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Xu S.,Tianjin University | Wang W.,CAS Tianjin Institute of Biomedical Engineering | Li X.,Tianjin Institute of Medical and Pharmaceutical Science | Liu J.,Tianjin University | And 3 more authors.
European Journal of Pharmaceutical Sciences | Year: 2014

As drug therapies become increasingly sophisticated, the synergistic benefits of two or more drugs are often required. In this study, we aimed at improving anti-tumor efficiency of paclitaxel (PTX)-incorporated thermo-sensitive injectable hydrogel by the synergy of burst release of doxorubicin hydrochloride (DOX·HCl). Thermosensitive injectable hydrogel composed of nanoparticles assembled from amphiphilic copolymer poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolaone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) was fabricated. Hydrophobic PTX and hydrophilic DOX·HCl were loaded simultaneously in the thermo-sensitive injectable hydrogel by a two-stage entrapment. Thermosensitive gelling behaviors of drug-loading PECT nanoparticle aqueous dispersions were studied. In vitro release profiles of PTX and DOX·HCl and in vivo anti-tumor effect by dual drugs from PECT hydrogel were investigated. The results showed that hydrophilic and hydrophobic drugs could be successfully entrapped in PECT hydrogel simultaneously without affecting its thermo-sensitive behavior. In vitro release profiles demonstrated the burst release of DOX·HCl and the sustained release of PTX. Anti-tumor effect was improved by a fast and tense attack caused by the burst release of hydrophilic DOX·HCl from hydrogel, which was continued by the sequent sustained release of PTX-incorporated nanoparticles and remnant DOX·HCl. Unintentionally, entrapped in PECT hydrogel, hydrophilic DOX·HCl was observed to have a sustained releasing pattern in vitro and in vivo. © 2014 Elsevier B.V. All rights reserved.

Wang W.,Tianjin University | Deng L.,Tianjin University | Xu S.,Tianjin University | Zhao X.,Tianjin Institute of Medical and Pharmaceutical Science | And 7 more authors.
Journal of Materials Chemistry B | Year: 2013

Combination delivery systems composed of injectable hydrogels and drug-incorporated micelles or nanoparticles with tunable and convenient properties for clinical operation and storage are urgently demanded in regional cancer chemotherapy to prolong and control drug release, enhance antitumor efficiency and decrease side effects. Previously, we developed a novel thermosensitive amphiphilic triblock copolymer, poly(ε-caprolactone-co-1,4, 8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolactone- co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT), and fabricated a reconstituted "two into one" combination system of thermosensitive injectable hydrogel PTX/PECTGel, assembled from paclitaxel (PTX)-loaded PECT nanoparticles (NPs). PTX/PECTGel could be stored as freeze-dried powders of paclitaxel-loaded PECT NPs, which could be reconstituted into aqueous fluid dispersions at ambient temperature just by mixing with water after gentle stirring for several minutes, and form a hydrogel at the injected site in vivo. Herein, the drug release, in vivo morphology, antitumor efficiency and pharmacokinetic properties of PTX/PECTGel were evaluated. The PTX/PECTGel combination system could continuously release PTX in a near linear manner over 42 days in vitro, and simultaneously, PTX/PECT NPs containing 75% of the total released PTX could dissociate from the PTX/PECT Gel. PTX/PECTGel exhibited remarkable in vitro anti-proliferative activities against Ehrlich ascites carcinoma (EAC) cancer cells. The peritumorally or intratumorally injected PECT gel could cover the entire surface or fill up the interior space of the tumor, respectively. A single peritumoral injection of the PTX/PECTGel formulation at a low dosage of 10 mg kg-1 could completely inhibit the growth of an EAC tumor inoculated in Balb/c mice after the first week, and the inhibition could be sustained for more than 21 days. The plasma pharmacokinetic study demonstrated that PTX/PECTGel could greatly decrease the systemic exposure of PTX, as confirmed by the rather low plasma concentration. On the other hand, the PTX concentration in normal tissues with the intratumoral injection of PTX/PECTGel was approximately 2 μg g-1, which was 3-10 times lower than that with the intraperitoneal or intratumoral injection of Taxol®, implying fewer off-target side effects. These data confirmed that the PTX/PECTGel combination local delivery system could vastly prolong the in vitro and in vivo paclitaxel release, enhance the local tumor inhibition effect and lower the systemic exposure and tissue distribution of paclitaxel. Hence, the "two into one" PTX/PECT Gel system holds underlying value for regional cancer chemotherapy. This journal is © 2013 The Royal Society of Chemistry.

