Hao Zou

Second Military Medical University, Shanghai, Shanghai, Shanghai Shi, China

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Publications (22)56.75 Total impact

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    ABSTRACT: Efficient gene release after intracellular uptake is very important for non-viral gene delivery systems. To construct a glutathione-responsive gene delivery system, we developed gold-cysteamine (AuCM)/plasmid DNA (pDNA)/poly TAT (pTAT)/hyaluronic acid (HA) nanocomplexes (AuCM/pDNA/pTAT/HA) in this study. The AuCM/pDNA/pTAT/HA nanocomplexes possessed a small size less than 200 nm and negative zeta potential of –17 ± 4 mV. The multilayer structure was verified by UV-Vis spectra, surface charges, dynamic light scattering. Morphology was observed by transmission electron microscope. The AuCM/pDNA/pTAT/HA nanocomplexes could completely protect pDNA against enzymatic degradation. These nanocomplexes showed effective cellular uptake in CD44 receptors over-expressed HepG 2 cells in a HA/CD44 interaction dependent manner. Moreover, transfection efficacy was significantly enhanced in AuCM/pDNA/pTAT/HA treated HepG 2 cells compared with AuCM/pDNA/pTAT, and was further enhanced in the presence of GSH, indicating that AuCM/pDNA/pTAT/HA was glutathione-responsive. Biodistribution revealed that AuCM/pDNA/pTAT/HA nanocomplexes mainly accumulated in liver. In conclusion, AuCM/pDNA/pTAT/HA nanocomplexes may serve as glutathione-responsive gene carriers for actively targeting gene delivery to CD44 receptors over-expressed liver cancers.
    No preview · Article · Mar 2016 · Journal of Biomedical Nanotechnology
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    ABSTRACT: Aims: To develop novel iRGD (internalizing Arg-Gly-Asp peptide)-conjugated DSPE-PEG2000 nanomicelles (M-SAL-iRGD) for delivery of salinomycin to both liver cancer cells and cancer stem cells (CSCs). Materials & methods: The characterization, antitumor activity and mechanism of action of M-SAL-iRGD were evaluated. Results & conclusion: M-SAL-iRGD possessed a small size of around 10 nm, and drug encapsulation efficacy higher than 90%. M-SAL-iRGD showed significantly increased cytotoxic effect toward both nontargeted M-SAL (salinomycin-loaded DSPE-PEG2000 nanomicelles) and salinomycin in both liver cancer cells and CSCs. The tissue distribution and antitumor assays in mice bearing liver cancer xenograft confirmed the superior penetration tumor efficacy and antitumor activity of M-SAL-iRGD. M-SAL-iRGD represent a potential effective nanomedicine against liver cancer.
    No preview · Article · Sep 2015 · Nanomedicine
  • WenQing LI · Hao ZOU · YanQiang ZHONG
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    ABSTRACT: Objective: To establish an HPLC method for simultaneous content determination of diazepam, nordazepam and flumazenil in Beagle dog plasma. Methods: The analysis was performed on Kromasil 100-5 C18 column(250 mm × 4.6 mm, 5 μm). Clonazepam was used as an internal standard. The mobile phase was composed of methanol(A)-water(B)-tetrahydrofuran(C)(55: 40: 5) at a flow rate of 1.0 ml/min. The detection wavelength was 254 nm and the column temperature was 25°C Results: Diazepam, nordazepam and flumazenil were in good linearity within the ranges of 0.025-1.000 μg/ml (r=0.999 9, 0.999 0, 0.998 9). Intra-day and inter-day RSD were both less than 6%(n = 5). Recovery rates were nearly 100%. Conclusion: The HPLC method is accurate, rapid, simple and could be used for simultaneous determination of diazepam, nordazepam and flumazenil in Beagle dog plasma.
