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ABSTRACT: The purpose of this study was to develop a high-drug-loading nanoemulsion by self-assembly to improve the oral absorption of high dosing poorly water-soluble drugs. Probucol was selected as a model drug and the probucol-loaded self-assembled nanoemulsion (PSN) was prepared and characterized. Moreover, the intestinal absorption and in vivo pharmacokinetic behavior of PSN were evaluated in rats after oral administration. The experimental results indicated that PSN was nanometer-sized droplets with the mean diameter of 40.32 ± 0.31 nm and polydispersity index of 0.184 ± 0.005. The aqueous solubility of probucol was remarkably increased after its incorporation into PSN. Compared with free drug suspension, the intestinal absorption of PSN was not significantly increased in duodenum, but obviously enhanced 3.62- and 13.1-fold in jejunum and ileum, respectively. In particular, the in vivo pharmacokinetic results indicated that the oral bioavailability of probucol was greatly improved 8.97-fold by PSN. Thereby, the high-drug-loading self-assembled nanoemulsion was very effective in enhancing the oral absorption of high-dosing poorly water-soluble drugs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Journal of Pharmaceutical Sciences 02/2013; · 3.06 Impact Factor
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ABSTRACT: Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer caused human death. In this work, we selected oncogene mouse double minute 2 (MDM2) as a therapeutic target for NSCLC treatment and proposed that sufficient MDM2 knockdown could inhibit tumor growth via induction of cell cycle arrest and cancer cell apoptosis. On this regard, a new pH-responsive diblock copolymer of poly(methacryloyloxy ethyl phosphorylcholine)-block-poly(diisopropanolamine ethyl methacrylate) (PMPC-b-PDPA)/siRNA-MDM2 complex nanoparticle with minimized surface charge and suitable particle size was designed and developed for siRNA-MDM2 delivery in vitro and in vivo. The experimental results showed that the nanoparticles were spherical with particle size around 50 nm. MDM2 knockdown in p53 mutant NSCLC H2009 cells induced significant cell cycle arrest, apoptosis and growth inhibition through upregulation of p21 and activation of caspase-3. Furthermore, the growth of H2009 xenograft tumor in nude mice was inhibited via repeated injection of PMPC-b-PDPA/siRNA-MDM2 complex nanoparticles. These results suggested that PMPC-b-PDPA/siRNA complex nanoparticles targeting a unique set of oncogenes could be developed into a new therapeutic approach for NSCLC treatment.
Biomaterials 01/2013; · 7.40 Impact Factor
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ABSTRACT: The therapeutic efficacy of lipophilic drugs is commonly restricted by the low systemic exposure after oral administration. In this work, a new delivery system combining the advantages of porous starch and self-assembled nanocarrier was designed to improve the oral absorption of lipophilic drugs. The lipophilic probucol loaded porous starch based self-assembled nano-delivery (PSN) system was developed and characterized. The probucol loaded nanocarrier (PLN) could be formed by self-assembly when PSN was dispersed into the gastrointestinal (GI) fluids. PLN was nanometer-sized particles with narrow size distribution and exhibited good stability in GI fluids. The aqueous solubility of probucol was increased over 50,000-fold by PSN delivery system and the cumulative release of lipophilic probucol was increased over 80% in GI fluids. The distribution of probucol in duodenum, jejunum and colon was respectively improved 7.17, 15.99 and 33.61-fold by PSN. In particular, the oral bioavailability of probucol from PSN was greatly improved about 9.96-fold than that from free drug suspension and 3.71-fold higher than that from the directed adsorbed probucol loaded porous starch system, which effectively confirmed the high potential of the strategy in enhancing the oral absorption of lipophilic drugs.
International journal of pharmaceutics 01/2013; · 2.96 Impact Factor
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ABSTRACT: Multidrug resistance (MDR) remains one of the main challenges in the successful chemotherapy of human cancer. RNA interference (RNAi) strategy aiming at only one cause of MDR was widely applied, nevertheless hardly obtained satisfactory tumor-suppressing effect. In this work, a new attempt to package two kinds of RNA with different functions into one vector and reverse MDR against two different mechanisms via RNAi was carried out. A new bioreducible poly (β-amino esters) (PAEs), poly[bis(2-hydroxylethyl)-disulfide-diacrylate-β-tetraethylenepentamine] (PAP) was synthesized by Michael addition reaction. The PAEs/RNA complex nanoparticles (PAEN) were prepared. The experimental results demonstrated that co-delivery of iMdr-1-shRNA and iSurvivin-shRNA could be achieved by a single vector, and interfering two genes simultaneously had a synergistic effect on overcoming MDR. PAEN lowered the IC(50) value of doxorubicin (DOX) in MDR tumor cells to a comparable level to that in the sensitive cell line through down-regulating the expression of P-gp and Survivin, and decreased the tumor volumes in mice xenograft model bearing DOX-resistant human breast cancer when combined with DOX. These results illustrated that PAEN could be applied as potential efficient non-viral RNA carriers for reversing MDR.
