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ABSTRACT: In this work, solid lipid nanoparticles loaded with cucurbitacin B (Cu B-SLNs) were prepared. It was found that the concentration of poloxamer 188 and soybean lecithin had effects on the mean particle size and size distribution. The zeta potentials were around -33 mV. In vitro release studies showed a sustained release after a burst release. Internalization of Cu B into HepG2 cells could be enhanced by the encapsulation of SLN matrix. The IC50 values of Cu B-SLNs were lower than that of Cu B solution. Both free Cu B and Cu B-SLNs had effectively inhibited the tumor growth and displayed a dose-dependent anti-tumor efficacy. Cu B-SLNs at a dose of 0.11 mg/kg produced the greatest anti-tumor effects (53.3%), which was significant higher than Cu B solution (31.5%, p < 0.05). Cu B-SLNs showed a longer MRT in vivo. The AUC of Cu B-SLNs for tumor increased 3.5 -fold when compared to Cu B solution. The targeting efficiency of Cu B-SLNs was 1.94 times higher in liver as compared to that of Cu B solution. These results indicated that Cu-B SLNs could passively target the tumor with EPR effect, improve the therapeutic efficacy of Cu B, and reduce the doses.
Drug Development and Industrial Pharmacy 07/2012; · 1.49 Impact Factor
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ABSTRACT: We prepared and optimized Ulex europaeus agglutinin I (UEAI)-modified Bovine serum albumin (BSA)-encapsulating liposomes (UEAI-LIP) as oral vaccine carriers and examined the feasibility of inducing systemic and mucosal immune responses by oral administration of UEAILIP. The prepared systems were characterized in vitro for their average size, zeta potential, encapsulation efficiency (EE%) and conjugation efficiency (CE%). In vitro release studies indicated that the presence of UEAI around the optimized liposomes was able to prevent a burst release of loaded BSA and provide sustained release of the encapsulated protein. In vivo immune-stimulating results in KM mice showed that BSA given intramuscularly generated systemic response only but both systemic and mucosal immune responses could be induced simultaneously in the groups in which BSA-loaded liposomes (LIP) and UEAI-LIP were administered intragastrically. Furthermore, the modification of UEAI on the surface of liposomes could further enhance the IgA and IgG levels obviously. In conclusion, this study demonstrated the high potential of lectin-modified liposomes containing the antigen as carriers for oral vaccine.
Archives of Pharmacal Research 11/2011; 34(11):1899-907. · 1.59 Impact Factor
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ABSTRACT: The objective of this work was to optimize the preparation of doxorubicin-loaded albumin nanoparticles (Dox-A-Nps) through desolvation procedures using response surface methodology (RSM). A central composite design (CCD) for four factors at five levels was used in this study.
Albumin nanoparticles were prepared through a desolvation method and were optimized in the aid of CCD. Albumin concentration, amount of doxorubicin, pH values, and percentage of glutaraldehyde were selected as independent variables, particle size, zeta potential, drug loading, encapsulation efficiency, and nanoparticles yield were chosen as response variables. RSM and multiple response optimizations utilizing a quadratic polynomial equation were used to obtain an optimal formulation.
The optimal formulation for Dox-A-Nps was composed of albumin concentration of 17 mg/ml, amount of doxorubicin of 2 mg/ml, pH value is 9 and percentage of glutaraldehyde of 125% of the theoretic amount, under which the optimized conditions gave rise to the actual average value of mean particle size (151 ± 0.43 nm), zeta potential (-18.8 ± 0.21 mV), drug loading efficiency (21.4 ± 0.70%), drug entrapment efficiency (76.9 ± 0.21%) and nanoparticles yield (82.0 ± 0.34%). The storage stability experiments proved that Dox-A-Nps stable in 4°C over the period of 4 months. The in vitro experiments showed a burst release at the initial stage and followed by a prolonged release of Dox from albumin nanoparticles up to 60 h.
This study showed that the RSM-CCD method could efficiently be applied for the modeling of nanoparticles, which laid the foundation of the further research of immuno nanoparticles.