    No preview · Article · Apr 2015
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    ABSTRACT: Scaffolds that can achieve cell adhesion and controlled release of protein drugs are very promising in bone tissue engineering. Due to their biocompatibility and injectablity, poly(lactide-co-glycolide acid) (PLGA) porous microspheres (PLGA-pMS) present potential scaffolds in bone tissue engineering. However, their application is hampered by the burst release of protein drugs and hydrophobicity that leads to poor cell adhesion. To overcome these drawbacks, we developed novel PLGA-pMS by incorporating bovine serum albumin (BSA) loaded chitosan microspheres (CS-MS) in Gly-Arg-Gly-Asp-Ser-Pro-Cys (GRGDSPC) modified PLGA-pMS (CS-MS/PLGA-pMS). GRGDSPC was used to enhance the hydrophilicity and cell affinity of the porous microspheres. Results showed that PLGA-pMS had a size of 446.77±19.46μm, with an average surface pore size of 21.56±3.02μm, whereas CS-MS had a size of 15.98±0.96μm and 16.35±0.38μm (5% and 10% TPP-prepared CS-MS, respectively). A scanning electron microscope (SEM) and a confocal laser scanning microscope (CLSM) revealed that CS-MS were partly embedded in the PLGA matrices and the integrity of CS-MS was retained. Thermogravimetry analyzer (TGA) also demonstrated that CS-MS were incorporated into PLGA-pMS. The CS-MS/PLGA-pMS had a size of 454.02±16.09μm, with a BSA encapsulation efficiency of 53.19±1.67% and 62.16±3.44% (5% and 10% TPP-prepared CS-MS, respectively). CS-MS/PLGA-pMS exhibited a sustained FITC-BSA release for 28 days. Modification of GRGDSPC significantly improved adhesion of MG-63 cells on the porous microspheres. In conclusion, CS-MS/PLGA-pMS may act as potential bifunctional scaffolds for bone tissue engineering.
    No preview · Article · Jun 2014 · Colloids and surfaces B: Biointerfaces
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    ABSTRACT: Nanoparticles designed for biomedical applications are often coated with polymers containing reactive functional groups, such as -COOH and -NH2, to conjugate targeting ligands or drugs. However, introducing highly charged surfaces promotes binding of the nanoparticles to biomolecules in biological systems through ionic interactions, causing the nanoparticles to aggregate in biological environments and consequently undergo strong non-specific binding to off-target cells and tissues. Developing a unique polymer with neutral surfaces that can be further functionalized directly would be critical to develop suitable nanomaterials for nanomedicine. Here, we report a thiol-reactive amphiphilic block copolymer poly(ethylene oxide)-block-poly(pyridyldisulfide ethylmeth acrylate) (PEO-b-PPDSM) for coating gold nanoparticles (AuNPs). The resultant polymer-coated AuNPs have almost neutral surfaces with slightly negative zeta potentials from -10 to 0 mV over a wide pH range from 2 to 12. Although the zeta potential is close to zero we show that the PEO-b-PPDSM copolymer-coated AuNPs have both good stability in various physiological conditions and reduced non-specific adsorption of proteins/biomolecules. Because of the multiple pyridyldisulfide groups on the PPDSM block, these individually dispersed nanocomplexes with an overall hydrodynamic size around 43.8 nm can be directly functionalized via disulfide-thiol exchange chemistry.