Li Y.-W.,Tianjin Medical University | Zhang Y.,Tianjin Huanhu Hospital | Zhang L.,Tianjin Huanhu Hospital | Li X.,Tianjin Institute of Medical and Pharmaceutical Science | And 9 more authors.
Gene | Year: 2014

Tea polyphenols (TP) was investigated in rats for its protective effect on renal ischemia/reperfusion injury (RIRI). Rats were randomized into groups as follows: (I) sham group (n = 10); (II) RIRI group (n = 10); (III) RIRI + TP (100. mg/kg) group (n = 5); (IV) RIRI + TP (200. mg/kg) group (n = 5); (V) RIRI + TP+ Astragalus mongholicus aqueous extract (AMAE) (300. mg/kg + 100. mg/kg) group (n = 5). For the IRI + TP groups, rats were orally given with tea polyphenols (100, 200 and 300. mg/kg body weight) once daily 10. days before induction of ischemia, followed by renal IRI. For the sham group and RIRI group, rats were orally given with equal volume of saline once daily 10. days before induction of ischemia, followed by renal IRI. Results showed that tea polyphenol pretreatment significantly suppressed ROS level and MDA release. On the other hand, in rats subjected to ischemia-reperfusion, the activities of endogenous antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GSH-Px) showed recovery, whereas the levels of urea nitrogen and serum creatinine were reduced by administration of tea polyphenols orally for 10. days prior to ischemia-reperfusion. Moreover, tea polyphenol pretreatment significantly decreased TLR4 and NF-κB p65 protein expression levels in RIRI rats. At the same time, tea polyphenol pretreatment attenuated the increased level of serum IL-1β, IL-6, ICAM-1 and TNF-α, and enhanced IL-10 production in RIRI rats. Furthermore, tea polyphenol pretreatment significantly decreased renal epithelial tubular cell apoptosis induced by renal ischemia/reperfusion, alleviating renal ischemia/reperfusion injury. These results cumulatively indicate that tea polyphenol pretreatment could suppress the TLR4/NF-κB p65 signaling pathway, protecting renal tubular epithelial cells against ischemia/reperfusion-induced apoptosis, which implies that antioxidants may be a potential and effective agent for prevention of the ischemic/reperfusion injury through the suppression extrinsic apoptotic signal pathway induced by TLR4/NF-κB p65 signal pathway. Moreover, supplement of AMAE can increased renal protection effect of TP. © 2014 Elsevier B.V.

Chen C.,Tianjin University | Wang L.,Tianjin Institute of Medical and Pharmaceutical Science | Deng L.,Tianjin University | Hu R.,Tianjin Institute of Medical and Pharmaceutical Science | Dong A.,Tianjin University
Journal of Biomedical Materials Research - Part A | Year: 2013

To improve the biocompatibility and application properties of injectable chitosan hydrogel, an injectable triple crosslinking network hydrogel (CTGP) is prepared by physical interaction, Michael addition and disulfide bond formation based on thiolated chitosan (CS-TGA), β-glycerophosphate (β-GP) and poly(ethylene glycol) diacrylate (PEGDA) without the addition of cytotoxic crosslinkers and catalysts. Compared with the short gelation time of 2 min of CTG hydrogel (without PEGDA) at 37°C, CTGP hydrogel containing different molecular weight of PEGDA exhibits controllable gelation times from 1 to 22 min, which could meet the different demands in clinical application. Further, the compressive modulus is improved differently by introducing PEGDA into the system. The presence of PEGDA in CTGP hydrogel imparts better swelling property, and there is a sustained protein release from the hydrogel without any initial burst. In vitro cytotoxicity and hemolysis reveal that the gel is biocompatible. In vivo subdermal injection into mice models further confirms the non-cytotoxicity of the hydrogel and the hydrogel is highly resistant to degradation. © 2012 Wiley Periodicals, Inc.

Liang Y.,Tianjin University | Qiao Y.,Tianjin University | Guo S.,Tianjin University | Wang L.,Tianjin Institute of Medical and Pharmaceutical Science | And 4 more authors.
Soft Matter | Year: 2010

