MT1-MMP Responsive Doxorubicin Conjugated Poly(lactic-<i>co</i>-glycolic Acid)/Poly(styrene-<i>alt</i>-maleic Anhydride) Core/Shell Microparticles for Intrahepatic Arterial Chemotherapy of Hepatic Cancer

Davaa, Enkhzaya,Lee, Junghan,Jenjob, Ratchapol,Yang, Su-Geun American Chemical Society 2017 ACS APPLIED MATERIALS & INTERFACES Vol.9 No.1

<P>In this study, we demonstrated, that the MT1-MMP-responsive peptide (sequence: GPLPLRSWGLK) and doxorubicin-conjugated poly(lactic-co-glycolic acid/poly-(styrene-alt-maleic anhydride) core/shell microparticles (PLGA/pSMA. MPs) can be applied for intrahepatic arterial injection for hepatocellular carcinoma (HCC). PLGA/pSMA MPs were prepared with a, capillary-focused microfluidic device: The particle size, observed by scanning electron microscopy (SEM), was, around 22 +/- 3 mu m. MT1-MMP-responsive peptide and doxorubicin (D-OX) were chemically conjugated with pSMA segments on the shell of MPs to form. a PLGA/pSMA-peptide-DOX complex, resulting in high encapsulation efficiency, (91.1%) and loading content (2.9%). DOX was released from PLGA/pSMA-peptide-DOX MPs in a pH-dependent manner (similar to 25% at pH 5.4 and similar to 8% at pH 7.4) and accumulated significantly in an MT1-MMP-overexpressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 h after the injection without any shunting to the lung. Moreover, MPs efficiently inhibited tumor growth of Hep3B hepatic tumor xenografted mouse models. We expect that PLGA/pSMA-peptide-DOX MPs can be Utilized as an effective intrahepatic drug delivery system for the treatment of HCC.</P>

Preliminary study to determine the optimal conditions for the simultaneous complexation of siRNA and plasmid DNA

DAVAA ENKHZAYA,안익현,강봉석,이상은,명창선,박정숙 한국약제학회 2013 Journal of Pharmaceutical Investigation Vol.43 No.6

We investigated the complexation ratio of siRNA and plasmid DNA combined with Lipofectamine for the effective delivery of genetic materials. First, the amount of Lipofectamine was varied with a fixed amount of DNA or siRNA to determine in which proportions they would form an optimal combination. Finally, to investigate the effect of DNA or siRNA on the co-complexation of both DNA and siRNA, the co-complex of DNA and siRNA was prepared at the various ratios with a fixed amount of DNA. All complexation was confirmed by gel retardation of DNA or siRNA on agarose gels. The effects of siRNA complexes on mRNA expression from plasmid DNA were explored post-transfection, while the influence of plasmid DNA complexes on the transfection of siRNA was determined in GFP-expressing H4IIE cells. The complex between DNA and Lipofectamine was formed at a weight ratio of 0.8:1, whereas the light band of siRNA/Lipofectamine disappeared at a weight ratio of 4:1. When the amounts of DNA, siRNA, and the mixture were fixed, the optimal ratio of nucleic acids and Lipofectamine in our composition was 110:80:350 (ng). Confocal images and flow cytometry showed that inhibition of GFP expression by siRNA was not interfered with by co-complexed plasmid DNA. Moreover, mRNA expression of adiponectin was not hampered by the addition of siRNA; rather, it was increased. Thus, co-complexation of siRNA and plasmid DNA may have a synergistic effect on delivery of the therapeutic gene and siRNA.

Complexation of Adiponectin-encoding Plasmid DNA with Rosiglitazone-Loaded cationic Liposomes

( Enkhzaya Davaa ),( Ui Hyeon Jeong ),( Baek Ki Shin ),( Soon Gil Choi ),( Chang Seon Myung ),( Jeong Sook Park ) 한국약제학회 2010 Journal of Pharmaceutical Investigation Vol.40 No.6

To enhance therapeutic effects of insulin-sensitizing adipokine, ADN gene and potent agonists, rosiglitazone for the PPARγ, cationic liposomes as non-viral vectors were formulated. The particle size and zeta potential of drug loaded and unloaded cationic liposomes were investigated. The complex formation between cationic liposomes and negatively charged plasmid DNA was confirmed and the protection from DNase was observed. In vitro transfection was investigated in HepG2, HeLa, and HEK293 cells by mRNA expression of ADN. Encapsulation efficacy of rosiglitazone-loaded liposomes was determined by UV detection. Particle sizes of cationic liposomes were in the range of 110-170 nm and those of rosiglitazone-loaded cationic liposomes were in the range of 130-180 nm, respectively. Gel retardation of complexes indicated that the complex was formed at weight ratios of cationic lipid to plasmid DNA higher than 20:1. Both complexes protected plasmid DNA from DNase either drug free or drug loading. Encapsulation efficiency of rosiglitazone-loaded emulsion was increased by drug dose. The mRNA expression levels of ADN were dose-dependently increased in cells transfected with plasmid DNA. Therefore, cationic liposomes could be potential co-delivery system for drug and gene.

