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ABSTRACT: Galactosylated trimethyl chitosan-cysteine (GTC) nanoparticles (NPs) were developed for oral delivery of a mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) siRNA (siMap4k4) to the activated macrophages for treatment of dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). siRNA loaded GTC NPs were prepared based on ionic gelation of GTC with anionic crosslinkers (tripolyphosphate (TPP) or hyaluronic acid (HA)). The types of crosslinkers involved in GTC NPs significantly affected their physicochemical characteristics. GTC/TPP NPs with smaller particle size and lower zeta potential possessed superior structural stability in gastrointestinal environment compared to GTC/HA NPs. Cellular uptake of GTC/TPP NPs in activated macrophages was significantly enhanced compared to trimethyl chitosan-cysteine (TC)/TPP NPs owing to galactose receptor-mediated endocytosis. The in vitro and in vivo gene knockdown measurement showed that siMap4k4 loaded GTC/TPP NPs effectively inhibited TNF-α production, which remarkably outperformed siMap4k4 loaded TC/TPP NPs. Compared to TC/TPP NPs, GTC/TPP NPs more efficiently promoted the distribution of siRNA in ulcerative colon following oral administration. Daily oral administration of GTC/TPP NPs containing siMap4k4 significantly improved DSS-induced body weight loss, colon length shortening, and increase of myeloperoxidase activity. This study would provide an effective approach for oral siRNA delivery in the treatment of inflammatory bowel diseases.
Biomaterials 05/2013; 34(14):3667-77. · 7.40 Impact Factor
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ABSTRACT: To elucidate the effect of binding affinity for siRNA on the in vivo antitumor efficacy of polyplexes, five kinds of galactose modified trimethyl chitosan-cysteine (GTC) conjugate-based polyplexes were developed through adjusting the incorporated ionic crosslinkers. The resultant polyplexes exhibited similar particle size (135-170 nm) and zeta potential (30-35 mV). Their distinct binding affinities for siRNA were evaluated by gel retardation, heparin displacement, and in vitro siRNA release assays. GTC polyplexes with weak polymer-siRNA binding were structurally unstable and highly susceptible to nuclease degradation, resulting in poor cellular uptake. However, strong binding affinity for siRNA was correlated to delayed intracellular dissociation of polyplexes. The polyplexes with optimized binding affinity for siRNA provided enough protection of siRNA prior to releasing it efficiently in the cytoplasm, resulting in efficient and persistent gene knockdown in vitro. Furthermore, they had remarkable antitumor efficacy in vivo with regard to the tumor growth retardation, gene knockdown, angiogenesis inhibition, and apoptosis induction in QGY-7703 tumor bearing mice. Therefore, tailoring of the binding strength between the polymeric vector and its siRNA cargo in polyplexes may serve as a feasible tool for improving their therapeutic efficacy.
Biomaterials 04/2013; · 7.40 Impact Factor
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ABSTRACT: Cellular and intracellular processing of DNA/polymer nanocomplexes was optimized by tailoring the composition of crosslinking agents for improving in vitro and in vivo transfection efficiency. Nanocomplexes composed of trimethyl chitosan-arginine conjugate (TMC-Arg), plasmid DNA (pDNA), and different proportions of sodium tripolyphosphate (TPP) and poly(γ-glutamic acid) (γ-PGA) were prepared. All TMC-Arg nanocomplexes (TANC) possessed similar particle sizes and preferable protection of pDNA against degradation. The Zeta potentials of TANC decreased with increasing amount of TPP, which were positively correlated to their cellular uptake levels. The composition of crosslinking agents affected their internalization mechanisms, wherein the addition of γ-PGA changed from clathrin-mediated endocytosis to caveolae-mediated one. The increment of TPP amount in TANC was responsible for their reduced binding affinity to pDNA and rapid pDNA release, which was related to their subcellular distribution and in vitro and in vivo transfection patterns. More compact TANC were associated with a delayed protein expression while easily dissociated ones gave a faster onset of action and higher short term gene transfer. However, TANC that dissociated too readily had the inability of gene transfection owing to pDNA degradation in the endolysosomes. Therefore, tailoring the composition of crosslinking agents in nanocomplexes may provide a feasible tool for improving transfection efficiency.