    No preview · Article · Apr 2014 · Polymer Chemistry
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    ABSTRACT: Objective To synthesize three kinds of surface-modified gold nanoparticles and to compare their size distribution, zeta potential, surface morphology, and stability. Methods Poly (vinyl pyrrolidone) (PVP) stabilized gold nanoparticles (PVP-AuNPs), didodecyldimethylammonium bromide (DODAB, a cationic lipid) coated gold nanoparticles (DODAB-AuNPs), and cysteamine modified gold nanoparticles (CA-AuNPs) were successfully synthesized by chemical reduction method. The size distribution, zeta potential, and surface morphology of the three kinds of gold nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM); and the stability of them was evaluated in various concentrations of sodium ions (0. 01, 0 1, 0. 5 and 1 mol/L NaCl; pH = 7. 2) and at different pH values (1. 0-14. 0) by UV-Vis absorption spectra. Results The mean diameters of PVP-AuNPs, DODAB-AuNPs, and CA-AuNPs were (15 0 + 3.1) nm, (22.7 + 6.1) nm, and (18. 0 + 4. 6) nm, respectively; and their zeta potentials were (- 19. 7 + 4. 1), (62. 8 + 4. 3), and (33. 3 + 7. 7) mV, respectively. It was also found that PVP-AuNPs and DODAB-AuNPs were very stable in NaCl solution and different pH environments. However, CA-AuNPs solution was sensitive to concentration of sodium ions and pH value changes and it could maintain stable only when the concentration of NaCl was 0. 01 mol/L or the pH value was within 4. 5-6. 5; otherwise there would be aggregation. Conclusion The three kinds of gold nanoparticles have a nano spherical shape and good stability, with different surface potentials when modified with different ligands; these findings provide reference for design of drug delivery carriers.
    No preview · Article · Nov 2013 · Academic Journal of Second Military Medical University
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    ABSTRACT: Breast cancer stem cells (BCSCs), which can fully recapitulate the tumor origin and are often resistant to chemotherapy and radiotherapy, are currently considered as a major obstacle for breast cancer treatment. To achieve the goal of both targeting BCSCs and bulk breast cancer cells, we developed 8-hydroxyquinoline-loaded hyaluronan modified mesoporous silica nanoparticles (MSN)-supported lipid bilayers (HA-MSS) and docetaxel-loaded MSS. The results showed that the size of all the nanoparticles was smaller than 200 nm. BCSCs were enriched from MCF-7 cells by a sphere formation method and identified with the CD44(+)/CD24(-) phenotype. Quantitative and qualitative analysis demonstrated that HA promotes the uptake of HA-MSS in CD44-overexpressing MCF-7 mammospheres, revealing the mechanism of receptor-mediated endocytosis. DTX or DTX-loaded MSS showed much enhanced cytotoxicity against MCF-7 cells compared with MCF-7 mammospheres, whereas 8-HQ or 8-HQ-loaded HA-MSS showed much enhanced cytotoxicity against MCF-7 mammospheres compared with MCF-7 cells. In the MCF-7 xenografts in mice, the combination therapy with DTX-loaded MSS plus 8-HQ-loaded HA-MSS produced the strongest antitumor efficacy, with little systemic toxicity (reflecting by loss of body weight) in mice. Thus, this combination therapy may provide a potential strategy to improve the therapy of breast cancer by eradication of breast cancer cells together with BCSCs.
    No preview · Article · Jul 2013 · Biomaterials
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    ABSTRACT: A subcutaneous exenatide delivery system was developed and characterized in vitro and in vivo. The results clearly showed that the exenatide loaded PLGA microspheres prepared by using a non-aqueous processing medium had low burst release and high drug encapsulation efficiency. Exenatide loaded in the microspheres preserved its bioactivity. The pharmacokinetics parameters were determined after subcutaneous administration of microspheres to SD rats. The plasma concentration of the single dose of the sustained-release microspheres attained Cmax of 108.19±14.92ng/ml at tmax of 1.33±0.58h and the t1/2 was 120.65±44.18h. There was a linear correlation between the in vitro and in vivo release behavior (R2=0.888). Exenatide loaded microspheres may prove to have great potential for clinical use.