The purpose of this study was to design injectable polymer formulations for controlled release of paclitaxel and Bovine serum albumin (BSA) using amphiphilic triblock copolymer (mPEG-b-P(OA-DLLA)-b-mPEG) consisting of methoxy poly(ethylene glycol) (mPEG), poly(octadecanedioic anhydride) (POA) and d,l-lactic acid oligomer (ODLLA). An aqueous dispersion of mPEG-b-P(OA-DLLA)-b- mPEG nanoparticle freeze-dried powder (NP-FDP) can undergo a sol-gel-sol transition as the temperature is increased from 4 to 90°C. The critical gelation concentration (CGC) and lower critical transition temperature (LCTT) are decreased with the increase of P(OA-DLLA) block length in copolymers. During the in vitro degradation process, the content of mPEG in hydrogels slightly changed after the initial sharp reduction, which makes the average particle size in the degradation liquid increase. In vitro release studies demonstrate that there is no initial burst of drug from both hydrogel formulations containing paclitaxel (1 wt%) and BSA (1 wt%). The in vivo hydrogel formation and biocompatibility results confirm that the copolymer NP hydrogel is biocompatible and non-cytotoxic. Therefore, mPEG-b-P(OA-DLLA)-b-mPEG NP hydrogel is suitable for the controlled release of incorporated drugs for long durations. © 2010 The Royal Society of Chemistry.

Wang W.,Tianjin University | Deng L.,Tianjin University | Liu S.,Tianjin University | Li X.,Tianjin Institute of Medical and Pharmaceutical Science | And 5 more authors.
Acta Biomaterialia | Year: 2012

The convenient and precise fabrication of drug-hydrogel formulations with satisfactory degradability and a well-controlled drug release profile are crucial factors for injectable hydrogel formulations in clinical applications. Here a new injectable thermosensitive hydrogel formed from poly(e-caprolactone) (PCL)- poly(ethylene glycol)-poly(e-caprolactone) amphiphilicco-polymers with 1,4,8-trioxa[4.6]spiro-9- undecanone (TOSUO) moieties incorporated in the poly(e-caprolactone) (PCL)block (PECT) was constructed to provide a route to tailor the degradation and drug release behavior. The effect of hydrophilic cyclic ether moieties on the degradation of and drug release by PECT hydrogels were evaluated in vitro and in vivo. The results indicated that a freeze-dried powder of paclitaxel-loaded PECT nanoparticles rapidly dissolved in water at ambient temperature with slightly shaking and formed a stable injectable in situ drug-hydrogel formulation at body temperature, which is convenient for clinical operations because it avoids the need for pre-quenching or long-term incubation. The paclitaxel distribution was also more quantitative and homogeneous on entrapping paclitaxel in PECT nanoparticles. Further, the small number of pendant cyclic ether groups in PCL could decrease the cystallinity and hydrophobicity and, as a result, the in vitro and in vivo retention time of PECT hydrogels and the release of entrapped paclitaxel could be tuned from a few weeks to months by varying the amount of PTOSUO in the hydrophobic block. Significantly, paclitaxel-loaded PECT nanoparticles and free paclitaxel could be simultaneously released during the in vitro paclitaxel release from PECT hydrogels. A histopathological evaluation indicated that in vivo injected PECT hydrogels produced only a modest inflammatory response. Thus pendant cyclic ether modification of PCL could be an effective way to achieve the desired degradation and drug release profiles of amphiphilicco-polymer thermosensitive hydrogels and PECT hydrogels may be suitable for local drug delivery. © 2012 Acta Materialia Inc.

Zhao Y.,Tianjin University | Gao S.,Tianjin University | Zhao S.,Tianjin University | Li Y.,Tianjin Institute of Medical and Pharmaceutical Science | And 3 more authors.
Materials Science and Engineering C | Year: 2012

In this paper, alginate was crosslinked by a condensation reaction of cystamine or cysteine with di-terminated amine groups to form hydrogels containing disulfide bonds. These hydrogels were easily decomposed or disintegrated under physiological reducible conditions by cleavage of disulfide crosslinkage to thiol groups. Porous alginate hydrogel scaffolds were prepared by freeze-drying technique. Results indicated that the pore structure and decomposition properties of the scaffolds were determined by a concentration of alginate solution as well as the amount and types of crosslinker. With surface modification using chitosan, the mechanical properties of the scaffolds were greatly improved. Cytotoxicity evaluation demonstrated that these alginate scaffolds were cytocompatible. © 2012 Elsevier B.V.

Wu B.,Nankai University | Zhang H.,China University of Petroleum - East China | Guo P.,Nankai University | Wang Q.,Tianjin Institute of Medical and Pharmaceutical Science | Chang S.,Nankai University
Journal of the Optical Society of America B: Optical Physics | Year: 2010

A multifunctional cross waveguide is designed based on the photonic crystal structure and the liquid crystal material. The different states of the cross waveguide controlled by the electric field make its various functions possible, including a switch with a high extinction ratio, a splitter that divides the terahertz wave into the desired proportions, and a through or 90° turn waveguide. The plane wave expansion method is used to calculate the bandgap in the photonic crystals, and coupling mode theory is adopted to analyze and eliminate the reflection loss. The finite element method is used to get the proper distribution of the external electric field. The properties of the cross waveguide are simulated by the finite difference time domain method, and the results show that the cross waveguide is a multifunctional device with high performance characteristics. © 2010 Optical Society of America.

