Shandong Provincial Qian Foshan Hospital

Jinan, China

Shandong Provincial Qian Foshan Hospital

Jinan, China
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Xu W.,Shandong University | Xu W.,Shandong Provincial Qian Foshan Hospital | Ling P.,Shandong University | Ling P.,Institute of Biopharmaceuticals of Shandong Province | Zhang T.,Institute of Biopharmaceuticals of Shandong Province
Journal of Drug Delivery | Year: 2013

Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs) can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained. © 2013 Wei Xu et al.


Xu W.,Shandong University | Xu W.,Shandong Provincial Qian Foshan Hospital | Ling P.,Shandong University | Ling P.,Institute of Biopharmaceuticals of Shandong Province | Zhang T.,Institute of Biopharmaceuticals of Shandong Province
International Journal of Pharmaceutics | Year: 2014

In this study, tacrolimus (FK506) was encapsulated into a biodegradable poly(ethylene glycol)-poly(d,l-lactide) (MPEG-PLA) block copolymer using a double emulsion-solvent evaporation technique. Drug loading (DL) and encapsulation efficiency (EE) can be changed by varying the mass ratio of FK506/MPEG-PLA. Furthermore, transmission electron microscope (TEM) and Malvern Zetasizer were used to investigate the properties of FK506/MPEG-PLA nanoparticles (DL = 9.5%), which were monodisperse (PDI = 0.100 ± 0.023) with a mean particle size of 90.5 ± 1.5 nm. Compared with FK506 capsule, in vitro release profile showed that FK506/MPEG-PLA nanoparticles exhibited sustained release. Meanwhile, the higher concentration and longer retention time in plasma were also confirmed in vivo. We further preliminarily evaluated immunosuppressive effect on liver transplantation in rat model. The survival time of the rat administrated FK506/MPEG-PLA nanoparticles was obviously prolonged than that of the control group administrated FK506 capsule. © 2013 Elsevier B.V.


Xu W.,Shandong University | Xu W.,Shandong Provincial Qian Foshan Hospital | Cui Y.,Shandong University | Ling P.,Shandong University | Li L.-B.,Shandong University
Drug Delivery | Year: 2012

The aim of this study was to construct novel targeting polymeric micelles. Folate-Poly (ethylenimine)-Pluronic copolymers were synthesized. A paclitaxel (PTX)-loaded mixed micelles consisting of Folate-Poly (ethylenimine)-Pluronic and Pluronic L121 copolymers have been developed. The mixed micelles showed nano-sized spherical morphology. The solubilization capacity of the mixed micelles was higher than Folate-Poly (ethylenimine)-Pluronic micelles because L121 has high solubilization capacity. MTT colorimetric test revealed that PTX in Folate-Poly (ethylenimine)-Pluronic micelles demonstrated the maximum anticancer activity. Pluronic-poly (ethylenimine) micelles and folate-modified Pluronic-poly(ethylenimine) micelles showed a marked increase of cellular accumulation compared with Pluronic P123 micelles. The biodistribution and retention of intravenously (i.v.) administered micelles to rats were determined. Folate-Poly (ethylenimine)-Pluronic micelles demonstrated enhanced pulmonary retention in rats after injection when compared to Pluronic P123 micelles. © 2012 Informa Healthcare USA, Inc.


Wang C.,Ocean University of China | Shan Y.,Ocean University of China | Yang J.,Shandong Provincial Qian Foshan Hospital | Xu X.,Ocean University of China | And 3 more authors.
Journal of Biomedical Nanotechnology | Year: 2015

Tumor-associated angiogenesis is triggered by multiple angiogenic factors. Vascular endothelial growth factor blockers are currently a major mechanism of angiogenesis inhibition; however, either insensitivity due to the targeting of single angiogenic factors or serious side effects due to non-specific exposure ultimately leads to the failure of treatment. The herb-derived compound triptolide (TP) can inhibit tumor growth through multiple mechanisms. However, its hydrophobicity and side effects have hindered its translation to the clinic. Here, we have prepared TP-polymeric micelles (TP-PMs) using methoxy poly(ethylene glycol)-block-poly(ε-caprolactone). The drug loading efficiency and encapsulation efficiency can reach 7.2±0.10% and 99.1±1.05%, respectively. The TP-PM solution consisted of monodispersed particles (PDI = 0.100±0.023), which were 53.1±1.2 nm in size. In vitro release profiles indicated that the TP-PM solution exhibited better sustained-release action when compared with free TP solution. Pharmacokinetic and tumor tissue distribution studies showed that TP-PMs facilitated TP accumulation in tumor tissues. The tumor inhibition rate upon treatment with TP-PMs was higher than 50%, and the survival time of B16-F10 melanoma bearing mice was efficiently prolonged after TP-PM administration. In addition, serum VEGF levels and tumor incidence of the TP-PM-treated group were both significantly reduced, and histological analyses revealed that the tumor vessel diameter and density in the TP-PM-treated group were much smaller than those observed in the control groups. These results indicated that TP-PMs serve as a potential angiogenesis inhibitor. Copyright © 2015 American Scientific Publishers.