Biomaterials 06/2012; 33(27):6495-506. · 7.40 Impact Factor
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ABSTRACT: A self-assembled nano-based delivery system was designed and developed to increase the oral bioavailability of poor hydrophilic and lipophilic daidzein.
Daidzein was firstly combined with lecithin to form the daidzein-lecithin complex, then self-assembled into micelles (DLMs) with lecithin and sodium bile. The physiochemical properties and intestinal absorption of DLMs were characterized, and the pharmacokinetic behavior was evaluated in rats.
DLMs exhibited nanometer-sized particles. DLMs were mainly distributed in the stomach and proximal intestine after oral administration. The intestinal absorption of DLMs was significantly improved, and DLMs could be absorbed via both endocytosis and passive transport. The AUC(0-t) value of daidzein in rats treated with DLMs was ninefold greater than that of free daidzein suspension.
The presented delivery system could provide a new promising strategy for enhancing the oral bioavailability of drugs with poor hydrophilicity and lipophilicity.
Nanomedicine 10/2011; 6(8):1365-79. · 5.05 Impact Factor
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ABSTRACT: A nano-based delivery system was developed to improve the oral absorption of daidzein, which has poor hydrophilicity and lipophilicity. A daidzein-phospholipid complex (DPC) was firstly prepared to improve its lipophilicity, and then encapsulated into lipid nanocarriers (DLNs) to verify the effectiveness of the strategy in enhancing the oral delivery of daidzein. DLNs were spherical nanosized particles with evidently increased dissolution. DLNs were mainly distributed in stomach and proximal intestine of mice after oral administration, and the intestinal permeability of DLNs in rats was significantly improved when compared with that of daidzein solution. The peak concentration of daidzein in rats after oral administration of DPC and DLNs was 6833 ± 1112 ng mL(-1) and 14,512 ± 2390 ng mL(-1), respectively, which was improved over 10-fold and 21-fold than that of free daidzein. Moreover, the areas under the concentration-time curve (AUC(0-t)) of DPC and DLNs were enhanced by 3.62-fold and 6.87-fold compared with that of free daidzein. These results suggested that DLNs could be an effective strategy to improve the oral absorption of poor hydrophilic and lipophilic drugs like daidzein.
Nanoscale 02/2011; 3(4):1780-7. · 5.91 Impact Factor
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ABSTRACT: Sixteen novel cationic click polymers (CPs) were parallelly synthesized via the conjugation of four alkyne-functionalized monomers to four azide-functionalized monomers by "click chemistry". The biocompatibility of CPs was evaluated by in vitro cytotoxicity (MTT assay, Hoechst/PI apoptosis/necrosis assay, and cell cycle analysis) and blood compatibility tests (hemolysis and erythrocyte aggregation). The experimental results showed that the kind of amine groups, charge density, and number of methylene or ethylene glycol groups brought about the effect on toxicity of CPs. Among all polymers, two polymers (B(1) and B(2)) showed good biocompatibility, inducing neither apoptosis nor necrosis at the test concentration and low hemolysis ratio and erythrocyte aggregation. In particular, B(1) and B(2) exhibited the comparable transfection efficiency compared with PEI (25 kDa) but much lower cytotoxicity. These results suggested that the novel cationic CPs could be promising carriers for gene delivery.
Biomacromolecules 09/2010; · 5.48 Impact Factor
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ABSTRACT: To achieve efficient gene delivery to the tumor after intravenous administration, biodegradable poly(2-(2-aminoethyoxy)ethoxy)phosphazene (PAEP) was modified by lactobionic acid, bearing a galactose group as a targeting ligand. Galactosylated poly(2-(2-aminoethyoxy)ethoxy)phosphazene (Gal-PAEP) with 4.9% substitution degree of galactose could condense pDNA into nanoparticles with a size around 130 nm at the polymer/DNA ratio (N/P) of 2-40. For BEL-7402 cells, the in vitro transfection efficiency of gal-PAEP/DNA complex nanoparticles (gal-PACNs) was much higher than that of the PAEP/DNA complex nanoparticles (PACNs). MTT assay indicated that the cytotoxicity of PACNs significantly decreased after conjugating with the galactose moiety. Gal-PACNs displayed the selective gene expression in the tumor and liver with relatively low gene expression in the lung or other organs compared with PACNs. These results suggested that gal-PACNs could be a promising targeting gene carrier to deliver a therapeutic gene in future.
