Hao Zou

University of Michigan, Ann Arbor, Michigan, United States

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Publications (14)46.04 Total impact

  • [Show abstract] [Hide abstract]
    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.
    Colloids and surfaces B: Biointerfaces 06/2014; · 4.28 Impact Factor
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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.
    Polymer Chemistry 04/2014; 5(8):2768-2773. · 5.23 Impact Factor
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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.
    Biomaterials 07/2013; · 8.31 Impact Factor
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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.
    Peptides 06/2013; · 2.52 Impact Factor
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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.
    International Journal of Nanomedicine 01/2013; 8:1573-93. · 4.20 Impact Factor
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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.
    International Journal of Nanomedicine 01/2013; 8:877-87. · 4.20 Impact Factor
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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.
    International Journal of Pharmaceutics 09/2010; 397(1-2):122-9. · 3.99 Impact Factor
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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.
    International Journal of Pharmaceutics 07/2009; 374(1-2):145-52. · 3.99 Impact Factor
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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.
    Macromolecular Research 01/2009; 17(1):19-25. · 1.64 Impact Factor
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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.
    Chromatographia 07/2008; 68(3):251-257. · 1.44 Impact Factor
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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.
    CHEMICAL & PHARMACEUTICAL BULLETIN 03/2008; 56(2):156-61. · 1.56 Impact Factor
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    ABSTRACT: The objective of this work was to develop and evaluate a floating-pulsatile drug delivery system intended for chronopharmacotherapy. Floating-pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, we generated the system which consisted of three different parts, a core tablet, containing the active ingredient, an erodible outer shell and a top cover buoyant layer. The dry coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer which is responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with Methocel K4M, Carbopol 934P and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their buoyancy, dissolution and pharmacokinetic, as well gamma-scintigraphically. The results showed that a certain lag time before the drug released generally due to the erosion of the dry coated layer. Floating time was controlled by the quantity and composition of the buoyant layer. Both pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time.
    Journal of Pharmaceutical Sciences 02/2008; 97(1):263-73. · 3.13 Impact Factor
  • Chemical & Pharmaceutical Bulletin - CHEM PHARM BULL TOKYO. 01/2008; 56(2):156-161.
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    ABSTRACT: A blend of floating and pulsatile principles of drug delivery system seems to present the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release. The objective of this study was to develop and evaluate a floating and pulsatile drug delivery system based on an impermeable cylinder. Pulsatile capsule was prepared by sealing the drug tablet and the buoyant material filler inside the impermeable capsule body with erodible plug. The drug delivery system showed typical floating and pulsatile release profile with a lag time followed by a rapid release phase. The lag time prior to the pulsatile drug release correlated well with the erosion properties of plugs and the composition of the plug could be controlled by the weight of the plug. The buoyancy of the whole system depended on the bulk density of the dosage form. Gamma-scintigraphic evaluation in humans was used to establish methodology capable of showing the subsequent in vivo performance of the floating and pulsatile release capsule. Developed formulations showed instantaneous floating with no drug release during the lag time followed by a pulse drug release. From the gamma-scintigraphic results, the pulsatile release capsule we prepared could achieve a rapid release after lag time in vivo, which was longer than that in vitro. The scintigraphic evaluation could confirm qualitatively that the system with in vitro lag time of 4.0 h provided, with relatively high reproducibility, a pulsatile release occurred around 5.0 h after administration.
    CHEMICAL & PHARMACEUTICAL BULLETIN 05/2007; 55(4):580-5. · 1.56 Impact Factor

Publication Stats

61 Citations
46.04 Total Impact Points

Institutions

  • 2014
    • University of Michigan
      • Department of Pharmaceutical Sciences
      Ann Arbor, Michigan, United States
  • 2007–2014
    • Second Military Medical University, Shanghai
      Shanghai, Shanghai Shi, China