Biomaterials 02/2013; · 7.40 Impact Factor
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ABSTRACT: Oral delivery of therapeutic siRNA is an appealing strategy for the treatment of many diseases, however poses numerous challenges to escort siRNA from the site of administration to the cytoplasm of the target cells. Mannose-modified trimethyl chitosan-cysteine (MTC) conjugate nanoparticles (NPs) were developed via ionic gelation and performed as highly effective polymeric vehicles for oral delivery of TNF-α siRNA. The chitosan backbone as well as trimethyl, thiol, and mannose groups of MTC NPs could be activated at proper time and location to overcome the extracellular and intracellular barriers to oral siRNA delivery, thereby promoting gene silencing efficiency. MTC NPs effectively improved siRNA integrity in physiological environment, enhanced siRNA permeation across the intestinal epithelium, facilitated siRNA uptake by macrophages through clathrin-independent endocytosis, and promoted cytoplasmic siRNA release. At equivalent TNF-α siRNA dose, MTC NPs notably outperformed Lipofectamine2000 in terms of in vitro knockdown of TNF-α production in macrophages. Orally delivered MTC NPs containing low amount of TNF-α siRNA (3.75 nm/kg) inhibited TNF-α production in macrophages in vivo, which protected mice with acute hepatic injury from inflammation-induced liver damage and lethality. This study could provide broad insights into the rational design of oral siRNA vehicles for the treatment of inflammatory diseases.
Biomaterials 01/2013; · 7.40 Impact Factor
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ABSTRACT: PURPOSE: Poor stability and inefficient absorption in the intestinal tract are major barriers confronting oral delivery of siRNA. We aimed to uncover if ternary polymeric nanoparticles (cationic polymer/siRNA/anionic component) can overcome these obstacles through changing the formulation-related parameters. METHODS: Ternary polymeric nanoparticles were prepared by ionic gelation of chitosan, N-trimethyl chitosan (TMC), or thiolated trimethyl chitosan (TTMC) with tripolyphosphate (TPP) or hyaluronic acid (HA), and siRNA was simultaneously encapsulated. Structural stabilities and siRNA protection of these nanoparticles were assessed in simulated intestinal milieu. Their transport across ex vivo rat ileum, macrophage uptake, in vitro gene silencing, and in vivo biodistribution after oral administration were investigated. RESULTS: Ternary polymeric nanoparticles formed by TTMC, siRNA, and TPP (TTMC/siRNA/TPP nanoparticles) showed suitable structural stability and siRNA protection in the intestinal tract, good permeability across ex vivo rat ileum, superior cellular uptake and gene silencing efficiency in Raw 264.7 cells, and high systemic biodistribution after oral administration. CONCLUSIONS: TTMC/siRNA/TPP nanoparticles demonstrated efficient gene silencing in vitro and systemic biodistribution in vivo, therefore, they were expected to be potential vehicles for oral siRNA delivery.
Pharmaceutical Research 01/2013; · 4.09 Impact Factor
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ABSTRACT: Polymeric nanoparticles have been widely applied to oral delivery of protein drugs, however, few studies focused on the systematical elucidation of the size-dependent oral absorption mechanism with well-defined polymeric nanoparticles. Rhodamine B labeled carboxylated chitosan grafted nanoparticles (RhB-CCNP) with different particle sizes (300, 600, and 1000 nm) and similar Zeta potentials (-35 mV) were developed. FITC labeled bovine serum albumin (FITC-BSA) was encapsulated into RhB-CCNP to form drug loaded polymeric nanoparticles (RhB-CCNP-BSA). RhB-CCNP-BSA with uniform particle size and similar surface charge possessed desired structural stability in simulated physiological environment to substantially guarantee the validation of elucidation on size-dependent absorption mechanisms of polymeric nanoparticles using in vitro, in situ, and ex vivo models. RhB-CCNP-BSA with smaller sizes (300 nm) demonstrated elevated intestinal absorption, as mechanistically evidenced by higher mucoadhesion in rat ileum, release amount of the payload into the mucus layer, Caco-2 cell internalization, transport across Caco-2 cell monolayers and rat ileum, and systemic biodistribution after oral gavage. Peyer's patches could play a role in the mucoadhesion of nanoparticles, resulting in their close association with the intestinal absorption of nanoparticles. These results provided guidelines for the rational design of oral nanocarriers for protein drugs in terms of particle size.
