma. More importantly, they were all rapidly hydrolyzed into the parent drug in hepatic homogenate, with the half-time values being 0.3-0.4h. In comparison to ATRA solution and ATRA prodrug-based nanomicelles, ATRA-PEG1000 showed the highest intestinal permeability. After oral administration, ATRA-PEG2000 and ATRA-PEG5000 nanomicelles were not nearly absorbed, while the oral bioavailability of ATRA-PEG500 and ATRA-PEG1000 demonstrated about 1.2- and 2.0-fold higher than ATRA solution. Our results indicated that PEG1000 chain length of ATRA-PEG prodrug nanomicelles has the optimal oral bioavailability probably due to improved stability and balanced mucus penetration capability and cell binding, and that the PEG chain length on a surface of nanoparticles cannot exceed a key threshold with the purpose of enhancement in oral bioavailability.

The studies of PLGA nanoparticles loading atorvastatin calcium for oral administration in vitro and in vivo

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Thiophenes from Echinops latifolius

Six thiophenes were isolated and purified from ethanol extract of the roots of Echinops latifolius Tausch. Their structures were identified on the basis of spectral data. Among them, 5-(3-hydroxmethyl-3-isovaleroyloxyprop-1-ynyl)-2,2′-bithiophene (6) is a new compound, and 5-(3-hydroxy-4-isovaleroyloxybut-1-ynyl)-2,2′-bithiophene (5) was isolated from this plant for the first time.

Development of Liposome containing sodium deoxycholate to enhance oral bioavailability of itraconazole

The aim of this study was to enhance oral bioavailability of itraconazole (ITZ) by developing Liposome containing sodium deoxycholate (ITZ-Lip-NaDC). The liposome, consisting of egg yolk lecithin and sodium deoxycholate, was prepared by thin-film dispersion method. Differential Scanning Calorimetry (DSC) results indicated an amorphous state in the liposome. The physicochemical characteristics including particle size, morphology, entrapment efficiency, dissolution properties were also investigated. The performance of single-pass intestinal infusion exhibited that the transport order of intestinal segment was jejunum, duodenum, colon and ileum, and that all the segments participated in the absorption of ITZ in intestinal tract. The bioavailability study in rats showed that the AUC0-72 of the liposome was nearly 1.67-fold higher than that of commercial capsules (SPORANOX) in terms of oral administration, and the RSD of AUC0-72 of ITZ-Lip-NaDC was also decreased. Our results indicated that ITZ-Lip-NaDC liposome was facilitated to improve dissolution efficiency, augment transmembrane absorption, and then enhance the oral bioavailability of ITZ, successfully.

Simultaneous determination of entecavir and lamivudine in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study

The studys aim is to develop and validate a rapid, selective and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with multiple reaction monitoring (MRM) mode method for the simultaneous determination of entecavir and lamivudine in rat plasma. Several important conditions were optimized systematically: solid-phase extraction (SPE) cartridges were used to extract the analytes from rat plasma; a hydrophilic interaction chromatography (HILIC) column was employed to separate the target compounds; a triple-quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source was applied to detect the drug. The method, which required a relatively small volume (50 μL) of plasma sample, was linear over the concentration ranges of 0.5–80 ng mL−1 for entecavir and 50–8000 ng mL−1 for lamivudine. The lower limit of quantitation (LLOQ) of entecavir and lamivudine was 0.5 and 50 ng mL−1, respectively. The method was demonstrated with acceptable accuracy and precision, where the intra-day and inter-day relative standard deviation (RSD) were less than 15% and the relative errors (RE) were within 15%. Furthermore, the results of both matrix effects and the extraction recoveries of this method were excellent. In conclusion, the developed method was successfully applied to the pharmacokinetic study of entecavir and lamivudine in rats following oral administration of them alone or in combination.

Polymeric nanoparticles developed by vitamin E-modified aliphatic polycarbonate polymer to promote oral absorption of oleanolic acid

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Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation

To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromolecular prodrugs after intravenous administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, respectively), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, especially the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.

A rapid and sensitive supercritical fluid chromatography/tandem mass spectrometry method for detection of ezetimibein dog plasma and its application in pharmacokinetic studies

The aim of this study is to develop and validate a rapid, high-selective and sensitive supercritical fluid chromatography/tandem mass spectrometry (SFC-MS/MS) with a multiple reactions monitoring (MRM) mode method for the detection of ezetimibe in dog plasma. Several conditions were optimized systematically as follows: lipid-lipid extraction (LLE) performances were used to extract analytes from dog plasma; an ACQUITY HSS C18 SB (1.8 μm, 3.0 × 100 mm) column was employed to separate the target compounds; the triple-quadrupole mass spectrometry equipped with electrospray ionization (ESI) source was applied to detect ezetimibe. The method, which required a relatively small volume of plasma (100 μL), was obtained at concentration ranging from 1.0 to 100 ng/mL(r2 > 0.99). The lower limit of quantification (LLOQ)for ezetimibe was found to be as low as 1.0 ng/mL. In addition, the validations of the methodology including sensitivity, recovery, matrix effect, intra- and inter-day precision, accuracy and stability were all within acceptable limits. The Cmax, AUC0-inf and Tmax values obtained in our study were 52.2 ± 6.3, 820.6 ± 4.3 and 1.25 ± 0.35 for reference formulation; 61.8 ± 12.6, 924.2 ± 4.7 and 2.00 ± 0 for test formulation. In conclusion, the method developed in this study can be successfully applied to pharmacokinetic studies after oral administration of ezetimibe in dogs.