Biomacromolecules 03/2010; 11(4):927-33. · 5.48 Impact Factor
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ABSTRACT: The biodegradable cationic poly(2-(2-aminoethoxy)ethoxy)phosphazene (PAEP) bearing primary amino groups and a new PAEP derivative, urocanic acid (UA) modified PAEP (UA-PAEP), were synthesized and investigated for gene delivery. The results indicated that PAEP was able to condense DNA into complex nanoparticles with the size around 120 nm at the polymer/DNA ratio (N/P) of 35, at which PAEP/DNA complex nanoparticles (PACNs) showed efficient transfection activity in complete medium. After conjugating with UA at the substitution degree of 7% (UA-PAEP7), UA-PAEP7/DNA complex nanoparticles (UP7CNs) exhibited higher transfection efficiency than PACNs and UA-PAEP25/DNA complex nanoparticles (UP25CNs) and much lower cytotoxicity compared with PEI/DNA complex nanoparticles (PEICNs). The transfection experiment using a proton pump inhibitor suggested that the gene expression of PACNs and UP-PAEP/DNA complex nanoparticles (UPCNs) was dependent on the endosomal acidification process. The acetate solution (20 mM, pH5.7) improved the transfection activity of UP7CNs in HeLa and COS 7 cell lines, which was almost comparable to PEICNs at the N/P ratio of 35. Therefore, the results suggested that UP7CNs could be a promising carrier for gene delivery.
Bioconjugate Chemistry 02/2010; · 4.93 Impact Factor
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ABSTRACT: A new "intelligent" nanoassembly (INA), consisting of a condensed core of pDNA with protamine sulfate (PS) and a dioleoylphosphatidyl ethanolamine (DOPE)-based lipid envelope containing poly(ethylene glycol)-disulfide-DOPE (PSD), was designed and investigated. The in vitro release experiment was carried out in solution containing 10mM of Glutathione, which reflected the redox potential of the intracellular environment. The experimental result indicated that PSD possessed a good ability of self-dePEGylation and could result in efficient release of content in the reductive environment. INAs showed higher transfection efficiency and much lower cytotoxicity compared with Lipofectamine 2000 on HEK 293 cells. Cellular uptake and subcellular localization, as well as the quantitation of nuclear transfer demonstrated that the superior transfection efficiency of INAs could result from both enhanced cellular uptake mediated by DOPE and efficient nuclear delivery mediated by PS. The biodistribution of INAs in nude mice bearing tumor implied that this PSD-based nanoassembly loading PS/DNA could be a promising gene delivery system for tumor therapy.
International journal of pharmaceutics 09/2009; 383(1-2):271-6. · 2.96 Impact Factor
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ABSTRACT: The selective introduction of a trimethylammonium cationic group into the C-6 position of chitosan (Cs) was successfully performed by "click chemistry" for the first time, and the 6-N,N,N-trimethyltriazole-Cs (TCs) showed good solubility in water. TCs showed strong DNA binding ability and high protection of DNA against nuclease degradation assessed by gel electrophoresis assay. TCNs showed lower degree of flocculation than Cs/DNA self-assembled nanoparticles (CsNs) in the presence of medium containing serum within 60 min. The introduction of trimethyltriazole group led to significantly increased cellular uptake compared with unmodified Cs, which resulted in higher transfection efficiency in HEK 293 and MDA-MB-468 cells. TCs were noncytotoxic, and viability of cells exposure to TCNs for 24 h was over 80% even at 50 microg/mL of polymer. These results suggested that TCs could be an efficient and safe material for gene delivery.