Biomaterials 08/2012; 33(33):8569-78. · 7.40 Impact Factor
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ABSTRACT: Here we describe the O-carboxymethyl chitosan nanoparticles (CMCNP) modified by glycyrrhizin (GL) with various substitution degrees as hepatocellular carcinoma (HCC)-targeted delivery vehicles, which could efficiently deliver paclitaxel (PTX) into HCC. The resultant CMCNP-GL exhibited spherical in shape and high stability in plasma with fixed negative charged (~-30 mV) and a size range of 100-205 nm. PTX was loaded into CMCNP-GL with a maximal encapsulation efficiency of 83.7% and performed a biphasic release. CMCNP-GL promoted liver cancer SMMC-7721 cell internalization by approximate 10.0-fold as compared to unmodified CMCNP. Within 72 h, the IC(50) of PTX/CMCNP-GL, PTX/CMCNP, and PTX injection was 2.7-3.2, 8.1, and 13.5 μg/mL, respectively. Biodistribution experiments revealed that PTX/CMCNP-GL exerted significantly superior targeting to tumor than PTX/CMCNP. The in vivo tumor inhibition ratio of PTX/CMCNP-GL was 87.5%, showing remarkably higher than that of PTX/CMCNP (64.0%) and PTX injection (34.5%). CMCNP-GL with different substitution degrees possessed similar targeting property and therapeutic efficacy. Furthermore, toxicity studies suggested that blank CMCNP-GL had no systemic or hepatic toxicity.
Biomaterials 07/2012; 33(30):7594-604. · 7.40 Impact Factor
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ABSTRACT: A multilayered hydrogel film system based on hyaluronic acid-cysteamine (HA-Cym) and polyvinylalcohol (PVA) was fabricated. It contained a drug-impermeable backing layer, a supporting layer preventing direct contact between the loaded drug and the backing layer, a drug-loading layer and a mucoadhesive layer. Scanning electron microscopy demonstrated the presence of the distinct layers. The composition and preparation procedure of the films influenced their mucoadhesion, swelling, in vitro release of insulin and loaded insulin stability. Vacuum drying and crosslinked PVA with glutaraldehyde might reduce mucoadhesion, and they partially decreased the bioactivity of loaded insulin. Lyophilized hydrogel film with uncrosslinked PVA as a mucoadhesive layer possessed high mucoadhesion and showed no influence on the bioactivity of loaded insulin. The application of vacuum-dried PVA-crosslinked HA-Cym/PVA hydrogel film as a drug-impermeable backing layer would provide a controllable unidirectional insulin release. Therefore, such a multilayered hydrogel film system could be a promising mucoadhesive delivery system for controlled macromolecular drug release.