Drug Development and Industrial Pharmacy 03/2011; 37(10):1170-80. · 1.49 Impact Factor
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ABSTRACT: Recently, dendrimers have been widely used in medical applications such as drug delivery and gene transfection. In this study, a pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and polyethylene glycol (PEG) modified by lactose (LA-PEG-b-PSD) was synthesized. The pK(a) value of the LA-PEG-b-PSD was also measured. Then, polyamidoamine (PAMAM) complexes were prepared with PAMAM (G4.0) and LA-PEG-b-PSD by electrostatic interaction. To investigate drug pH-sensitive release in vitro, doxorubicin (DOX) was loaded in PAMAM. A higher drug cumulative release from LA-PEG-b-PSD/PAMAM complexes in phosphate buffered saline (PBS) was found at pH 6.5 than at pH 7.4. The cytotoxicity and cellular uptake of PAMAM complexes were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and confocal microscopy. LA-PEG-b-PSD/PAMAM/DOX complexes were able to enhance the cytotoxicity of DOX against HepG2 cells at pH 7.4. Confocal microscopy showed a higher cellular uptake of PEG-b-PSD/PAMAM complexes at pH 6.5. PAMAM complexes modified by lactose showed a higher affinity for hepatic cancer cells than those without lactose at pH 7.4. These results suggest that LA-PEG-b-PSD/PAMAM complexes exhibit selective targeting and cytotoxicity against HepG2 cells. In vivo antitumor studies showed that the LA-PEG-b-PSD/PAMAM/DOX complexes displayed higher antitumor efficacy compared with non-targeted PAMAM/DOX and DOX solution. These results indicate that this strategy should be applicable to the treatment of liver cancers.
Chemical & pharmaceutical bulletin 01/2011; 59(1):63-71. · 1.70 Impact Factor
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ABSTRACT: This study intended to prepare liver-targeting solid lipid nanoparticles (SLNs) with a hepatoprotective drug, cucurbitacin B (Cuc B), using a galactosylated lipid, N-hexadecyl lactobionamide (N-HLBA). The galactosyl-lipid N-HLBA was prepared via the lactone form intermediates of lactobionic acid and synthesized by anchoring galactose to hexadecylamine lipid. The Cuc B-loaded galactosylated and conventional SLNs were successfully prepared by a high-pressure homogenization method. The two SLNs showed similar physical and pharmaceutical properties, including: the particle size measured by laser diffraction was 135 nm for galactosylated SLN (GalSLN) and 123 nm for conventional SLNs (CSLN); zeta potentials were -31.6 mV (GalSLN) and -34.3 mV(CSLN); in vitro release behavior of the two SLNs was similar, and both showed the biphasic drug release pattern with burst release at the initial stage and prolonged release afterwards. In contrast, the two SLNs demonstrated a marked difference in in vitro cellular cytotoxicity and in vivo tissue distribution performances. The IC(50) values of Cuc B in the two SLNs were by far lower than those of Cuc B solution and further Cuc B-GalSLN had about half the IC(50) value of Cuc B-CSLN. These results indicated that the encapsulation of Cuc B in SLNs resulted in the enhancement of cytotoxic activity, and galactosyl ligand could further enhance the cellular accumulation and cytotoxicity of Cuc B. The weighted-average overall drug targeting efficiency (Te) was used to evaluate the liver targetability. Cuc B-GalSLN gave a relatively high (Te)(liver) value of 63.6%, approximately 2.5-times greater than that of Cuc B-CSLN (25.3%) and Cuc B solution (23.8%). In summary, the incorporation of N-HLBA into SLNs significantly enhanced the liver targetability of Cuc B-loaded SLNs and GalSLN had a great potential as a drug delivery carrier for improved liver targetability.
Drug Delivery 02/2010; 17(3):114-22. · 1.46 Impact Factor
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ABSTRACT: To study the feasibility of digalactosyl diglyceride (DGDG) , which was used as a new type of emulsifier to prepare submicro-emulsion of bay oil.
Bay oil was employed as the model drug, emulsifer in oil method was used to prepare foremilk. Through single factor investigation and central composite design-response surface methodology (CCD-RSM) , we optimized the preparation technology and formula respectively. The stability of sub-microemulsion was studied.