    No preview · Article · Jun 2013 · Peptides
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    ABSTRACT: pH-sensitive liposomes represent an effective gene vector in cancer therapy. However, their use is greatly hampered by their relatively low transfection efficiency. To improve the transfection efficiency of pH-sensitive liposomes, we prepared complexes containing 3β-[N-(N',N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) and dioleoylphosphatidyl ethanolamine (DOPE) liposomes and pH-sensitive liposomes composed of cholesteryl hemisuccinate (CHEMS) and DOPE, and evaluated the influence of various factors on plasmid DNA (pDNA) transfection efficiency. All DC-Chol/DOPE liposome/pDNA and pH-sensitive liposome complexes showed similarly potent pH sensitivity. In the presence of serum-containing medium, two optimized complexes of DC-Chol/DOPE liposomes/pDNA and pH-sensitive PEGylated liposomes showed high transfection efficiency of 22.94% and 20.07%, respectively. Notably, DC-Chol/DOPE (2:3) liposomes/pH-sensitive PEGylated (1%) liposome complexes with a charge ratio of 1:1 (m/m [+/-]) showed enhanced accumulation in tumors in vivo. Our results show the influence of various factors on pDNA transfection efficiency in complexes of DC-Chol/DOPE liposomes and pH-sensitive PEGylated liposomes. Understanding of such mechanisms will lead to better design of complexes of DC-Chol/DOPE liposomes and pH-sensitive liposomes for gene therapy.
    Full-text · Article · Apr 2013 · International Journal of Nanomedicine
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    ABSTRACT: The aim of this report was to introduce a novel "core-membrane" microgel drug-delivery device for spontaneously pulsed release without any external trigger. The microgel core was prepared with alginate and chitosan. The semipermeable membrane outside the microgel was made of polyelectrolytes including polycation poly(allylamine hydrochloride) and sodium polystyrene sulfonate. The drug release of this novel system was governed by the swelling pressure of the core and the rupture of the outer membrane. The size of the core-membrane microgel drug-delivery device was 452.90 ± 2.71 μm. The surface charge depended on the layer-by-layer coating of polyelectrolytes, with zeta potential of 38.6 ± 1.4 mV. The confocal microscope exhibited the layer-by-layer outer membrane and inner core. The in vitro release profile showed that the content release remained low during the first 2.67 hours. After this lag time, the cumulative release increased to 80% in the next 0.95 hours, which suggested a pulsed drug release. The in vivo drug release in mice showed that the outer membrane was ruptured at approximately 3 to 4 hours, as drug was explosively released. These data suggest that the encapsulated substance in the core-membrane microgel delivery device can achieve a massive drug release after outer membrane rupture. This device was an effective system for pulsed drug delivery.
    Full-text · Article · Feb 2013 · International Journal of Nanomedicine
  • Fei-Fei Yu · Hao Zou · Yan-Qiang Zhong
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    ABSTRACT: Now the layer-by-layer self-assembling (LbL) technique has become an attention-getting reparative methodology for ultrathin film formation. Many scientists in different academic areas including bioengieering, medical science, drug controlled release, optoelectronics dive into this technology. Among of them, carriers with structures which can be flexibly controlled are more useful since functional structure units can be assembled in layer-by-layer fashion, which is simplicity, chemical mildness, concealment, can achieve targeted drug delivery and so on. In this review, we have discussed the advantage, development, influential factors and applications of LbL. We have focused on reviewing the applications and perspective of nanoparticles, microgels and capsules were both fabricated via the LbL assembling at drug delivery.
    No preview · Article · Mar 2012 · Yao xue xue bao = Acta pharmaceutica Sinica
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    ABSTRACT: Objective: To synthesize a new type of cationic polymers (β-ammo esters) (PBAE) and to study its role as a gene vector. Methods: PBAE was synthesized by the Michael addition reaction. PBAE/pDNA complex nanoparticles were prepared by self-assembly, and the gene tranfection efficiency mediated by the nanoparticles into HEK293 cells in vitro was observed. Results: When weight ratio of PBAE/pDNA was 50: 1, pDNA was completely wrapped. And the transfection efficiency of PBAE/pDNA nanoparticles (PBAE/pDNA weight ratio being 200: 1) was significantly higher than PEI/pDNA nanoparticles (43.3% ± 3.7% vs 30.3% ± 2.1%, P < 00.05). Conclution: Cationic poly(β-amino esters) can electrostatically bind to and condense anionic DNA into nanometersized parties. PBAE/pDNA nanopartides has a high transfection efficiency in in vitro transfection experiments.
