Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center

Yeonsu gu, South Korea

Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center

Yeonsu gu, South Korea
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Ramasamy T.,Yeungnam University | Ramasamy T.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center | Ruttala H.B.,Andhra University | Shanmugam S.,Osmania University | Umadevi S.K.,Osmania University
Drug Delivery | Year: 2013

The aim of this study was to develop a pectin-based colon-specific multiparticulate delivery system. Aceclofenac was used as a model drug owing to its potential therapeutic efficacy in rheumatoid arthritis. Pectin microspheres were prepared using emulsion dehydration technique. These microspheres were coated with Eudragit S-100 using solvent evaporation method. The effect of different variables (polymer, emulsifier, stirring speed and stirring time) was investigated in terms of size, surface morphology, entrapment efficiency, in vitro release and in vivo studies. The size of uncoated microspheres ranged from 30 to 55 μm and exhibited 5-40% of drug release in the upper gastrointestinal tract; however, continuous high release of drug was observed at colonic pH. In addition, the release of drug from the microspheres was found to be higher in the presence of rat cecal contents with maximum release at the 8th hour. This is one of the prerequisites for the effective treatment of rheumatoid arthritis, indicating the effect of colonic enzymes on the pectin microspheres. In vivo studies suggest the maintenance of therapeutic concentration of drug for 24 h with significant anti-inflammatory effect. Therefore, these findings clearly suggest that the Eudragit-coated pectin microspheres offer an exciting mode of aceclofenac delivery to colon in the chronopharmacological treatment of rheumatoid arthritis. © 2013 Informa UK Ltd All rights reserved.

Cho H.,Catholic University of Korea | Cho Y.-W.,Korea Institute of Toxicology | Kang S.-W.,Korea Institute of Toxicology | Kwak M.-K.,Catholic University of Korea | And 4 more authors.
Molecular Pharmaceutics | Year: 2017

The clinical application of intracellular gene delivery via nanosized carriers is hindered by intracellular multistep barriers that limit high levels of gene expression. To solve these issues, four different intracellular or external stimuli that can efficiently activate a gene carrier, a gene, or a photosensitizer (pheophorbide A [PhA]) were assessed in this study. The designed nanosized polymeric gene complexes were composed of PhA-loaded thiol-degradable polycation (PhA@RPC) and cytomegalovirus (CMV) promoter-equipped pDNA. After cellular internalization of the resulting PhA@RPC/pDNA complexes, the complexes escaped endosomal sequestration, owing to the endosomal pH-induced endosomolytic activity of RPC in PhA@RPC. Subsequently, intracellular thiol-mediated polycation degradation triggered the release of PhA and pDNA from the complexes. Late exposure to light (for example, 12 h post-treatment) activated the released PhA and resulted in the production of reactive oxygen species (ROS). Intracellular ROS successively activated NF-κB, which then reactivated the CMV promoter in the pDNA. These sequential, stimuli-responsive chemical and biological reactions resulted in high gene expression. In particular, the time-point of light exposure was very significant to tune efficient gene expression as well as negligible cytotoxicity: early light treatment induced photochemical internalization but high cytotoxicity, whereas late light treatment influenced the reactivation of silent pDNA via PhA-generated ROS and activation of NF-κB. In conclusion, the quadruple triggers, such as pH, thiol, light, and ROS, successively influenced a gene carrier (RPC), a photosensitizer, and a genetic therapeutic, and the tempo-spatial activation of the designed quadruple stimuli-activatable nanosized gene complexes could be potential in gene delivery applications. © 2017 American Chemical Society.

Gao Z.-G.,University of Utah | Gao Z.-G.,Chinese Academy of Sciences | Tian L.,University of Utah | Hu J.,University of Utah | And 3 more authors.
Journal of Controlled Release | Year: 2011

This study primarily focused on the anti-metastatic activity of doxorubicin (DOX) loaded in a pH-sensitive mixed polymeric micelle formed from two block polymers: poly(l-lactide) (PLLA) (Mn 3000)-b-poly(ethylene glycol) (PEG) (Mn 2000)-folate and poly(l-histidine) (PHis) (Mn 4700)-b-PEG (Mn 2000). Tumor formation and metastasis in mice were examined using a murine mammary carcinoma cell of 4T1 which is one of the most aggressive metastatic cancer cell lines. The efficacy was evaluated by tumor size, body weight change, survival rate, dorsal skin fold window chamber model, and histological observation of the lung, heart, liver and spleen after treatment with various DOX formulations. When the tumor reached 50-100 mm3 in size, the mice were treated 4 times at a 3-day interval at a dose of 10 mg DOX/kg. The mixed micelle formulation resulted in retarded tumor growth, no weight loss, and no death for 4-5 weeks. In another set of the in vivo test for histological evaluation of the organs, the mice were similarly treated but the formulations were injected one day after 4T1 cell inoculation. The treatment by DOX loaded mixed micelle showed no apparent metastasis till 28 days. However, significant metastasis to the lung and heart was observed on Day 28 when the mice were treated with DOX carried by PBS, PLLA-b-PEG micelle and PHis-b-PEG micelle. © 2011 Elsevier B.V.