Acta biomaterialia 06/2012; 8(10):3643-51. · 3.98 Impact Factor
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ABSTRACT: The structure-activity relationships between hydrophobic and hydrophilic modification on chitosan and resultant physicochemical properties along with performances in dealing with critical gene delivery barriers were investigated through amphiphilic linoleic acid(LA) and poly (β-malic acid) (PMLA) double grafted chitosan (LMC)/plasmid DNA (pDNA) nanocomplexes. LMC polymers with various LA and PMLA substitution degrees were synthesized and their hydrophilicity/hydrophobicity was characterized. Compared to chitosan, LMC nanoparticles retained the pDNA binding ability at pH 5.5 when they formed nanocomplexes with pDNA encoding enhanced green fluorescence protein (pEGFP) and the resultant complexes showed diameters below 300 nm. Hydrophobic LA and hydrophilic PMLA substitution contributed to suppressed non-specific adsorption, reduced interactions inside LMC/pDNA nanocomplexes, and enhanced pDNA dissociation. However, enzymatic degradation resistance, cell adsorption, and cellular uptake through clathrin-mediated pathway were promoted by hydrophobic LA grafting while being inhibited by hydrophilic PMLA substitution. In vitro transfection assay suggested the optimal LMC/pEGFP nanocomplexes mediated an 8.0-fold improved transfection compared to chitosan/pEGFP nanocomplexes. The 4.2-fold and 2.2-fold higher intramuscular gene expression in mice compared to chitosan/pEGFP and polyethyleneimine (PEI)/pEGFP nanocomplexes further demonstrated the superiority of LMC/pDNA nanocomplexes. Therefore, amphiphilic chitosan derivates with appropriate combination of hydrophobic and hydrophilic modification would be promising gene delivery nanocarriers.
Biomaterials 03/2011; 32(20):4630-8. · 7.40 Impact Factor
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ABSTRACT: The current formulation of paclitaxel causes significant side effects, so there is a need to develop a safer delivery system. In this study, novel semi-solid lipid nanoparticles (PEG-PE-SSLN) were prepared, and evaluated as delivery vehicles for paclitaxel. The PEG-PE-SSLN are approximately 213 nm in size with a zeta-potential of -37 mV, compared to Span60-SSLN with a particle size of over 275 nm and zeta-potential of -29 mV. The encapsulation efficiency of PEG-PE-SSLN could be as high as 98%. Furthermore, differential scanning calorimetry (DSC) analysis indicated that paclitaxel in the nanoparticles existed in an amorphous form. A sustained release of 85% of the loaded paclitaxel from PEG-PE-SSLN within 12 days was observed while release from Span60-SSLN particles was complete within 6 days. PEG-PE-SSLN can effectively decrease phagocytosis of murine peritoneal macrophages. Lyopholization of SSLNs in the presence of trehalose tended to preserve their stability. Therefore, PEG-PE-SSLN represents an improved and promising paclitaxel delivery system.
Pharmazie 07/2010; 65(7):493-9. · 1.01 Impact Factor
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ABSTRACT: Trimethyl chitosan-cysteine conjugate (TMC-Cys) was evaluated as non-viral gene carriers to combine the advantages of TMC and thiolated chitosan. TMC-Cys with various molecular weights (30, 100, and 200 kDa) and quaternization degrees (15 and 30%) was allowed to form polyelectrolyte nanocomplexes with plasmid encoding enhanced green fluorescence protein (pEGFP), which demonstrated preferable diameters of below 200 nm and zeta potentials of +15 to +20 mV. Cell binding and uptake of TMC-Cys/pEGFP nanocomplexes (TMC-Cys NC) were enhanced 2.4-3.0 and 1.4-3.0 folds, respectively, compared to TMC/pEGFP nanocomplexes (TMC NC). pEGFP could be easily released from TMC-Cys NC at the intracellular glutathione concentration, which promoted its nuclear transport and accumulation. Consequently, TMC-Cys NC showed a 1.4 to 3.2-fold increase in the transfection efficiency in HEK293 cells as compared to TMC NC and the optimal TMC-Cys(100,30) NC showed a 1.5-fold enhancement than Lipofectamine2000. Such results were further confirmed by in vivo transfection with a 2.3-fold and 4.1-fold higher transfection efficiency of TMC-Cys(100,30) NC than TMC(100,30) NC and Lipofectamine2000, respectively. Therefore, TMC-Cys/DNA nanocomplexes could be a promising gene delivery system with in vitro and in vivo superiority to Lipofectamine2000.