    No preview · Article · May 2011 · Academic Journal of Second Military Medical University
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    ABSTRACT: The purpose of this study was to develop poly(lactide-co-glycolide) (PLGA) based in situ forming implants (ISFI) for controlled release of thymosin alpha 1 (Talpha1). The ISFI was prepared by dissolving PLGA in N-methyl-2-pyrrolidone (NMP) or mixtures of NMP and triacetin. Talpha1 microparticles, prepared by spray-freeze drying method with chitosan or bovine serum albumin as a protectant, were suspended in PLGA solutions. The effects of Talpha1 pre-encapsulation, PLGA molecular weight, PLGA concentration and organic solvents composition on the in vivo Talpha1 release were evaluated by subcutaneously injecting Talpha1-loaded ISFI into Sprague-Dawley Rats. The pharmacological efficacy of Talpha1-loaded ISFI was examined using immunosuppressive BALB/c mice induced by cyclophosphamide. The ISFI composed of Talpha1 pre-encapsulated with chitosan, higher molecule-weight PLGA at higher concentration and more triacetin showed a lower initial release and a longer sustained release period. The optimal prescription of our study showed a low initial release of 29.3% (24 h), followed by a slow and continuous drug release up to 28 d in vivo. An in vitro release device was designed to mimic the in vivo release of Talpha1, and good correlation was observed between the in vitro and in vivo releases, with the linear correlation coefficient of 0.9899. Talpha1-loaded ISFI showed low cytotoxicity as tested by CCK-8 assay. Talpha1-loaded ISFI significantly increased the thymic index and spleen index of immunosuppressive mice. These results suggest that the ISFI is a suitable system for controlled release of Talpha1.
    No preview · Article · Sep 2010 · International Journal of Pharmaceutics
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    ABSTRACT: Pulsed drug delivery (PDD), which can be released at well-defined time points as the therapy needs, can decrease the frequency and avoid taking drug at night, thus improving patient compliance. Here we introduce three kinds of programmed PDD systems independent of external chemical triggering; they are divided according to the triggering mechanisms, degradation-triggered PDD, osmotic pressure-triggered PDD, and both degradationi and osmotic pressure-triggered PDD. This paper reviews preparing technique, release mechanisms and influencing factors of the three PDD systems. The release profiles of pulsatile PDD can be regulated for different therapeutic needs, requiring no external triggers; especially that the PDD system triggered by both degradation and osmotic pressure has a bright future.
    No preview · Article · Jul 2010 · Academic Journal of Second Military Medical University
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    ABSTRACT: Objective: To prepare rh-endostatin loaded poly (lactic-co-gtycolic acid) (PLGA) microspheres and to evaluate their release behavior in vitro. Methods: Rh-endostatin PLGA microspheres were prepared by W/O/W process. The content and in vitro cumulative release was determined by a HPLC method. Results: The prepared microspheres were well-shaped, with a mean diameter of 122.7 μm. The drug loading and encapsulation efficiency were 1.28% and 38.65%, respectively. The rh-Endo solution (250 μg/ml) showed good stability after placed at 4°C and 25°C for 108 h. The cumulative in vitro release was up to 67.37% in 28 days. Conclusion: The rh-Endo can be encapsulated in microspheres to yield sustained release using biodegradable polymers PLGA as the carrier material.