Li D.-D.,Tianjin Institute of Medical and Pharmaceutical Science | Tao Z.-W.,Tianjin Institute of Medical and Pharmaceutical Science
Transition Metal Chemistry | Year: 2014

Six binuclear complexes, [Cu2(1,4-tpbd)(bpy) 2(ClO4)2](ClO4)2· 2DMF (1); [Zn2(1,4-tpbd)(bpy)2(ClO4) 2](ClO4)2·4H2O (2); [Ni 2(1,4-tpbd)(phen)2(DMF)2](ClO4) 4·0.5H2O (3); [Cd2(1,4-tpbd)(phen) 2(Cl)2](ClO4)2·6H 2O (4); [Co2(1,4-tpbd)(DMF)6](ClO 4)4 (5); and [Ni2(1,4-tpbd)(DMSO) 2(NCS)4] (6) (1,4-tpbd = N,N,N',N'-tetrakis(2- pyridylmethyl)benzene-1,4-diamine), have been synthesized and investigated as artificial nucleases. Single crystal diffraction reveals that the metal atoms in these complexes are all in a distorted octahedral geometry. The interactions of the complexes with calf thymus DNA (CT-DNA) have been investigated by UV absorption, fluorescence spectroscopy, circular dichroism spectroscopy and viscosity measurements, and modes of CT-DNA binding for the complexes are proposed. Further experiments showed that these complexes can also induce DNA cleavage, and their activities are promoted by external agents. The Zn(II)/H2O2 and Cd(II)/H2O2 systems display efficient oxidative cleavage of supercoiled DNA, which is attributed to a peroxide ion coordinated to the metal center. © 2014 Springer International Publishing Switzerland.

Li D.-D.,Tianjin Institute of Medical and Pharmaceutical Science | Tao Z.-W.,Tianjin Institute of Medical and Pharmaceutical Science
Journal of Coordination Chemistry | Year: 2013

Seven new transition metal complexes formulated as [M2(1,4-tpbd)(diimine) 2(H2O)2]4+ [M = Zn, Co, Ni, Cd; 1,4-tpbd = N,N,N′,N′- tetrakis(2-pyridylmethyl)benzene-1,4-diamine; diimine is a N,N-donor heterocyclic base like 1,10-phenanthroline (phen), 2,2′-bipyridine (bpy), 4,5-diazafluoren-9-one (dafo)] have been synthesized and structurally characterized by X-ray crystallography: [Zn2(1,4-tpbd)(phen)2(H2O)2] 4+ (1), [Zn2(1,4-tpbd)(bpy)2(H2O)2]4+ (2), [Co2(1,4-tpbd)(phen)2(H2O)2]4+ (3), [Ni2(1,4-tpbd)(phen)2(H2O)2] 4+ (4), [Ni2(1,4-tpbd)(bpy)2(H2O)2]4+ (5), [Ni2(1,4-tpbd)(dafo)2(H2O)2]4+ (6) and [Cd2(1,4-tpbd)(phen)2(H2O)2] 4+ (7). Single crystal diffraction reveals that the metals in the complexes are all in a distorted octahedral geometry. The interactions of the seven complexes with calf thymus DNA (CT-DNA) have been investigated by UV absorption, fluorescence, circular dichroism spectroscopy and viscosity measurements. The apparent binding constants (Kapp) are calculated to be 5.2 × 105 M-1 for 1, 1.05 × 105 M -1 for 2, 5.76 × 105 M-1 for 3, 4.57 × 105 M-1 for 4, 1.29 × 105 M -1 for 5, 1.7 × 105 M-1 for 6, 2.53 × 105 M-1 for 7, the binding propensity to the calf thymus DNA in the order: 3 (Co-phen) > 1 (Zn-phen) > 4 (Ni-phen) > 7 (Cd-phen) > 6 (Ni-dafo) > 5 (Ni-bpy) > 2 (Zn-bpy). Furthermore, these complexes display efficient oxidative cleavage of supercoiled DNA; the Zn(II)/H2O2 and Cd(II)/H2O2 systems efficiently cleave DNA attributed to the peroxide ion coordinated to the Zn(II) and Cd(II), which enhanced their nucleophilicity, this is rare. © 2013 © 2013 Taylor & Francis.

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