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1.
Biomol Ther (Seoul) ; 24(5): 475-81, 2016 Sep 01.
Article in English | MEDLINE | ID: mdl-27169823

ABSTRACT

PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine D3 receptors (D3R), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine D2 receptor (D2R) and D3R in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of D2R were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of D3R were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on D3R functions.

2.
J Nanosci Nanotechnol ; 15(2): 1831-41, 2015 Feb.
Article in English | MEDLINE | ID: mdl-26353739

ABSTRACT

A self-emulsifying drug delivery system (SEDDS) containing tacrolimus has been developed to enhance the bioavailability and lymphatic delivery of tacrolimus. Solubility tests, combination tests, and phase diagrams were constructed for different sorts and ratios of oils, surfactants, and cosurfactants to identify optimal formulation. Optimized SEDDS was assessed for droplet size, zeta potential, stability in various media, and in vitro release. The tacrolimus-loaded SEDDS and commercial capsule (Prograf®) were orally administered (5 mg/kg) to rats. Whole blood, and mesenteric and axillary lymph node samples were taken and the concentrations of tacrolimus were measured to evaluate pharmacokinetic characteristics and the lymphatic delivery effects. The optimized SEDDS droplets were approximately 40 nm in size and stable enough to endure gastric pH environments. The release rate of tacrolimus from SEDDS was significantly higher than that from the commercial capsule. The bioavailability of tacrolimus in SEDDS after oral administration was significantly improved versus that of Prograf®. The lymphatic targeting efficiency of the prepared SEDDS formulation showed significantly greater than that of Prograf®. Our research indicates that prepared SEDDS can be an alternative to the conventional oral formulation of tacrolimus. Furthermore, SEDDS should be explored as a potential drug carrier for other lipophilic drugs.


Subject(s)
Emulsifying Agents/chemistry , Lymph Nodes/metabolism , Nanocapsules/chemistry , Tacrolimus/administration & dosage , Tacrolimus/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Diffusion , Drug Synergism , Emulsions , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacokinetics , Male , Metabolic Clearance Rate , Nanocapsules/ultrastructure , Rats , Rats, Sprague-Dawley , Tacrolimus/chemistry
3.
J Nanosci Nanotechnol ; 11(8): 7078-81, 2011 Aug.
Article in English | MEDLINE | ID: mdl-22103128

ABSTRACT

Polyethylenimine (PEI) has been shown to be an efficient nonviral delivery vector. To improve its specificity and reduce its cytotoxicity, PEI should be modified. Transferrin (Tf) is a cell-binding ligand and Tf-receptors are expressed in malignant cells. Modification of cationic polymer by polyethylene glycol (PEG) can reduce the protein interaction and cell cytotoxicity of delivery vectors. We have synthesized PEG-Tf-PEI conjugate as an efficient and safe carrier of plasmid DNA (pDNA). Nanocomplexes of conjugates with pDNA were characterized by measuring the particle size and the surface charge. Transfection efficiency of nanocomplexes in Jurkat cells was improved and cytotoxicity was decreased compared with those of PEI complex. This was due to a reduction in the membrane damaging effect via shielding of the positive charge on the nanocomplex surface by PEG.


Subject(s)
Nanostructures , Polyethylene Glycols/chemistry , Polyethyleneimine/chemistry , Transfection , Transferrin/chemistry , DNA/chemistry , Humans , Jurkat Cells , Plasmids
4.
J Nanosci Nanotechnol ; 11(2): 1795-8, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21456294

ABSTRACT

In order to develop a prolonged circulating drug carrier and to overcome p-glycoprotein-mediated multidrug resistance to adriamycin (ADR), which is a potent chemotherapeutic agent in the treatment of various cancers, poly(lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) nanoparticles were prepared and characterized. ADR-loaded PLGA-PEG nanoparticles prepared by the emulsification-diffusion method were spherical and homogeneous with smooth surfaces when assessed by scanning electron microscopy. The nanoparticles were 200-230 nm in size and the encapsulation efficiency of ADR in the nanoparticles was 30 approximately 35%. The release of ADR from nanoparticles was extended compared to that from free ADR solution. After intravenous administration of adriamycin-loaded PLGA-PEG nanoparticles to rats, the plasma level of ADR from PLGA-PEG nanoparticle was extended until 24 hours and the mean residence time of ADR of nanoparticles was increased compared to that of ADR solution. And ADR-loaded nanoparticles showed a higher growth inhibitory effect than free ADR solution in an ADR resistant MCF-7 human breast carcinoma cell line. The prepared ADR-loaded PLGA-PEG nanoparticles can be used as a good delivery system for ADR.