Journal of Controlled Release 05/2010; 144(1):46-54. · 5.73 Impact Factor
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ABSTRACT: Superporous hydrogel containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan interpenetrating polymer networks (SPH-IPN) was evaluated as the oral delivery vehicle for insulin, emphasizing on the effect of polymer integrity on insulin absorption mechanisms. The integral SPH-IPN (I-SPH-IPN) and powdered SPH-IPN (P-SPH-IPN) exhibited potent and equivalent in vitro enzymatic inhibition capacities, which were attributed to both enzyme incorporation and Ca(2+) deprivation. Nevertheless, I-SPH-IPN showed marked superiority to P-SPH-IPN in in vivo enzymatic inhibition. Through reversible opening of epithelial tight junctions, I-SPH-IPN notably enhanced paracellular permeability of insulin in Caco-2 cell monolayers and excised rat intestine by 4.9 and 4.2 folds, respectively, wherein I-SPH-IPN outperformed P-SPH-IPN by 2.5 and 2.3 folds, respectively. Besides, orally delivered I-SPH-IPN could retain in rat intestine for more than 8 h while P-SPH-IPN was quickly eliminated, suggesting better retentive properties of I-SPH-IPN. Such results were further confirmed by in vivo assessment in that oral administration of insulin-loaded I-SPH-IPN yielded notable insulin absorption and hypoglycemic effect, while P-SPH-IPN was ineffective. Finally, an oral acute and sub-acute toxicity study in mice confirmed biocompatibility of SPH-IPN. Therefore, the detailed mechanism assessment confirmed that I-SPH-IPN was an effective and safe peroral carrier for protein drugs.
Biomaterials 04/2010; 31(12):3347-56. · 7.40 Impact Factor
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ABSTRACT: To elucidate the effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles (NPs), rhodamine B (RhB) labeled carboxymethyl chitosan grafted NPs (RhB-CMCNP) and chitosan hydrochloride grafted NPs (RhB-CHNP) were developed as the model negatively and positively charged polymeric NPs, respectively. These NPs owned well defined particle sizes (150-500 nm) and Zeta potentials (-40 mV - +35 mV). FITC labeled protamine sulfate (FITC-PS) loaded RhB-CMCNP and camptothecin (CPT) loaded RhB-CHNP with high encapsulation efficiency were prepared. The fluorescence stability in plasma and towards I(-) was investigated, and the result indicated it was sufficient for qualitative and quantitative analysis. NPs with high surface charge and large particle size were phagocytized more efficiently by murine macrophage. Slight particle size and surface charge differences and different cell lines had significant implications in the cellular uptake of NPs, and various mechanisms were involved in the uptake process. In vivo biodistribution suggested that NPs with slight negative charges and particle size of 150 nm were tended to accumulate in tumor more efficiently. These results could serve as a guideline in the rational design of drug nanocarriers with maximized therapeutic efficacy and predictable in vivo properties, in which the control of particle size and surface charge was of significance.
Biomaterials 02/2010; 31(13):3657-66. · 7.40 Impact Factor
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ABSTRACT: As a promising anticancer drug, severe side-effects of current clinical formulations for paclitaxel have restricted its use, developing a better technical-economical formulation for paclitaxel delivery is needed.
In this study, the compound of folate-poly(ethylene glycol) (PEG)-phosphatidylethanolamine was synthesized and characterized with Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The solid-liquid lipid nanoparticle (SLLN) for paclitaxel modified with folate and poly(ethylene glycol) (folate-PEG-SLLN) was prepared and characterized. Morphology of folate-PEG-SLLN was examined by transmission electron microscopy. The particle size and zeta potential were performed by Zetapals. Encapsulation efficiency was analyzed by HPLC. The in vitro drug release of paclitaxel was investigated via membrane dialysis. The in vivo pharmacokinetics was measured with male Sprague-Dawley rats. Treatment efficiency was investigated with the mouse with sarcoma180 ascites tumor.
Paclitaxel loaded on the newly designed binary SLLN showed a longer and sustained in vitro releasing property. More importantly, S180 tumor-bearing mice treated with paclitaxel-loaded SLLN exhibited higher tumor inhibition rate, comparing with animals administered with paclitaxel injection alone (45.3% and 37.3%, respectively).