    No preview · Article · Jan 2010 · Academic Journal of Second Military Medical University
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    ABSTRACT: We previously reported the development of PE38KDEL-loaded anti-HER2 poly(lactic-co-glycolic acid) (PLGA) nanoparticles that bind and internalize in HER2-overexpressing breast cancer cells, enabling potent anti-tumor activity. To overcome the problems associated with the short half-lives of this drug delivery system, we have constructed PE38KDEL-loaded anti-HER2 PEGylated liposomes (PE-HER-liposomes). PE-HER-liposomes were constructed with Fab' of recombinant humanized anti-HER2 monoclonal antibody (anti-HER2 Fab') covalently linked to PEGylated liposomes containing PE38KDEL (PE-liposomes). We attached anti-HER2 Fab' to the terminus of PEG (polyethylene glycol) on PEGylated liposomes. Incorporation of pyridylthiopropionoylamino-PEG-distearoylphosphatidylethanolamine (PDP-PEG-DSPE) into PEGylated liposomes followed by mild thiolysis of the PDP groups resulted in the formation of reactive thiol groups at the periphery of the liposomes. Efficient attachment of maleimide-derivatized anti-HER2 Fab' took place under mild conditions. The characterization of PE-HER-liposomes, such as particle size, was evaluated by dynamic light-scattering detector. The Micro BCA method was used to determine the encapsulation efficiency of PE38KDEL and the quantity of conjugated Fab'. Flow cytometry and confocal microscopy showed that PE-HER-liposomes possessed receptor-specific binding and internalization for HER2-overexpressing SK-BR3 cells. Remarkably, PE-HER-liposomes were more cytotoxic than non-targeted PE-liposomes in HER2-overexpressing breast cancer cells. In conclusion, PE-HER-liposomes could serve as a promising therapeutic candidate for the treatment of HER2-overexpressing breast cancers.
    No preview · Article · Jul 2009 · International Journal of Pharmaceutics
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    ABSTRACT: In order to enhance the gene delivery efficiency and decrease the cytotoxicity of polyplexes, we synthesized Solutol-g-PEI by conjugating polyethyleneimine (PEI) to Solutol (polyoxyethylene (10) stearate), and evaluated its efficiency as a possible nonviral gene carrier candidate. Structural analysis of synthesized polymer was performed by using1H-NMR. Gel retardation assay, particle sizes and zeta potential measurement confirmed that the new gene carrier formed a compact complex with plasmid DNA. The complexes were smaller than 150 nm, which implicated its potential for intracellular delivery. It showed lower cytotoxicity in three different cell lines (Hela, MCF-7, and HepG2) than PEI 25 kDa. pGL3-lus was used as a reporter gene, and the transfection efficiency wasin vitro measured in Hela cells. Solutol-g-PEI showed much higher transfection efficiency than unmodified PEI 25 kDa.
    Preview · Article · Jan 2009 · Macromolecular Research
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    ABSTRACT: A simple, rapid and sensitive liquid chromatography/electrospray tandem mass spectrometry quantitative detection method, using amantadine as internal standard, was developed for the simultaneous analysis of paracetamol, pseudoephedrine and chlorpheniramine concentrations. Analytes were extracted from plasma samples by liquid–liquid extraction with n-hexane–dichloromethane–2-propanol (2:1:0.1, v/v), separated on a C18 reversed-phase column with 0.1% formic acid–methanol (40:60, v/v) and detected by electrospray ionization mass spectrometry in positive multiple reaction monitoring mode. Calibration curves for plasma were linear over the concentration range 10–10,000ngmL−1 of paracetamol, 2–2,000ngmL−1 of pseudoephedrine and 0.2–200ngmL−1 of chlorpheniramine. The method has a lower limit of quantitation of 10ngmL−1 for paracetamol, 2.0ngmL−1 for pseudoephedrine and 0.2ngmL−1 for chlorpheniramine. Recoveries, precision and accuracy results indicate that the method was reliable within the analytical range, and the use of the internal standard was very effective for reproducibility by LC-MS-MS. This method is feasible for the evaluation of pharmacokinetic profiles of a novel multicomponent sustained release formulation containing 325mg of paracetamol, 30mg of pseudoephedrine hydrochloride and 2mg of chlorpheniramine maleate. It is the first time the pharmacokinetic evaluation of a novel sustained-action formulation containing paracetamol, pseudoephedrine and chlorpheniramine has been elucidated in vivo using LC-MS-MS.