The optima technology was following: emulsifer in oil method was used to prepare foremilk, temp was 60 degrees C, the micro emulsion was prepared by two-step high pressure homogen method with that the pressure was 80 Pa, 10 times, micropore film was used to sterilize, filling and sealing at the preservation of nitrogen. The best formula was following: soybean oil was 1.1%, DGDG was 1.6%, and sodium oleate was 0. 16%. The particle size of three batch submicro-emulsions were from 168.0 to 169.3 nm; Zeta potential were from-25.53 to 24.90 mV, pH value were from 8.48 to 8.52. The deviation between measured value and predictive value was 1.8%. It was stable in high temperature and illumination.
DGDG can be used as the emulsifier of bay oil sub-microemulsion.
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica 09/2009; 34(17):2172-6.
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ABSTRACT: In the present study, various gradients were evaluated for efficient loading of weak acid into liposomes. Several salt gradients showed efficient loading of ferulic acid (FA) into liposomes and the optimized conditions were established in calcium acetate gradient method to obtain 80.2 +/- 5.2% entrapment efficiency (EE). Unilamellar vesicles were observed in micrographs and liposomal FA showed good stability. 80% of FA was released from liposomes within 5 h in vitro. There is a novel finding in this study: that drugs could be entrapped with a high solubility in the intraliposomal buffer in contrast to the low solubility in the extraliposomal buffer. The results of body distribution in rats indicated that liposomes could improve the body distribution of FA. For FA liposome, the concentration of FA in brain was two-fold higher than that of free FA. Liposomal FA was a promising approach to improve the body distribution of FA.
Drug Development and Industrial Pharmacy 07/2008; 34(6):602-8. · 1.49 Impact Factor
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ABSTRACT: Thermosensitive PLGA-PEG-PLGA triblock copolymers with the DL-lactide/glycolide molar ratio ranging from 6/1 to 15/1 were synthesized by bulk copolymerization of DL-lactide, glycolide and PEG1500. The resulting copolymers are soluble in water to form a freely flowing fluid at room temperature but become hydrogels at body temperature. The release of IL-2 from the copolymer-based hydrogel in the phosphate buffer (pH 7.2) was studied at 37 degrees C under agitation. IL-2 was released from the copolymer-based hydrogels over 20 days in vitro and the release rate decreased with increasing copolymer concentration. The change of DL-lactide/glycolide molar ratio in the PLGA block of the copolymer had little effect on the IL-2 release. The released IL-2 remained 57-90% of its original activity during the release period. To evaluate the anti-tumor effect of the IL-2 loaded copolymer, solutions were injected subcutaneously to H22 tumor-bearing mice. IL-2 loaded copolymer hydrogel for in vivo use showed good anti-tumor effect. These results indicate that the thermosensitive PLGA-PEG-PLGA triblock copolymers could be a promising platform for sustained delivery of IL-2.
Pharmazie 02/2008; 63(1):27-30. · 1.01 Impact Factor
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ABSTRACT: The objectives of this study were to investigate the potential interactions between the model protein drug (bee venom peptide, BVP) and thermosensitive poly(dl-lactide-co-glycolide-b-ethyleneglycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA) copolymers and to examine the drug-copolymer interactions on the in vitro drug release and hydrogel degradation. The PLGA-PEG-PLGA copolymers were synthesized by ring-opening copolymerization of dl-lactide and glycolide with PEG as an initiator. Drug-copolymer co-precipitate blends were prepared and analyzed by Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) to characterize the specific interactions between drug and copolymer. For the better understanding the drug-copolymer interactions on drug release, insulin was selected for comparison. The release of the two protein drugs from the copolymer-based hydrogels and hydrogel degradation was studied at 37 degrees C under agitation. The results of FTIR and XRD indicated that the hydrogen bonding interactions existed between the NH group of BVP and CO group of the copolymers. The insulin and BVP released from the copolymer hydrogel over 15 and 40 days, respectively. The BVP-copolymer interactions retarded the BVP release rate and degradation of hydrogel, but did not significantly affect the biological activity of BVP. These results indicate that the drug-copolymer interactions need to be considered when attempting to use PLGA-PEG-PLGA hydrogels as sustained delivery carriers of protein or peptide drugs.