The newly developed paclitaxel delivery system may have improved in vivo antitumor activity. The results demonstrated a great interest to use folate-mediated SLLN as a prospective drug delivery system for paclitaxel.
Drug Development and Industrial Pharmacy 10/2009; 36(4):439-48. · 1.49 Impact Factor
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ABSTRACT: Trimethyl chitosan-cysteine conjugate (TMC-Cys) was synthesized in an attempt to combine the mucoadhesion and the permeation enhancing effects of TMC and thiolated polymers related to different mechanisms for oral absorption. TMC-Cys with various molecular weights (30, 200, and 500 kDa) and quaternization degrees (15 and 30%) was allowed to form polyelectrolyte nanoparticles with insulin through self-assembly, which demonstrated particle size of 100-200 nm, zeta potential of +12 to +18 mV, and high encapsulation efficiency. TMC-Cys/insulin nanoparticles (TMC-Cys NP) showed a 2.1-4.7-fold increase in mucoadhesion compared to TMC/insulin nanoparticles (TMC NP), which might be partly attributed to disulfide formation between TMC-Cys and mucin as evidenced by DSC measurement. Compared to insulin solution and TMC NP, TMC-Cys NP induced increased insulin transport through rat intestine by 3.3-11.7 and 1.7-2.6 folds, promoted Caco-2 cell internalization by 7.5-12.7 and 1.7-3.0 folds, and augmented uptake in Peyer's patches by 14.7-20.9 and 1.7-5.0 folds, respectively. Such results were further confirmed by in vivo experiment with the optimal TMC-Cys NP. Biocompatibility assessment revealed lack of toxicity of TMC-Cys NP. Therefore, self-assembled nanoparticles between TMC-Cys and protein drugs could be an effective and safe oral delivery system.
Biomaterials 08/2009; 30(29):5691-700. · 7.40 Impact Factor
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ABSTRACT: The hyaluronic acid (HA) coated poly(butyl cyanoacrylate) (PBCA) nanoparticles were synthesized through radical polymerization of butyl cyanoarylate (BCA) initiated by cerium ions in the presence of HA. The chemical coupling between HA and PBCA was demonstrated by FTIR, (1)H NMR and X-ray diffraction. The sizes of the nanoparticles with different HA/BCA ratios were 291-325 nm at cerium concentration of 0.8 mmol/L and HA molecular weight of 18,000 Da. Paclitaxel (PTX), a model anticancer drug, was encapsulated in negatively charged nanoparticles with a maximal encapsulation efficiency of 90%. In vitro release demonstrated that HA modification could effectively reduce the initial burst release in the first 10h and provide a sustained release in the subsequent 188 h. As evidenced by the hemolysis assay and MTT assay, HA coating could significantly reduce the cytotoxicity. Cellular uptake indicated that uptake of HA-PBCA nanoparticles by Sarcoma-180 (S-180) cells was 9.5-fold higher than that of PBCA nanoparticles. PTX-loaded HA-PBCA nanoparticles were more potent in tumor growth suppression than PTX-loaded PBCA nanoparticles or PTX injection following intravenous administration to S-180 tumor bearing mice. Therefore, the HA-PBCA nanoparticles could be an effective and safe vehicle for systemic administration of hydrophobic anticancer drugs.
International journal of pharmaceutics 06/2009; 373(1-2):165-73. · 2.96 Impact Factor
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ABSTRACT: To improve the efficiency of insulin via oral administration, pH-sensitive carboxylated chitosan grafted poly(methyl methacrylate) nanoparticles (CCGN) were prepared. CCGN were characterized by (1)H NMR, dynamic light scattering, zeta potential, and transmission electron microscopy, and the hypoglycemic effect of insulin loaded CCGN via the oral route was evaluated in normal and diabetic rats. CCGN exhibited a homogeneous morphology and a spherical shape with core-shell structure. They were aggregated in simulated gastric fluid while separated in simulated intestinal fluid. Insulin was mainly located in the shell of the CCGN via hydrogen bonding, electrostatic interaction, and Van der Waals force. Insulin release from the CCGN exhibited a pH-sensitive property in that it had a slow release rate at pH 2.0 and a fast release rate at pH 6.8 and 7.4. The pharmacological bioavailability after oral administration of insulin loaded CCGN at a dose of 25 IU/kg was found to be 9.7%. Besides, CCGN showed desirable tissue and blood compatibility. Therefore, the CCGN would be a promising delivery carrier for protein drugs via the oral route.