    No preview · Article · Jul 2008 · Chromatographia
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    ABSTRACT: The gut hormone glucagon-like peptide-1 (GLP-1) is proposed for treatment of Type II diabetes mellitus. However, the short half life of GLP-1 in vivo is a major limitation for its application due to the frequent invasive administrations. To provide a optimal formulation to overcome this limitation, we developed a GLP-1 entrapped microspheres to achieve sustained release GLP-1 for 4-week. GLP-1 was stabilized by GLP-1-zinc complexation with zinc carbonate and encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) with S/O/O solvent extraction to obtain GLP-1 loaded PLGA microspheres (MS). The characteristics of MS were evaluated as follows: The surface morphology was assessed by scanning electron microscopy (SEM); The drug encapsulation efficiency and GLP-1 controlled release profile was tested by HPLC; The sustained release of GLP-1 MS in vivo and pharmacological efficacy were studied in normal mice and streptozotocin (STZ)-induced diabetic mice model after subcutaneous administration of GLP-1 MS. GLP-1-zinc complexation significantly reduced initial burst release from 37.2 to 7.5%. The controlled release bioactive GLP-1 in vitro was achieved for 4-week period by zinc complexation and addition of ZnCO(3). The optimal and complete cumulative release of GLP-1 from MS was increased from 23 to 63% in 28 d by using low MW PLGA (MW 14000). The in vivo testing in normal mice and diabetic mice suggest that this zinc-stabilized technique combined with S/O/O method in the presence of water insoluble antacid additive ZnCO(3) preserve the biological activity of GLP-1. GLP-1 MS formulation achieved controlled released in vivo for 28 d and exhibit sustained long term pharmacological efficacy to decrease blood glucose level in diabetic mice. This GLP-1 MS formulation provides a practical formulation for long-term sustained delivery of GLP-1 to treat Type II diabetes.
    No preview · Article · Mar 2008 · CHEMICAL & PHARMACEUTICAL BULLETIN
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    ABSTRACT: The gut hormone glucagon-like peptide-1 (GLP-1) is proposed for treatment of Type II diabetes mellitus. However, the short half life of GLP-1 in vivo is a major limitation for its application due to the frequent invasive administrations. To provide a optimal formulation to overcome this limitation, we developed a GLP-1 entrapped microspheres to achieve sustained release GLP-1 for 4-week. GLP-1 was stabilized by GLP-1-zinc complexation with zinc carbonate and encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) with S/O/O solvent extraction to obtain GLP-1 loaded PLGA microspheres (MS). The characteristics of MS were evaluated as follows: The surface morphyology was assessed by scanning electron microscopy (SEM); The drug encapsulation efficiency and GLP-1 controlled release profile was tested by HPLC; The sustained release of GLP-1 MS in vivo and pharmacological efficacy were studied in normal mice and streptozotocin (STZ)-induced diabetic mice model after subcutaneous administration of GLP-1 MS. GLP-1-zinc complexation significantly reduced initial burst release from 37.2 to 7.5%. The controlled release bioactive GLP-1 in vitro was achieved for 4-week period by zinc complexation and addition of ZnCO3. The optimal and complete cumulative release of GLP-1 from MS was increased from 23 to 63% in 28 d by using low MW PLGA (MW 14000). The in vivo testing in normal mice and diabetic mice suggest that this zinc-stabilized technique combined with S/O/O method in the presence of water insoluble antacid additive ZnCO3 preserve the biological activity of GLP-1. GLP-1 MS formulation achieved controlled released in vivo for 28 d and exhibit sustained long term pharmacological efficacy to decrease blood glucose level in diabetic mice. This GLP-1 MS formulation provides a practical formulation for long-term sustained delivery of GLP-1 to treat Type II diabetes.
    No preview · Article · Feb 2008 · CHEMICAL & PHARMACEUTICAL BULLETIN