Ursolic acid (UA), a natural pentacyclic triterpenoid, has been reported to possess a variety of pharmacological activities, but the poor oral bioavailability of UA owing to the poor aqueous solubility and membrane permeability limits the further clinical application.The purpose of the present study was to develop UA nanocrystals and microcrystals employing high pressure homogenization (HPH) and to evaluate their effects on UA oral bioavailability.The crystalline morphology of UA nanocrystals and microcrystals prepared by HPH was observed by scanning electron microscopy and the crystalline state was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution rate of UA nanocrystals in different pH conditions was tested. Oral bioavailability of UA nanocrystals and microcrystals comparing with UA coarse suspension was evaluated in SD rats after 50 mg·kg-1 administration.UA nanocrystals and microcrystals, the size of which ranged between 291.7 nm and 1299.3 nm were obtained. The results of DSC and PXRD revealed a degree of crystalline-amorphous transformation during HPH preparation. A significant increase was observed in the dissolution rate of UA nanocrystals. The relative bioavailability of UA nanocrystals and microcrystals exhibited 2.56 and 1.40-fold enhancement than that of UA coarse suspension, respectively, along with an increased peak concentration and a prolonged retention.The nanosized UA crystal is a viable and efficient approach to improve the oral bioavailability of UA.
Objective: Inhibition of tumor angiogenesis has become a new targeted tumor therapy. In this study, we established a micellar carrier with a tumor neovascularization-targeting effect modified by the neovascularization-targeting peptide NGR. Methods: The targeted polymer poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) modified with Asn–Gly–Arg (NGR) peptide was prepared and characterized by 1 H nuclear magnetic resonance and Fourier-transform infrared spectrometry. NGR-PEG-PLGA was used to construct curcumin (Cur)-loaded micelles by the solvent evaporation method. The physicochemical properties of the micelles were also investigated. Additionally, we evaluated the antitumor efficacy of the polymer micelles (PM) using in vitro cytology experiments and in vivo animal studies. Results: The particle size of Cur-NGR-PM was 139.70 ± 2.51 nm, and the drug-loading capacity was 14.37 ± 0.06%. In vitro cytological evaluation showed that NGR-modified micelles showed higher cellular uptake through receptor-mediated endocytosis pathways than did unmodified micelles, leading to the apoptosis of tumor cells. Then, in vivo antitumor experiments showed that the modified micelles significantly inhibited tumor growth and were safe. Conclusions: NGR-modified micelles significantly optimized the therapeutic efficacy of Cur. This strategy offers a viable avenue for cancer treatment.
Liver cancer, otherwise known as hepatocellular carcinoma, is a chronic disease condition with an excessive deposition and growth of malignant cells in the body. The high incidence and prevalence rates of liver cancer continue to be problems, as well as its poor prognosis and therapeutic limitations involving severe drug adverse reactions linked to the use of synthetic chemotherapeutic compounds. Continuous experimental studies, as well as utilization of pure herbal-based compounds, are essential towards finding more potent cures for liver cancer. Natural bioactive compounds, particularly alkaloids (eg, berberine), have been shown to be highly beneficial in the treatment of various diseases. Berberine (BBR), an isoquinoline alkaloid, is obtained from stem, bark, roots, rhizomes, and leaves of several medicinal plants, including Berberis species. It is commonly synthesized from the benzyltetrahydroisoquinoline system with the incorporation of an additional carbon atom as a bridge. The multiple attributes of BBR involving effective inhibitory and cytotoxic actions against the proliferation of cancer cells have been demonstrated. The use of BBR in experimental studies (in vivo and in vitro) for over a decade for liver cancer treatment has proven to be highly effective, safe, and potent. Until now, the poor solubility of BBR remains one of the contributing factors leading to its minimal clinical bioavailability. Therefore, BBR could serve as a prospective drug candidate in the future towards drug formulation for liver cancer treatment. The relevant information regarding this review was obtained electronically through the use of databases such as PubMed, Google Scholar, Springer, Hindawi, Embase, Web of Science, and China National Knowledge Infrastructure. All the aforementioned databases were searched from 1981 to 2020. This literature represents an update of previous review papers discussing the various positive pharmacological and mechanistic effects (oxidative stress regulation, inflammation reduction, apoptosis activation, overcoming drug resistance, and metastasis inhibition) of BBR for liver cancer treatment, which would be of great significance to drug development and clinical research.