Biomacromolecules 04/2009; 10(5):1253-8. · 5.48 Impact Factor
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ABSTRACT: Insulin was modified with monomethoxypoly(ethylene glycol) 5000 (MPEG5000) by reaction of insulin amino groups with activated MPEG5000, and mono-, di- and tri-PEGylated insulin were obtained. Circular dichroism demonstrated that the attachment of MPEG5000 to insulin did not alter the tertiary structure of insulin. PEGylation of insulin could inhibit the self-association tendency of insulin, which decreased with the increase of substitution degree. The physical stability and proteolytic stability of insulin increased after MPEG conjugation, and the stabilities of the conjugates depended on the PEGylation degree. In vivo biological activity of mono-PEGylated insulin following parenteral administration both in mice and rats was preserved while di- and tri-PEGylated insulin showed a great loss in biological activity. In addition, mono-PEGylated insulin administered subcutaneously in mice as well as intravenously in rats displayed extended action profiles. These results indicated that mono-substituted MPEG5000-insulin conjugate was a good candidate for insulin replacement therapy.
Pharmazie 04/2009; 64(3):190-6. · 1.01 Impact Factor
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ABSTRACT: Novel chitosan derivatives carrying linoleic acid (LA) as hydrophobic moieties and poly(beta-malic acid) (PMLA) as hydrophilic moieties (LA/PMLA double grafted chitosan, LMC) were synthesized. It self-assembled into nanoparticles of 190-350 nm in water, which carried negative surface charges in physiological pH. The critical aggregation concentration of the LMC deceased with an increase in the LA content. Paclitaxel (PTX) was loaded into the LMC nanoparticles with a high loading efficiency and the maximum loading capacity of 9.9 +/- 0.4%. PTX-LMC nanoparticles exhibited a sustained release within 24 h in pH 7.4 phosphate-buffered saline (PBS), and the release rate was affected by the LA content and PMLA length. Hemolysis and acute toxicity assessment indicated that the LMC nanoparticles were safe drug carriers for i.v. administration. Additionally, PTX-LMC showed significantly potent tumor inhibition efficacy relative to that of TAXOL in S-180 bearing mice. Therefore, the LMC nanoparticles could be an effective and safe vehicle for systemic administration of hydrophobic drugs, especially PTX.
Biomacromolecules 02/2009; 10(3):565-72. · 5.48 Impact Factor
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ABSTRACT: This manuscript describes the development of a new porous, flexible bilaminated film for buccal protein administration by a simple and mild casting procedure. It consists of a mucoadhesive layer (chitosan-ethylenediaminetetraacetic acid hydrogel film) containing protein drugs and an impermeable protective layer made of ethylcellose. The obtained mucoadhesive layer was characterized in terms of Fourier transform infrared spectroscopy, rheology, swelling, and mucoadhesion. Rheology results showed that chitosan-ethylenediaminetetraacetic acid hydrogel (10:2) possessed the greatest degree of viscoelasticity and was well-structured compared with other hydrogels. The in vitro mucoadhesion studies also showed that the mucoadhesive force of the hydrogel remained over 17,000 N/m2 during 4 h in the simulated oral cavity. The insulin loaded bilaminated film showed a pronounced hypoglycemic effect following buccal administration to healthy rats, achieving a 17% pharmacological availability compared with subcutaneous insulin injection. According to these results, the bilaminated film would be a promising delivery carrier for protein drugs via the buccal route.
Journal of Biomedical Materials Research Part A 06/2008; 89(4):1063-71. · 2.63 Impact Factor