Biomacromolecules 09/2009; 10(8):2175-82. · 5.48 Impact Factor
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ABSTRACT: The aim of this work is to investigate the effect of betaine substitution degree of chitosan N-betainates (CsB) on cellular uptake, cytotoxicity and transfection efficiency of CsB/DNA complex nanoparticles (CsBNs) against COS-7 and MDA-MB-468 cells. The polymers with three substitution degrees (CsB12, CsB47 and CsB85) complexed with pDNA formed CsBN12s, CsBN47s and CsBN85s. The CsBNs showed less pH dependency with smaller particle size and higher zeta potential than that of chitosan/pDNA complex nanoparticles (CsNs) at neutral pH. CsBN85s showed stronger cellular uptake than that of CsBN47s or CsBN12s. CsBNs showed higher cytotoxicity than CsNs, and a trend increasing toxicity with substitution degree increasing. In COS-7 cells, the transfection efficiency increased with the substitution degree increasing, while the opposite result was observed in MDA-MB-468 cells. Chitosan modified with betaine could increase its ability to facilitate DNA uptake and its cytotoxicity, both of which showed the influence on transfection efficiency. It was able to increase cellular uptake and transfection efficiency of complex nanoparticles in COS-7 cells to increase betaine substitution of CsB, however, the higher sensitivity of MDA-MB-468 cells to CsBs led to decreased transfection efficiency due to the increased cytotoxicity with betaine substitution increasing. The predominant role of cellular uptake or toxicity in affecting transfection efficiency was different in two cell lines. These results provided an important guidepost for further development of chitosan derivatives/pDNA complexes as non-viral gene vectors.
International journal of pharmaceutics 01/2009; 371(1-2):156-62. · 2.96 Impact Factor
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ABSTRACT: The conception of a modular designed and viruslike nonviral vector has been presented for gene delivery. Recently, we constructed a new smart nanoassembly (SNA) with multifunctional components that was composed of a condensed core of pDNA with protamine sulfate (PS) and a dioleoyl phosphatidylethanolamine (DOPE)-based lipid envelope containing poly(ethylene glycol)--vinyl ether--DOPE (PVD). SNAs with mPEG 2000 (SNAs1) or mPEG 5000 (SNAs2) loading PS/DNA were prepared by the lipid film hydration technique. The particle size was about 160 nm for SNAs1 and 240 nm for SNAs2 loading PS/DNA (10:1 w/w), and the zeta potential was about 4 mV for two SNAs. The in vitro release experiment indicated that PVD possessed a good ability for self-dePEGylation, which could result in the recovery of an excellent fusogenic capacity of DOPE at low pH. SNAs showed a higher transfection efficiency and much lower cytotoxicity than did Lipofectamine 2000 on HEK 293, HeLa, and COS-7 cells. The cellular uptake and subcellular localization demonstrated that the superior transfection efficiency of SNAs could result from the fact that the DOPE-based lipid envelope containing PVD increased PS/DNA in the cytoplasm, and protamine enhanced the nuclear delivery or overcame the nuclear membrane barrier. These results implied that the PVD-based nanoassembly loading PS/DNA could be a promising gene delivery system.
Biomacromolecules 11/2008; 9(11):3119-26. · 5.48 Impact Factor
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ABSTRACT: Daidzein is a very good candidate for treating cardio-cerebrovascular diseases, but its poor oral absorption and bioavailability limit its curative efficacy. In this work, daidzein-loaded solid lipid nanoparticles (SLNs) with PEGylated phospholipid as stabilizer were successfully prepared by hot homogenization method. SLNs showed the mean particle size 126+/-14 nm with entrapment efficiency 82.5+/-3.7%. In vitro release of SLNs demonstrated a sustained release manner with cumulative release over 90% within 120 h in bovine serum albumin solution (4%, w/v). The pharmacokinetic behavior showed that SLNs loading daidzein could significantly increase circulation time compared with orally administrated daidzein suspension or intravenously delivered daidzein solution. SLNs showed the better effect on cardiovascular system of the anesthetic dogs by reducing the myocardial oxygen consumption (MOC) and the coronary resistance (CR) in heart compared with oral suspension or intravenous solution. The SLNs demonstrated the best effect on cerebrovascular system by increasing cerebral blood flow (CeBF) and reducing cerebrovascular resistance (CeR) in anesthetized dogs, and the protective effect on rats with ischemia-reperfusion injury model among three formulations. These results suggested that SLNs could be a potential candidate for the treatment of cardio-cerebrovascular diseases.