Subject(s)
Doxorubicin/administration & dosage , Drug Carriers , Nanoparticles , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Doxorubicin/pharmacokinetics , Drug Carriers/chemistry , Female , Humans , Injections, Intravenous , Nanoparticles/chemistry , Nanoparticles/ultrastructure , Nanotechnology , Particle Size , Polyethylene Glycols/chemistry , Polyglactin 910/chemistry , Rats
5.
Arch Pharm Res ; 33(5): 761-7, 2010 May.
Article in English | MEDLINE | ID: mdl-20512475

ABSTRACT

For a new anticancer drug carrier, we synthesized 4 compositions of amphiphilic stearic acidconjugated pullulan (SAP) and characterized them with FT-IR spectroscopy. Crystalline changes were verified by x-ray diffraction patterns before and after synthesis of the SAP conjugate. SAP nanoparticles were prepared by a diafiltration method, and the fluorescence spectroscopy using pyrene showed particle self-assembly in water. SAP nanoparticles were spherical in TEM photos, and particle size ranged between 200 approximately 500 nm in photon correlation spectroscopy. Release of all-trans-retinoic acid from the SAP nanoparticles was maintained over 5 weeks. For further study in vivo, we tested the cytotoxicity of SAP nanoparticles using an MTT assay, and cytotoxicity was augmented as the molar mass of stearic acid increased in human liver carcinoma HepG2 cells. Therefore, SAP nanoparticles might be a promising longterm delivery carrier for hydrophobic therapeutic molecules with the appropriate composition.


Subject(s)
Drug Carriers/chemistry , Drug Carriers/chemical synthesis , Glucans/chemistry , Nanoparticles/adverse effects , Nanoparticles/chemistry , Stearic Acids/chemistry , Cell Survival/drug effects , Chemistry, Pharmaceutical/methods , Crystallization , Drug Compounding/methods , Hep G2 Cells , Humans , Particle Size , Tretinoin/pharmacokinetics
6.
J Nanosci Nanotechnol ; 10(5): 3224-7, 2010 May.
Article in English | MEDLINE | ID: mdl-20358927

ABSTRACT

We tested the effects of poloxamer 188 on the preparation and characteristics of poly(lactice-co-glycolide) (PLGA) nanoparticles containing all-trans retinoic acid (ATRA). Spherical nanoparticles incorporated ATRA were prepared by an emulsification-diffusion method increasing concentrations of poloxamer 188 decreased nanoparticle size. The endothermic peak of ATRA at 183 degrees C disappeared in the nanoparticles and X-ray diffraction measurements showed the disappearance of characteristics of ATRA suggesting the change of the crystallinity of ATRA in the nanoparticles to an amorphous state. ATRA release in vitro increased as the concentration of poloxamer increased. The mean residence time of ATRA-loaded nanoparticles after the administration of a single intravenous dose to rats was longer than that of the sodium ATRA solution. The anti-cancer activity of ATRA-loaded nanoparticles in the human leukemia-60 cell line was similar to free ATRA. Thus, PLGA/poloxamer nanoparticles can provide a sustained release preparation of ATRA.