Formulation Parameters Influencing the Physicochemical Characteristics of Rosiglitazone-loaded Cationic Lipid Emulsion

DAVAA ENKHZAYA,박정숙 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.7

To enhance the solubility of rosiglitazone, rosiglitazone-loaded cationic lipid emulsion was formulated using cationic lipid DOTAP, DOPE, castor oil, tween 20, and tween 80. The formulation parameters in terms of droplet size were optimized focused on the effect of the cationic lipid emulsion composition ratio on drug encapsulating efficiency, in vitro drug release, and cellular uptake of the rosiglitazone-loaded emulsion. Droplet sizes of a blank cationic emulsion and a rosiglitazone-loaded cationic emulsion ranged between 195-230 nm and 210-290 nm, respectively. The encapsulation efficiency of the rosiglitazone-loaded emulsion was more than 90%. The rosiglitazone-loaded cationic emulsion improved in vitro drug release over the drug alone and showed a much higher cellular uptake than rosiglitazone alone. Moreover, drug loading in cationic emulsions increased cellular uptake of rosiglitazone in insulin-resistant HepG2 cells more than the normal HepG2 cells. Taken together, these results indicate that cationic lipid emulsions could be a potential delivery system for rosiglitazone and could enhance its cellular uptake efficiency into target cells.

Complexation of Adiponectin-encoding Plasmid DNA with Rosiglitazone-loaded Cationic Liposomes

Davaa, Enkhzaya,Jeong, Ui-Hyeon,Shin, Baek-Ki,Choi, Soon-Gil,Myung, Chang-Seon,Park, Jeong-Sook The Korean Society of Pharmaceutical Sciences and 2010 Journal of Pharmaceutical Investigation Vol.40 No.6

To enhance therapeutic effects of insulin-sensitizing adipokine, ADN gene and potent agonists, rosiglitazone for the $PPAR{\gamma}$, cationic liposomes as non-viral vectors were formulated. The particle size and zeta potential of drug loaded and unloaded cationic liposomes were investigated. The complex formation between cationic liposomes and negatively charged plasmid DNA was confirmed and the protection from DNase was observed. In vitro transfection was investigated in HepG2, HeLa, and HEK293 cells by mRNA expression of ADN. Encapsulation efficacy of rosiglitazone-loaded liposomes was determined by UV detection. Particle sizes of cationic liposomes were in the range of 110-170 nm and those of rosiglitazone-loaded cationic liposomes were in the range of 130-180 nm, respectively. Gel retardation of complexes indicated that the complex was formed at weight ratios of cationic lipid to plasmid DNA higher than 20:1. Both complexes protected plasmid DNA from DNase either drug free or drug loading. Encapsulation efficiency of rosiglitazone-loaded emulsion was increased by drug dose. The mRNA expression levels of ADN were dose-dependently increased in cells transfected with plasmid DNA. Therefore, cationic liposomes could be potential co-delivery system for drug and gene.

Photo-cured PMMA/PEI core/shell nanoparticles surface-modified with Gd-DTPA for T1 MR imaging

Enkhzaya DAVAA,Ha Neul LEE,Hyo Sang LIM,Chung Kil SONG,Don Haeng LEE,Sunintaboon PANYA,Su-Geun YANG 한국생물공학회 2014 한국생물공학회 학술대회 Vol.2014 No.4

트리암시놀론 아세토니드를 함유한 구강점막 부착성 패치의 제조 및 평가

엥흐자야,여동기,박진석,이은주,이경록,박정숙 충남대학교 약학대학 의약품개발연구소 2013 藥學論文集 Vol.28 No.-

The objective of this study was to prepare triamcinolone acetonide-loaded buccal adhesive patch. The adhesive patch was formulated by casting method using aqueous soluble polymer povidone K17 (PVP 17PF) as a film-forming agent and hydroxypropylmethylcellulose (HPMC) as an adhesive agent. To compare the effect of HPMC type, different molecular weight of K4M and K15M HPMC was used. The physicochemical properties of patches such as appearance, thickness, in vitro release, and adhesiveness were investigated. The concentration of triamcinolone acetonide was determined spectrophotometrically at a wavelength of 240 nm. The appearance of prepared patches was semi-transparent, light-yellow or almost colorless, and odorless. Thickness of each patches (n=6) was 0.942 ± 0.026 mm for K4M patch and 0.703 ± 0.036 mm for K15M patch, respectively. In vitro release test, both K4M and K15M patches showed over 20% release within 30 min. At 120 min, K4M and K15M patches demonstrated 80% and 76% release of triamcinolone acetonide, respectively, and up to 240 min, both patches released drug completely. Maximum adhesive force of K4M and K15M patches was 4.66 ± 0.76 gf and 2.69 ± 0.90 gf, respectively. Moreover, it took 28.73 ± 0.44 sec and 28.68 ± 0.61 sec for K4M and K15M patch to peel off them after adhesion, showing no significant difference. In conclusion, thickness, in vitro release, and maximum adhesive force could be modulated by alteration of polymer types.