Xu W.,Shandong Provincial Qian Foshan Hospital | Fan X.,Shandong University | Zhao Y.,Shandong University | Li L.,Shandong University
Colloids and Surfaces B: Biointerfaces | Year: 2015

The aim of the present study is to construct a cysteine modified polyion complex micelles made of Pluronic F127-chitosan (PF127-CS), Pluronic F127-cysteine (PF127-cysteine) and sodium cholate (NaC) and to evaluate the potential of the micelles as an oral drug delivery system for paclitaxel. Systematic studies on physicochemical properties including size distribution, zeta-potential and morphology were conducted to validate the formation of micelle structure. Compared with Pluronic micelles, drug-loading capacity of PF127-CS/PF127-cysteine/NaC micelles was increased from 3.35% to 12.77%. Both the critical micelle concentration and the stability test confirmed that the PF127-CS/PF127-cysteine/NaC micelles were more stable in aqueous solution than sodium cholate micelles. Pharmacokinetic study demonstrated that when oral administration the area under the plasma concentration-time curve (AUC0-∞) and the absolute bioavailability of paclitaxel-loaded micelles were five times greater than that of the paclitaxel solution. In general, PF127-CS/PF127-cysteine/NaC micelles were proven to be a potential oral drug delivery system for paclitaxel. © 2015 Elsevier B.V.


Xu W.,Shandong University | Xu W.,Shandong Provincial Qian Foshan Hospital | Deng Z.,Shandong Academy of Sciences | Guo H.,Jinan Stomatological Hospital | Ling P.,Shandong University
Biomedical Chromatography | Year: 2012

A sensitive, accurate, rapid and robust LC-MS-MS method for the quantification of aucubin, a major bioactive constituent of Aucuba japonica, Eucommia ulmoides and Plantago asiatica, was established and validated in rat plasma. Plasma samples were simply precipitated by adding methanol and the supernatant was chromatographed by a Diamonsil® C18(2) column with the mobile phase comprising a mixture of 10mm ammonium acetate in methanol and that in water with the ratio of 50:50 (v/v). Quantification of aucubin was performed by mass spectrometry in the multiple-reaction monitoring mode with positive atmospheric ionization at m/z 364→149 for aucubin, and m/z 380→165 for catalpol (IS), respectively. The retention time was 2.47 and 2.44min for aucubin and the IS, respectively. The calibration curve (10.0-30,000ng/mL) was linear (r2>0.99) and the lower limit of quantification was 10.0ng/mL in the rat plasma sample. The method showed satisfactory results such as sensitivity, specificity, precision, accuracy, recovery, freeze-thaw and long-term stability. This simple LC-MS method was successfully applied in a pharmacokinetic study carried out in Sprague-Dawley rats after oral administration of aucubin at a single dose of 50mg/kg. Herein the pharmacokinetic study of aucubin is reported for the first time. © 2011 John Wiley & Sons, Ltd.


Liu G.-X.,Jinan Stomatological Hospital | Fang G.-Q.,Jinan Stomatological Hospital | Xu W.,Shandong Provincial Qian Foshan Hospital
International Journal of Molecular Sciences | Year: 2014

Combinations of chemotherapeutic drugs with nucleic acid has shown great promise in cancer therapy. In the present study, paclitaxel (PTX) and DNA were co-loaded in the hyaluronic acid (HA) and folate (FA)-modified liposomes (HA/FA/PPD), to obtain the dual targeting biomimetic nanovector. The prepared HA/FA/PPD exhibited nanosized structure and narrow size distributions (247.4 ± 4.2 nm) with appropriate negative charge of -25.40 ± 2.7 mV. HA/FA/PD (PTX free HA/FA/PPD) showed almost no toxicity on murine malignant melanoma cell line (B16) and human hepatocellular carcinoma cell line (HepG2) (higher than 80% cell viability), demonstrating the safety of the blank nanovector. In comparison with the FA-modified PTX/DNA co-loaded liposomes (FA/PPD), HA/FA/PPD showed significant superiority in protecting the nanoparticles from aggregation in the presence of plasma and degradation by DNase I. Moreover, HA/FA/PPD could also significantly improve the transfection efficiency and cellular internalization rates on B16 cells comparing to that of FA/PPD (p < 0.05) and PPD (p < 0.01), demonstrating the great advantages of dual targeting properties. Furthermore, fluorescence microscope and flow cytometry results showed that PTX and DNA could be effectively co-delivered into the same tumor cell via HA/FA/PPD, contributing to PTX/DNA combination cancer treatment. In conclusion, the obtained HA/FA/PPD in the study could effectively target tumor cells, enhance transfection efficiency and subsequently achieve the co-delivery of PTX and DNA, displaying great potential for optimal combination therapy. © 2014 by the authors.