Subject(s)
Nanoparticles/chemistry , Poloxamer/chemistry , Polyglactin 910/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Male , Poloxamer/administration & dosage , Poloxamer/pharmacokinetics , Polyglactin 910/administration & dosage , Polyglactin 910/pharmacokinetics , Rats , Rats, Sprague-Dawley , Tretinoin/administration & dosage , Tretinoin/chemistry , Tretinoin/pharmacokinetics , X-Ray Diffraction
7.
Arch Pharm Res ; 31(1): 96-102, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18277614

ABSTRACT

Non-viral vectors such as liposomes, polycations, and nanoparticles have been used as gene delivery systems. In this study, we prepared and characterized biodegradable poly(L-lactic acid) (PLA)/polyethylenimine (PEI) nanoparticles as gene carriers. pCMV/beta-gal and pEGFP-C1 were utilized as model plasmid DNAs (pDNA). Nanoparticles were prepared using a double emulsion-solvent evaporation technique, and their pDNA binding capacity was assessed by agarose gel electrophoresis. Transfection was studied in HEK 293 and HeLa cell lines, and the transfection efficiencies were determined by beta-galactosidase assay or flow cytometry. Three kinds of PLA/PEI systems were studied by varying the molecular weight of PEI. The PLA/PEI 25K system had a higher transfection efficiency than the PLA/PEI 0.8K or PLA/PEI 750K systems. The transfection efficiency was found to be dependent on the ratio of PLA/PEI nanoparticles to pDNA with an optimum ratio of 60:1 (w/w). The cytotoxicity was dependent on the quantity of PLA/PEI nanoparticles used, but it was comparable to that of commercial Lipofectin. These results demonstrate the potential of PLA/PEI nanoparticles as gene carriers.


Subject(s)
DNA/administration & dosage , Drug Carriers , Lactic Acid/chemistry , Nanoparticles , Plasmids/administration & dosage , Polyethyleneimine/chemistry , Polymers/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Chemical Phenomena , Chemistry, Physical , DNA/chemistry , Electrochemistry , Electrophoresis, Polyacrylamide Gel , HeLa Cells , Humans , Particle Size , Plasmids/chemistry , Polyesters , Transfection
8.
J Control Release ; 108(2-3): 557-67, 2005 Nov 28.
Article in English | MEDLINE | ID: mdl-16253376

ABSTRACT

The asialoglycoprotein receptor (ASGP-R) on the hepatocyte membrane is a specific targeting marker for gene and drug delivery. Polyethylenimine (PEI) is a polycationic nonviral vector that is used for gene transfer. We have synthesized galactosylated polyethylenimine-graft-poly(ethylene glycol) (GPP) for performing gene delivery to the hepatocytes. The present study reports on the in vitro and in vivo data that was achieved in hepatoma bearing transgenic mice. The cytotoxicity was decreased with the increasing PEG content. The particle size of the complex was increased with the increasing PEG at an N/P ratio of 3.0, while the zeta potentials were decreased. The (99m)Tc labeled complexes were transfected into HepG2 and HeLa cells, while the GFP reporter genes were mainly expressed in the HepG2 cells. The in vivo data was achieved in ALB/c-Ha-ras transgenic mice. (99m)Tc labeled GPP(50)/DNA was injected into the mice via the tail vein, and the gamma images were acquired at 5, 15 and 30 min. The (99m)Tc labeled complexes were mainly localized in the heart and liver, and they were excreted through the kidneys. The GFP gene was mainly expressed in the proliferating cells at the tumor periphery. This result was confirmed by PCNA staining. The GPP(50)/DNA complexes were bound to ASGP-R of the proliferating hepatocytes in vitro and in vivo. The present results demonstrate the feasibility of nonviral gene transfer using galactosylated PEI-PEG in vivo.