International Journal of Pharmaceutics 01/2008; 345(1-2):116-24. · 3.35 Impact Factor
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ABSTRACT: The conjugation of lectins onto PLGA nanoparticles has been demonstrated to effectively improve the intestinal absorption of thymopentin. In this study, thymopentin-loaded nanoparticles made from fluorescein isothiocyanate labeled PLGA were modified with wheat germ agglutinin (WGA). The specific bioadhesion of nanoparticles on rat intestinal mucosa was studied ex vivo. An important increase of interaction between WGA-conjugated nanoparticles and the intestinal segments was observed compared with that of the unconjugated one (p<0.05). Fluorescence photomicrographs confirmed the bioadhesion of WGA-conjugated nanoparticles on intestinal villous epithelium as well as Peyer's patches. Biodistribution of nanoparticles was evaluated using tissues obtained from rats, to which nanoparticles were orally administered. The highest amount of WGA-conjugated nanoparticles was detected in small intestine, suggesting an increase of intestinal bioadhesion and endocytosis. The systemic uptake was as high as 6.48-13.4% of dose at 1 day and 7.32-15.26% at 7 days, which representing an increase of almost 1.4-3.1 fold across the intestine compared to <4.9% of the unconjugated one. The enhanced uptake was related to the increasing of WGA density on nanoparticles. These results further revealed the promising potential of lectin-conjugated nanoparticles on the improvement of intestinal bioadhesion and absorption for oral drug delivery.
Journal of Controlled Release 10/2007; 123(1):27-38. · 5.73 Impact Factor
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ABSTRACT: RGD conjugation liposomes (RGD-liposomes) were evaluated for brain-targeting drug delivery. The flow cytometric in vitro study demonstrated that RGD-liposomes could bind to monocytes and neutrophils effectively. Ferulic acid (4-hydroxy-3-methoxycinnamic, FA) was loaded into liposomes. Rats were subjected to intrastriatal microinjections of 100 units of human recombinant IL-1beta to produce brain inflammation and caudal vein injection of three formulations (FA solution, FA liposome and RGD-coated FA liposome). Animals were sacrificed 15, 30, 60 and 120 min after administration to study the body distribution of the FA in the three formulations. HPLC was used to determine the concentration of FA in vivo with salicylic acid as internal standard. The results of body distribution indicated that RGD-coated liposomes could be mediated into the brain with a 6-fold FA concentration compared to FA solution and 3-fold in comparison to uncoated liposome. Brain targeted delivery was achieved and a reduction in dosage might be allowed.
Yakugaku zasshi journal of the Pharmaceutical Society of Japan 10/2007; 127(9):1497-501. · 0.39 Impact Factor
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ABSTRACT: In the present study, RGD peptide was coupled with ferulic acid (FA) liposomes for binding to monocytes and neutrophils in peripheral blood for brain targeting in response to leukocyte recruitment. Cholesterol (Ch) was esterified with succinic anhydride to introduce a carboxylic end group (Ch-COOH). Soybean phosphatidylcholine, cholesterol and Ch-COOH were in a molar ratio of 1 : 0.23 : 0.05. FA was loaded into liposomes with 80.2+/-5.2% entrapment efficiency (EE) using a calcium acetate gradient method since it was difficult to load FA by other methods. RGD peptide was a novel compound coupled with Ch-COOH via carbodiimide and N-hydroxysulfosuccinimide. The results of the in vitro flow cytometric study showed that RGD conjugation liposomes (RGD-liposomes) could bind to monocytes/neutrophils efficiently. The rats were subjected to intrastriatal microinjections of 100 microl of human recombinant IL-1beta to produce brain inflammation and subsequently sacrificed after 15, 30, 60 and 120 min of administration of three formulations (FA solution, FA liposome, RGD-coated FA liposome). The body distribution results showed that RGD-liposomes could be directed to the target site, i.e. the brain, by cell selectivity in case of an inflammatory response. For RGD coated liposomes, the concentration of FA in brain was 6-fold higher than that of FA solution and 3-fold higher than that of uncoated liposomes. MTT assay and flow cytometry were used in the pharmacodynamic studies where it was found that FA liposomes exhibited greater antioxidant activity to FA solution on U937 cell.