PubMed | Shandong Provincial Qian Foshan Hospital and Shandong University
Type: | Journal: Materials science & engineering. C, Materials for biological applications | Year: 2016

Dendrimers as a new class of polymeric materials have a highly ordered branched structure, exact molecular weight, multivalency and available internal cavities, which make them extensively used in biology and drug-delivery. Concurrent with the development of dendrimers, much more attention is drawn to a novel block copolymer which combines linear chains with dendritic macromolecules, the linear-dendritic block copolymer (LDBC). Because of the different solubility of the contrasting regions, the amphiphilic LDBCs could self-assemble to form aggregates with special core-shell structures which exhibit excellent properties different from traditional micelles, such as lower critical micelle concentration, prolonged circulation in the bloodstream, better biocompatibility, and lower toxicity. The present review briefly describes the type of LDBC, the self-assembly behavior in solution, and the application in delivery system including the application as drug carriers and gene vectors. The interactions between block copolymers and drugs are also summarized to better understand the release mechanism of drugs from the linear-dendritic block copolymers.


PubMed | Ocean University of China, Hong Kong Jockey Club Institute of Chinese Medicine and Shandong Provincial Qian Foshan Hospital
Type: Journal Article | Journal: Oncotarget | Year: 2016

Chemoresistance is the major impediment for treating pancreatic cancer. Herb-derived compound triptolide (TP) can inhibit proliferation of chemo-resistant pancreatic cancer (CPC) cell lines through multiple mechanisms, which exhibited superior anticancer efficacy compared with gemcitabine. However, toxicity due to non-specific exposure to healthy tissues hindered its clinical translation. Herein we successfully achieved targeting CPC cells and avoiding exposure to healthy tissues for TP by nucleolin-specific aptamer (AS1411) mediated polymeric nanocarrier. We conjugated AS1411 aptamer to carboxy terminated poly(ethylene glycol)-block-poly(d, l-lactide) (HOOC-PEG-PDLLA), then prepared AS1411-PEG-PDLLA micelle loading TP (AS-PPT) through solid dispersion technique. AS-PPT showed more antitumor activity than TP and equivalent specific binding ability with gemcitabine-resistant human pancreatic cancer cell (MIA PaCa-2) to AS1411 aptamer in vitro. Furthermore, we studied the distribution of AS-PPT (Cy3-labed TP) at tissue and cellular levels using biophotonic imaging technology. The results showed AS1411 facilitated TP selectively accumulating in tumor tissues and targeting CPC cells. The lifetime of the MIA PaCa-2 cell-bearing mice administrated with AS-PPT was efficiently prolonged than that of the mice subjected to the clinical anticancer drug Gemzar in vivo. Such work provides a new strategy for overcoming the drug resistance of pancreatic cancer.


PubMed | Ocean University of China and Shandong Provincial Qian Foshan Hospital
Type: | Journal: Colloids and surfaces. B, Biointerfaces | Year: 2016

Poor corneal penetration and short residence time on the ocular surface are two major bottlenecks for conventional ophthalmic formulations. To overcome the foregoing dilemmas, we prepared two novel formulations of pimecrolimus nanomicelles (PNM) with particle size of 37.85 1.21 nm and thermosensitive hydrogel (PTH) for treating Keratoconjunctivitis Sicca (KCS). PNM were investigated by transmission electron microscopy (TEM), Malvern laser particle size analyzer, X-ray diffraction (XRD) system, and the content of drug in PNM was measured by high-performance liquid chromatography (HPLC). The drug loading and encapsulation efficiency reached to 7.57% 0.10% and 97.9% 1.26%, respectively. PTH displayed special gel-sol transition behavior with temperature increasing from 4 C to 37 C. The in vitro release profile demonstrated that PNM and PTH exhibited sustained-release behavior compared with free pimecrolimus oil-based eye drop (FPO). In addition, we established a mouse model of KCS induced by benzalkonium chloride to evaluate the therapeutic outcome of different pimecrolimus formulations. The production of tear, fluorescein staining scores and histopathologic examinations of the cornea were assessed in detail. The results confirmed that PNM had the best therapeutic effect among all formulations based on its higher drug encapsulation capability, favourable permeability and sustained release. All these indicated that PNM could serve as a potent ophthalmologic agent for KCS.

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