Biomaterials 11/2008; 29(30):4129-36. · 7.40 Impact Factor
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ABSTRACT: Human hepatocellular carcinoma (HCC) is one of the major causes of death worldwide. Targeted uptake of therapeutic agent in the cell-, tissue- or disease-specific manner represents a potential technology for the treatment of HCC. A new docetaxel-loaded hepatoma-targeted solid lipid nanoparticle (tSLN) was designed and prepared with galactosylated dioleoylphosphatidyl ethanolamine. The cellular cytotoxicity, cellular uptake, subcellular localization, in vivo toxicity, therapeutic effect, biodistribution and histology of tSLNs were investigated. The tSLNs showed the particle size about 120nm with encapsulation efficiency >90%, a low burst effect within the first day and a sustained release for the next 29 days in vitro. Cytotoxicity of tSLNs against hepatocellular carcinoma cell line BEL7402 was superior to Taxotere and non-targeted SLNs (nSLNs). The tSLNs also showed better tolerant and antitumor efficacy in murine model bearing hepatoma compared with Taxotere or nSLNs. The studies on cellular uptake and biodistribution indicated that the better antitumor efficacy of tSLNs was attributed to both the increased accumulation of drug in tumor and more cellular uptake by hepatoma cells. The histology demonstrated that tSLNs had no detrimental effect on both healthy liver and liver with fibrosis. These results implied that this targeted nanocarrier of docetaxel could enhance its antitumor effect in vivo with low systemic toxicity for the treatment of locally advanced and metastatic HCC.
Biomaterials 10/2008; 30(2):226-32. · 7.40 Impact Factor
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ABSTRACT: Chitosan (Cs) is a natural cationic polysaccharide that has shown potential as non-viral vector for gene delivery because of its biocompatibility and low toxicity. However, chitosan used for gene delivery is limited due to its poor water solubility and low transfection efficiency. The purpose of this work was to prepare Arginine-chitosan (Arg-Cs)/DNA self-assemble nanoparticles (ACSNs), and determine their in vitro characteristics and transfection efficiency against HEK 293 and COS-7 cells. Our experimental results showed that the particle size and zeta potential of ACSNs prepared with different N/P ratios were 200-400nm and 0.23-12.25mV, respectively. The in vitro transfection efficiency of ACSNs showed dependence on pH of transfection medium, and the highest expression efficiency was obtained at pH 7.2. The transfection efficiency increased with the ratio of chitosan-amine/DNA phosphate (N/P ratio) from 1 to 5, and reached the highest level with the N/P ratio 5. Effect of plasmid dosage on the transfection efficiency showed the highest transfection efficiency was obtained at 4microg/well for HEK 293 cells and 6microg/well for COS-7 cells. The transfection efficiency of ACSNs was much higher than that of Cs/DNA self-assemble nanoparticles (CSNs). The average cell viability of ACSNs was over 90%. These results suggested that ACSNs could be a safe and effective non-viral vector for gene delivery.
International Journal of Pharmaceutics 08/2008; 359(1-2):241-6. · 3.35 Impact Factor
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ABSTRACT: A new cationic derivate of polyphosphazene with imidazole and 2-dimethylaminoethylamino (DMAEA) as side groups, poly(imidazole/DMAEA)phosphazene (PIDP), was synthesized and investigated for gene delivery. The half-lives of PIDP degradation under neutral (pH 7.4) and acidic conditions (pH 5.0) were 22 and 3 days at 37 degrees C, respectively. The cytotoxicity of PIDP assayed by MTT was much lower than that of poly(2-dimethylaminoethylamino)phosphazene (PDAP) and PEI 25K. PIDP could condense DNA into nanoparticles with a size around 100 nm and zeta potential (+25 mV) at the ratio of 10:1 (PIDP/DNA, w/w). The transfection efficiency of PIDP/DNA complex nanoparticles (PICNs) against 293T, COS-7 and Hela cells was much higher than that of PDAP/DNA complexes nanoparticles (PDCNs) and PEI/DNA complexes nanoparticles (PECNs) at 10:1 (polymer/DNA, w/w). Therefore, PIDP could be a safe, efficient and promising cationic polymer for gene therapy.
Journal of Controlled Release 06/2008; 127(3):273-9. · 5.73 Impact Factor
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ABSTRACT: Cationic polyorganophosphazene has shown the ability to deliver gene. To obtain more efficient transfection, His(Boc)-OMe bearing histidine moiety was introduced to synthesize a new derivative of cationic polyphosphazenes with another side group of 2-dimethylaminoethylamine (DMAEA). The poly(DMAEA/His(Boc)-OMe)phosphazene (PDHP) and DNA could self-assemble into nanoparticles with a size around 110 nm and zeta potential of +15 mV at the PDHP/DNA ratio of 10:1 (w/w). The maximum transfection efficiency of PDHP/DNA self-assembled nanoparticles (PHSNs) against 293 T cells was much higher than that of poly(di-2-dimethylaminoethylamine) phosphazenes (PDAP)/DNA self-assembled nanoparticles (PASNs) and PEI 25/DNA self-assembled nanoparticles (PESNs) at the polymer/DNA ratio of 10:1, but the cytotoxicity of PDHP assayed by MTT was much lower than that of PDAP and PEI 25. These results suggested that PDHP could be a good candidate with high transfection efficiency and low cytotoxicity for gene delivery.