Determination and Preliminary Semi-micro HPLC Method Validation of Rosiglitazone in Human Plasma with UV Detection

Semi Yu,Enkhzaya Davaa,Gyeong-Rok Lee,Eun Joo Lee,Jeong-Sook Park 충남대학교 약학대학 의약품개발연구소 2012 藥學論文集 Vol.27 No.-

The objective of this study was to validate a reliable analytical method for the determination of rosiglitazone in human plasma by a semi-micro high performance liquid chromatography (HPLC) system with UV detection. Rosiglitazone was dissolved in methanol. Separation was performed on a SPcolumn C18 UG120 (4.6 mm × 150 mm) using mobile phase of acetonitrile, methanol and acetate buffer (pH 4.0) at a volume ratio of 20:10:70. The signals were monitored by UV detector at 214 nm with flow-rate of 1 ml/min. The intra- and inter-day precision expressed as the relative standard deviation was less than 15%. The retention time of rosiglitazone was 7.6 min. The detection limit of rosiglitazone in human plasma was 2 μg/ml and the limit of quantification was 5 μg/ml. The calibration curve was linear in the concentration range of 5~100 μg/ml (r2=0.999). The accuracy was from 1.0% to 13.5% while the intra-day and inter-day coefficient of variation of the same concentration range was less than 15%. This analytical method should be improved to be applied to determine rosiglitazone in human plasma.

Dopa-Empowered Schiff Base Forming Alginate Hydrogel Glue for Rapid Hemostatic Control

송충길,김민경,이정한,DAVAA ENKHZAYA,Rengarajan Baskaran,양수근 한국고분자학회 2019 Macromolecular Research Vol.27 No.2

In this study we prepared tissue-adhesive hemostatic glue and assessed hemostatic effects on hepatic bleeding animal model. Alginate was used as primary polymer for the fabrication of hemostatic glue, oxidized for the introduction of the tissue-adhesive Schiff base forming aldehyde and then encoded with mussel-inspired dopa. In addition, polyallylamine (PAA) was selected for as an intra-structuring polymer which ensures the gel strength and allows instantaneous glue formation on the bleeding spot. Primary glue (OA glue) was quickly formed within 5 to 10 seconds after the mixing oxidized alginate (OA) with PAA. The degree of oxidation and the mixing ratio of OA and PAA were precisely determined based on glue formation time and gel strength. And the extend of dopa conjugation on OA was determined by the tissue adhesion force and the elasticity of the glue (Dopa-OA glue). Especially, elasticity of Dopa-OA glue was significantly enhanced after introduction of dopa to OA. Functional assay of Dopa-OA glue on hepatic bleeding animal model showed much enhanced hemostatic action. Dopa-OA glue is expected to provide novel injectable tissue adhesives for the treatment of hemorrhage caused by clinical procedures or trauma.

Enhanced thermodynamic, pharmacokinetic and theranostic properties of polymeric micelles via hydrophobic core-clustering of superparamagnetic iron oxide nanoparticles

강예흠,이정한,Jin-Myung Seo,Enkhzaya Davaa,신경주,양수근 한국생체재료학회 2022 생체재료학회지 Vol.26 No.2

Background Superparamagnetic iron oxide nanoparticles (SPIO) have been applied for decades to design theranostic polymeric micelles for targeted cancer therapy and diagnostic MR imaging. However, the effects of SPIO on the physicochemical, and biological properties of polymeric micelles have not yet been fully elucidated. Therefore, we investigated potential effect of SPIO on the physical and biological properties of theranostic polymeric micelles using representative cancer drug (doxorubicin; Doxo) and polymer carrier (i.e., poly (ethylene glycol)-co-poly(D,L-lactide), PEG-PLA). Methods SPIO were synthesized from Fe(acetyl acetonate)3 in an aryl ether. SPIO and Doxo were loaded into the polymeric micelles by a solvent-evaporation method. We observed the effect of SPIO-clustering on drug loading, micelle size, thermodynamic stability, and theranostic property of PEG-PLA polymeric micelles. In addition, cellular uptake behaviors, pharmacokinetic and biodistribution study were performed. Results SPIO formed hydrophobic geometric cavity in the micelle core and significantly affected the integrity of micelles in terms of micelle size, Doxo loading, critical micelle concentration (CMC) and in vitro dissociation. In vivo pharmacokinetic studies also showed the enhanced Area Under Curve (AUC) and elongated the half-life of Doxo. Conclusions Clustered SPIO in micelles largely affects not only MR imaging properties but also biological and physical properties of polymeric micelles.