A UHPLC-QQQ-MS/MS method was developed to quantify the significant constituents in Wen-Dan Decoction (WDD), a traditional Chinese medicine. Analysis of 19 compounds was conducted on an ACQUITY UPLC® BEH C18 Column (2.1 × 50 mm, 1.7 μm) using elution with a gradient elution of acetonitrile and 0.05% (v/v) formic acid in water. A triple quadrupole mass spectrometer was operated in negative ionization mode and positive ionization mode by multiple reaction monitoring (MRM), respectively. All calibration curves showed acceptable linearity (r ≥ 0.9950). The RSDs of intra- and inter-day precisions of low, mid and high concentrations were ≤ 8.88%. The repeatabilities (RSDs ≤ 7.17%) and stabilities (RSD ≤ 4.79%) of the samples were qualified. The recoveries were found in the range of 93.07 ± 3.86 to 103.98 ± 2.98% with the RSD varying between 1.30 and 7.86%. The final rapid, sensitive, precise, accurate and reliable UHPLC-QQQ-MS/MS method was used for the simultaneous quantification of 19 constituents in WDD and its commercial preparations. The strategy of combining the contents of the 19 chemicals in a daily dose of the WDD preparations with the hierarchical cluster analysis and the 3D principal component analysis was employed to effectively distinguish the WDD preparations provided by the different suppliers, which represents a contribution to the evaluation and control of the quality of WDD (or other decoctions consisting of the same herbs) and the preparations of WDD in other dosage forms such as tablets and granules.
Systemic absorption of ocularly administered Brimonidine Tartrate has been reported to give rise to several side-effects. Hence, it has become crucial to develop a delivery system that could increase efficacy and reduce systemic absorption. Therefore, the present work aims to develop Brimonidine Tartrate gels with different concentrations (0.05%, 0.1%, and 0.2% w/v, respectively) using Carbopol 974 P and HPMC E4M, and compare the therapeutic efficacy and systemic absorption with that of eye drop (0.2%, w/v) by UPLC-MS/MS. The result of histological analysis did not show any morphological or structural changes after the administration of formulations. In vitro residence time studies demonstrated that the gels exhibited a better precorneal residence time as compared with the eye drop. The gels with lower concentrations of the drug (0.05% and 0.1%, w/v) could significantly decrease intraocular pressure (IOP) in both normal and water-loaded rabbits as compared to the eye drop. Finally, the values of the ratio of AUC(0→∞) in comparison to eye drop showed the gels with lower concentrations of Brimonidine Tartrate could decrease the systemic absorption. From the result, it can be concluded the 0.1% ophthalmic gel has a potential to improve therapeutic efficacy and reduce the potential toxicity caused by systemic absorption.
In targeting delivery system research on salvianolic acid B, it's vital but hard to evaluate the tissue distribution for its low concentrations in tissues. So the simple, rapid, selective and sensitive UPLC-MS/MS method was provided hereby to determine the concentration of salvianolic acid B in mice tissues after intravenous administration of salvianolic acid B injections, conventional liposomes and long-circulating liposomes. The UPLC was conducted by a C(18) column with a gradient mobile phase consisting of acetonitrile and water containing 0.1% formic acid. The tandem mass spectrometry was operated in negative-electrospray ionization selected-reaction-monitoring mode, and the optimized characteristic precursor to product ion transition m/z 717.3→519.1 was selected. The biosamples were homogenized and treated with a protein precipitation, which led to an acceptable matrix effect and extraction recovery. The linear calibration curves were plotted in the given concentration ranges. The intra-day and inter-day precisions were less than 13.9% and the accuracies were in the range of 86.3-109.2%. The tissue distribution results determined by UPLC-MS/MS we developed showed that the conventional and long-circulating liposomes we made had succeeded in prolonging the retention time and increasing the level of salvianolic acid B in certain distribution tissues such as liver, kidney and brain.
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