CHEMICAL & PHARMACEUTICAL BULLETIN 09/2007; 55(8):1192-7. · 1.59 Impact Factor
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ABSTRACT: The purpose of this study was to design and evaluate lectin-conjugated PLGA nanoparticles for oral delivery of thymopentin. Thymopentin loaded PLGA nanoparticles (TP5-NPs) were prepared by a double emulsion-solvent evaporation technique. Novel WGA-PLGA conjugates were synthesized by coupling the amino groups of wheat germ agglutinin (WGA) to the carbodiimide-activated carboxylic groups of PLGA, and were incorporated into nanoparticles preparation to take mucoadhesive properties. Important characteristics such as particle size, zeta potential, entrapment efficiency, storage stability, as well as in vitro drug release behavior were investigated. The retention of biorecognitive activity of WGA after covalent coupling was confirmed by haemagglutination test. In vitro experiments with pig mucin (PM) demonstrated that the conjugation of WGA enhanced the interaction about 1.8-4.2 fold compared with that of the non-conjugated nanoparticles, and still exhibited sugar specificity. The pharmacodynamical studies on oral administration of WGA-TP5-NPs were performed in FACScan flow cytometry. The values of CD4(+)/CD8(+) ratios were significantly increased compared with that of TP5-NPs (p<0.01). The enhanced uptake was related to the increasing of WGA content on nanoparticles. These results confirmed that the conjugation of WGA onto PLGA nanoparticles effectively improved the intestinal absorption of TP5 due to specific bioadhesion on GI cell membrane.
Journal of Controlled Release 01/2007; 116(3):337-45. · 5.73 Impact Factor
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ABSTRACT: The aim of this work is to prepare N-succinyl-chitosan (Suc-Chi) and measure physical-chemical properties for Suc-Chi as excipients. Suc-Chi were prepared via ring-opening reactions with succinic anhydride in Dimethyl Sulfoxide system. The physical-chemical properties of Suc-Chi, such as the degree of substitution (DS), solubility, isoelectric point (pI), glass transition temperature (Tg), partition coefficient (P(app)) and zata potential were detected respectively in order to evaluate their possibility as drug carriers. We obtained Suc-Chi DAC-90 (DS=0.33) and the data of physical-chemical properties for the product. The knowledges of physical-chemical properties for Suc-Chi are valuable for basic or applied purposes in biomedical and pharmaceutical sciences stabilization.
Yakugaku zasshi journal of the Pharmaceutical Society of Japan 10/2006; 126(9):789-93. · 0.39 Impact Factor
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ABSTRACT: Peptides in bee venom (PBV) have attracted considerable attention for anti-cancer therapy. In this study, sterically stabilized liposomal PBV (PBV-SL) was prepared using Soybean phosphatidylcholine, cholesterol, and the cholesterol derivatives of PEG with terminal COOH groups. The humanized anti-hepatoma disulfide-stabilized Fv (hdsFv25) was coupled to sterically stabilized liposomes. The hdsFv25-immunoliposome has strong affinity and specificity to SMMC-7721 cells in vitro. PBV-loaded sterically stabilized liposomes modified with the hdsFv25 can kill SMMC-7721 cells in vitro with higher efficiency than non-targeted liposomes. These results demonstrate that this strategy should also be applicable to immunotherapy for other cancers.