Subject(s)
Asialoglycoprotein Receptor/drug effects , Asialoglycoprotein Receptor/genetics , Drug Delivery Systems , Genetic Therapy/methods , Polyethylene Glycols/chemistry , Transfection/methods , Animals , Cell Line, Tumor , Cell Survival/drug effects , DNA/biosynthesis , DNA/genetics , Electrochemistry , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Genes, ras/genetics , Green Fluorescent Proteins/genetics , Hepatocytes/drug effects , Liver Neoplasms, Experimental/diagnostic imaging , Liver Neoplasms, Experimental/therapy , Mice , Mice, Transgenic , Radionuclide Imaging , Technetium , Tetrazolium Salts , Thiazoles
9.
Arch Pharm Res ; 28(8): 983-7, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16178427

ABSTRACT

Hydrogels composed of glycidyl methacrylate dextran (GMD) and poly(acrylic acid, PAA) were prepared by UV irradiation method for colon-specific drug delivery. GMD was synthesized by coupling of glycidyl methacrylate to dextran in the presence of 4-(N,N-dimethylamino)pyridine. GMD was photo-polymerized by ammonium peroxydisulfate as initiating system in phosphate-buffered solution (0.1 M, pH 7.4). And then, acrylic acid monomer was added and subsequently heat-polymerized by 2,2'-azobisisobutyronitrile as an initiator. The hydrogels exhibited high swelling ratio (about 20) at 37 degrees C, and showed a pH-dependent swelling behavior. In addition, the swelling ratio of the hydrogel was remarkably enhanced to about 45 times in the presence of dextranase at pH 7.4. The swelling-deswelling behavior proceeded reversibly for the GMD/PAA hydrogels between pH 2 and pH 7.4. Release of 5-aminosalicylic acid from the GMD/PAA hydrogels was evaluated in simulated gastrointestinal pH fluids in the absence or presence of dextranase. We concluded that the hydrogels prepared could be used as a dual-sensitive drug carrier for sequential release in gastrointestinal tract.


Subject(s)
Drug Carriers/chemistry , Hydrogels/chemistry , Acrylic Resins/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Dextranase/metabolism , Dextrans/chemistry , Drug Carriers/chemical synthesis , Epoxy Compounds/chemistry , Hydrogels/chemical synthesis , Hydrogels/metabolism , Hydrogen-Ion Concentration , Mesalamine/chemistry , Mesalamine/metabolism , Methacrylates/chemistry , Solubility , Time Factors
10.
Arch Pharm Res ; 28(6): 722-9, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16042083

ABSTRACT

With the aim to improve the specificity and to reduce the cytotoxicity of polyethylenimine (PEI), we have synthesized the conjugates of the branched PEI (25 kDa) with transferrin. The transferrin-PEI (TP) conjugates with five compositions were synthesized using periodate oxidation method and confirmed by FT-IR spectroscopy and gel permeation chromatography. The free amine contents of TP conjugates, which were able to condense and deliver DNA, increased as the amount of PEI increased. TP/DNA polyplexes were characterized by measuring gel electrophoresis, ethidium bromide fluorescence quenching, particle size and zeta potential of complexes. Complete complexation of the polyplexes was observed above the N/P ratio of 5 in TP/ DNA, and above 3 in PEI/DNA, respectively. The zeta potential of the complexes decreased as the amount of transferrin in TP conjugates increased. Transfection efficiency of TP conjugates was evaluated in HeLa cell and Jurkat cell systems. Among the five compositions of TP conjugates, TP-2 system mediated a higher beta-galactosidase gene expression than PEI system in Jurkat cell which was known to express elevated numbers of transferrin receptors. From the results of the cell viability based on MTT assay, TP conjugates showed lower cytotoxicity compared with the PEI system. We expect that the TP conjugate can be used efficiently as a nonviral gene delivery vector.


Subject(s)
Drug Carriers/pharmacology , Polyethyleneimine/analogs & derivatives , Transferrin/analogs & derivatives , Cell Survival/drug effects , Electrophoresis, Agar Gel , Formazans , Genetic Vectors , HeLa Cells , Humans , Jurkat Cells , Particle Size , Polyethyleneimine/pharmacology , Polyethyleneimine/toxicity , Receptors, Transferrin/metabolism , Spectrometry, Fluorescence , Tetrazolium Salts , Transfection , Transferrin/genetics , Transferrin/pharmacology
11.
Int J Pharm ; 298(1): 255-62, 2005 Jul 14.
Article in English | MEDLINE | ID: mdl-15941631