International Journal of Pharmaceutics 05/2008; 353(1-2):277-82. · 3.35 Impact Factor
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ABSTRACT: The aim of this work was to design a new multifunctional nano device (MND) for gene delivery. This MND was equipped with folic acid as ligand, which was conjugated to terminal amido of poly(aminopoly(ethylene glycol)cyanoacrylate-co-hexadecyl cyanoacrylate) (poly(H(2)NPEGCA-co-HDCA)) to synthesize poly(Folate-HNPEGCA-co-HDCA), protamine sulfate (PS) as DNA condenser and for nuclear transfer, PEG chain from poly(Folate-HNPEGCA-co-HDCA) for decreasing macrophages recognition and extending half-life, dioleoyl phosphatidylethanolamine (DOPE) for endosomal escape, and we supposed that the latent DOPE fusogenicity could be gently restored along with fast degradation of poly(Folate-HNPEGCA-co-HDCA) in MND membrane within endosome. Our experimental results showed that optimum complexation ( approximately 97%) of DNA was achieved at DNA:PS=1:3 (w/w). The MND showed different loading ratio by lipid film hydration technique with the highest loading ratio about 12%, the particle size range 200-400 nm, surface charge range 8 mV-15 mV. MND1 (poly(Folate-HNPEGCA-co-HDCA)/DOPE, 5:95, molar ratio) exhibited a high burst release effect with 60% of pDNA/PS released within 1 day at PBS (pH 4.5), but with 21.4% and 8.1% pDNA/PS release at PBS with pH 5.8 and 7.4 within 24 h, respectively. However, lesser pDNA/PS release occurred in MND2 (poly(Folate-HNPEGCA-co-HDCA)/DOPE, 10:90, molar ratio) with 46%, 16.9% and 7.8% of pDNA/PS released at PBS with pH 4.5, 5.8 and 7.4 within 24 h, respectively. After 1 day, pDNA/PS displayed a sustained release pattern. The amount of cumulated pDNA/PS release over 3 days was 75% and 51.2% at PBS with pH 4.5 for MND1 and MND2, respectively. The MND loading pDNA/PS showed that luciferase activity was over 0.5 ng luciferase/mg protein in KB cells, in particular, the MND1 showed the highest transfection efficiency (0.66 ng luciferase/mg protein) in KB cells, which was much higher compared with in A549 cells or other formulations such as LipofectAMINE, free pDNA/PS and control multifunctional nano device (CMND), whose lipid film was consisted of poly(H(2)NPEGCA-co-HDCA) and DOPE. In addition, MND also showed good protection during encapsulation and low cytotoxicity. As a result, MND could be a more potential non-viral vector for delivery of DNA.
Journal of Controlled Release 05/2007; 118(3):381-8. · 5.73 Impact Factor
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ABSTRACT: The purpose of this work is to prepare donepezil microparticles (DM) and evaluate its advantage as a sustained release delivery system with subcutaneous injection once a month. DM was prepared using poly (d,l-lactide-co-glycolide) (PLGA) by an oil-water emulsion solvent evaporation technique. DM showed the loading ratio 13.2+/-2.1% (w/w) and yield 54.8+/-0.8% with mean particle size about 75mum. In vitro release of DM showed that donepezil completely released within 28 days in water, but the cumulative release percentages up to day 30 were 98.4% and 49.1% for phosphate buffer saline (PBS, pH 5.8) and PBS (pH 7.4), respectively. The in vivo experiment demonstrated that DM (90mg/kg) produced a sustained release process in rats, and reached steady-state concentration at day 8 and maintained until day 27 with steady-state levels of donepezil between 130.3+/-7.8 and 121+/-9.8ng/ml, which was accordance with that of free donepezil by oral application route (3mg/kgday). DM (90mg/kg) by subcutaneous infusion in rats produced the same pharmacological role as free donepezil (3mg/kgday) by oral application route. These results implicated that DM as a sustained release delivery strategy could substitute for its oral formulation for therapy of AD and come true its administration once a month.
Biomaterials 05/2007; 28(10):1882-8. · 7.40 Impact Factor