Pharmazie 09/2006; 61(8):685-8. · 1.01 Impact Factor
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ABSTRACT: Biodegradable thermosensitive poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with DL-lactide/glycolide molar ratio ranging from 6/1 to 15/1 were synthesized from monomers of DL-lactide, glycolide and polyethylene glycol and were evaluated for sustained release of bee venom peptide in vitro. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The gelation temperature of the copolymer solutions can be influenced by the concentration and DL-lactide/glycolide molar ratio of the copolymers. The release of bee venom peptide from the copolymer-based hydrogel and hydrogel degradation in the phosphate buffer (pH 7.4) was studied at 37 degrees C under agitation. Bee venom peptide was released from the copolymer-based hydrogels over 40 days in vitro and the variation of DL-lactide/glycolide molar ratio in the PLGA block of the copolymer did not significantly affect the release rate of bee venom peptide (P > 0.05). The hydrogels undergo slower degradation and then faster degradation rate during the whole release stage. Accordingly, the mechanism of bee venom peptide was Fickian diffusion during initial stage and then may be a combination of diffusion and degradation. The synthesized copolymers have the advantage of gelation temperature over the ReGel system. These results indicate that the PLGA-PEG-PLGA copolymer-based hydrogel could be a promising platform for sustained delivery of bee venom peptide.
Pharmazie 03/2006; 61(3):199-202. · 1.01 Impact Factor
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ABSTRACT: Polypeptides in bee venom (PBV) produced a significant growth inhibition against SMMC-7721 human hepatoma cell line. Analysis of the mechanisms of cell death indicated that PBV induced an apoptotic cell death. SMMC-7721 cells exposed to PBV (10.0 microg mL(-1)) produced an insignificant morphological change. Analysis of the cytotoxicity with the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay confirmed that the cytotoxic effects of PBV were dose- and timedependent. The result of Ki67 immunohistochemistry demonstrated that the proliferation of SMMC-7721 cells treated with PBV (10.0 mug mL(-1)) was inhibited. The apoptotic cell death was then confirmed by annexin V, propidium iodide staining and DNA fragmentation analysis. In in-vivo experiments, treatment with PBV (1.5 or 3 mg kg(-1)) resulted in a significant retardation of SMMC-7721 cell growth in Balb/c nude mice. These findings suggested that PBV could be used as a chemotherapeutic agent against tumours.
Journal of Pharmacy and Pharmacology 02/2006; 58(1):83-9. · 2.17 Impact Factor
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ABSTRACT: Recently the use of peptides in bee venom (PBV) for cancer therapy has attracted considerable attention. However, PBV's extensive use is prohibited by its intense hemolytic activity. In this study, the sterically stabilized liposomal PBV (PBV-SL) was prepared using soybean phosphatidylcholine, cholesterol, and cholesterol-PEG-COOH. The humanized antihepatoma disulfide-stabilized Fv (hdsFv25) was reengineered, expressed, and coupled to sterically stabilized liposomes using the N-hydroxysuccinimide ester method. The hdsFv25-immunoliposomes (SIL [hdscFv25]) were immunoreactive as determined by ELISA assay. PBV-SIL [hdscFv25] can kill SMMC-7721 cells in vitro with higher efficiency than nontargeted liposomes. PBV-SIL [hdsFv25] displayed high antitumor activity and resulted in a significant reduction in tumor size compared to nontargeted liposomes and PBV. These results indicated that this strategy should be applicable to applicable in the treatment of other cancers.
Journal of Pharmaceutical Sciences 02/2006; 95(1):192-9. · 3.06 Impact Factor
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ABSTRACT: The recombinant adenovirus vector carrying antisense multidrug resistance-associated protein (MRP) was constructed for use in gene therapy to overcome drug resistance in hepatocellular carcinoma.
The fragment of MRP gene encoding 5' region was cloned reversely into the shuttle plasmid pAdTrack-CMV, with the resultant plasmid and the backbone plasmid pAdEasy-1, the homologous recombination took place in the E. coli BJ5183 and the recombinant adenoviral plasmid was generated. The adenoviruses were packaged and amplified in the 293 cells. Then the viral titer was checked by GFP.
The recombinant adenovirus vector carrying antisense MRP was constructed successfully. The viral titer was 2.5 x 10(9).
The recombinant adenovirus vector constructed by us could introduce the antisense MRP into the human drug-resistant hepatocellular cell line effectively, which would provide experimental basis for the mechanisms and reversal methods of the multidrug resistance in human hepatocellular carcinoma.
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 02/2003; 34(1):131-4.