ABSTRACT

Polymer nanoparticles have been used as non-viral gene delivery systems and drug delivery systems. In this study, biodegradable poly(L-lactic acid) (PLA)/polyethylenimine (PEI) and poly(D,L-lactide-co-glycolide) (PLGA)/PEI nanoparticles were prepared and characterized as gene delivery systems. The PLA/PEI and PLGA/PEI nanoparticles, which were prepared by a diafiltration method, had spherical shapes and smooth surface characteristics. The size of nanoparticles was controlled by the amount of PEI, which acted as a hydrophilic moiety, which effectively reduced the interfacial energy between the particle surface and the aqueous media. The nanoparticles showed an excellent dispersive stability under storage in a phosphate-buffered saline solution for 12 days. The positive zeta-potentials for the nanoparticles decreased and changed to negative values with increasing plasmid DNA (pDNA) content. Agarose gel electrophoresis showed that the complex formation between the nanoparticles and the pDNA coincided with the zeta-potential results. The results of in vitro transfection and cell viability on HEK 293 cells indicated that the nanoparticles could be used as gene delivery carriers.


Subject(s)
Drug Delivery Systems , Gene Transfer Techniques , Lactic Acid/administration & dosage , Nanostructures , Polyethyleneimine/administration & dosage , Polymers/administration & dosage , Cell Survival , Drug Stability , Genetic Vectors , Lactic Acid/chemistry , Particle Size , Polyesters , Polyethyleneimine/chemistry , Polyglycolic Acid , Polylactic Acid-Polyglycolic Acid Copolymer , Polymers/chemistry , Transfection
12.
Eur J Pharm Biopharm ; 60(1): 67-71, 2005 May.
Article in English | MEDLINE | ID: mdl-15848058

ABSTRACT

To develop the new gel formulations that show sustained release for a period of time, the bioadhesive carbopol gels containing tretinoin were prepared. The release characteristics of drug from the carbopol gel were studied according to temperature, receptor medium and drug concentration. For the enhancement of its percutaneous absorption, some kinds of penetration enhancer were used. As the concentration of drug increased, the release of drug from the gel increased, showing concentration dependency. The increase of temperature showed the increased drug release, depending on the activation energy of permeation. Among the enhancers used such as the glycols and the non-ionic surfactants, polyoxyethylene 2-oleyl ether showed the best enhancing effect. The carbopol gels of tretinoin containing an enhancer could be developed for the enhanced transdermal delivery of drug.


Subject(s)
Keratolytic Agents/administration & dosage , Keratolytic Agents/pharmacokinetics , Tretinoin/administration & dosage , Tretinoin/pharmacokinetics , Acrylic Resins , Administration, Cutaneous , Algorithms , Animals , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Diffusion , Gels , Hydrogen-Ion Concentration , In Vitro Techniques , Male , Polyvinyls , Rats , Rats, Sprague-Dawley , Temperature
13.
Int J Pharm ; 235(1-2): 141-7, 2002 Mar 20.
Article in English | MEDLINE | ID: mdl-11879749

ABSTRACT

Triprolidine-containing matrix was fabricated with poly(4-methyl-1-pentene) (TPX) polymer to control the release of the drug. Effect of penetration enhancer and stripping of skin on the permeation of triprolidine through the excised mouse skin was studied. Penetrating enhancers showed the increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene-2-oleyl ether showed the best enhancement. The permeability of triprolidine was markedly increased with stripping the mouse skin to remove the stratum corneum, which acts as a barrier of skin permeation. For the controlling delivery of triprolidine, the TPX matrix containing permeation enhancer could be developed.


Subject(s)
Drug Delivery Systems/methods , Membranes, Artificial , Polyenes/administration & dosage , Polymers/administration & dosage , Triprolidine/administration & dosage , Administration, Cutaneous , Animals , Anti-Allergic Agents/administration & dosage , Anti-Allergic Agents/pharmacokinetics , Male , Mice , Mice, Inbred ICR , Polyenes/pharmacokinetics , Polymers/pharmacokinetics , Skin Absorption/drug effects , Skin Absorption/physiology , Triprolidine/pharmacokinetics
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