Yin H.,University of Utah | Kang H.C.,Catholic University of Korea | Huh K.M.,Chungnam National University | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Colloids and Surfaces B: Biointerfaces | Year: 2014

In our previous study, a histidine-based AB2 miktoarm polymer, methoxy poly(ethylene glycol)-b-poly(l-histidine)2 (mPEG-b-(PolyHis)2), was designed to construct pH-sensitive polymersomes that transform in acidic pH; the polymer self-assembles into a structure that mimics phospholipids. In this study, the polymersomes further imitated liposomes due to the incorporation of cholesterol (CL). The hydrodynamic radii of the polymersomes increased with increasing CLwt% (e.g., 70nm for 0wt% vs. 91nm for 1wt%), resulting in an increased capacity for encapsulating hydrophilic drugs (e.g., 0.92μL/mg for 0wt% vs. 1.42μL/mg for 1wt%). The CL incorporation enhanced the colloidal stability of the polymersomes in the presence of serum protein and retarded their payload release. However, CL-incorporating polymersomes still demonstrated accelerated release of a hydrophilic dye (e.g., 5(6)-carboxyfluorescein (CF)) below pH 6.8 without losing their desirable pH sensitivity. CF-loaded CL-incorporating polymersomes showed better cellular internalization than the hydrophilic CF, whereas doxorubicin (DOX)-loaded CL-incorporating polymersomes presented similar or somewhat lower anti-tumor effects than free hydrophobic DOX. The findings suggest that CL-incorporating mPEG-b-(PolyHis)2-based polymersomes may have potential for intracellular drug delivery of chemical drugs due to their improved colloidal stability, lower drug loss during circulation, acidic pH-induced drug release, and endosomal disruption. © 2014 Elsevier B.V.

Kang H.C.,University of Utah | Kang H.-J.,Kyung Hee University | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Biomaterials | Year: 2011

To improve transfection efficiency and reduce the cytotoxicity of polymeric gene vectors, reducible polycations (RPC) were synthesized from low molecular weight (MW) branched polyethyleneimine (bPEI) via thiolation and oxidation. RPC (RPC-bPEI0.8 kDa) possessed MW of 5 kDa-80 kDa, and 50%-70% of the original proton buffering capacity of bPEI0.8 kDa was preserved in the final product. The cytotoxicity of RPC-bPEI0.8 kDa was 8-19 times less than that of the gold standard of polymeric transfection reagents, bPEI25 kDa. Although bPEI0.8 kDa exhibited poor gene condensing capacities (∼2 μm at a weight ratio (WR) of 40), RPC-bPEI0.8 kDa effectively condensed plasmid DNA (pDNA) at a WR of 2. Moreover, RPC-bPEI0.8 kDa/pDNA (WR ≥2) formed 100-200 nm-sized particles with positively charged surfaces (20-35 mV). In addition, the results of the present study indicated that thiol/polyanions triggered the release of pDNA from RPC-bPEI0.8 kDa/pDNA via the fragmentation of RPC-bPEI0.8 kDa and ion-exchange. With negligible polyplex-mediated cytotoxicity, the transfection efficiencies of RPC-bPEI0.8 kDa/pDNA were approximately 1200-1500-fold greater than that of bPEI0.8 kDa/pDNA and were equivalent or superior (∼7-fold) to that of bPEI25 kDa/pDNA. Interestingly, the distribution of high MW RPC-bPEI0.8 kDa/pDNA in the nucleus of the cell was higher than that of low MW RPC-bPEI0.8 kDa/pDNA. Thus, the results of the present study suggest that RPC-bPEI0.8 kDa has the potential to effectively deliver genetic materials with lower levels of toxicity. © 2010 Elsevier Ltd.

Mishra D.,University of Utah | Kang H.C.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Biomaterials | Year: 2011

This study investigated the potential of creating a charged polymeric micelle-based nucleic acid delivery system that could easily be reconstituted by the addition of water. (PLGA36kDa)2-b-bPEI25kDa (PLGA MW 36 kDa, bPEI Mw 25 kDa, PLGA:bPEI block ratio = 2) was synthesized and used to prepare cationic micelles. The copolymer retained proton-buffering capability from the bPEI block within the endosomal pH range. Micelle/pDNA complexes retained their particle size (100-150 nm) and surface charge (30-40 mV) following reconstitution. It was found that adding a small amount of low molecular weight bPEI (1.8 kDa) completely shielded pDNA in the micelle/pDNA complexes and enhanced transfection efficiency 50-100 fold for both fresh and reconstituted complexes without affecting complex size. Transfection efficiency for " reconstituted" micelle/pDNA/bPEI1.8kDa (WR 1) complexes was 16-fold higher than its " fresh" counterpart. Although transfection levels achieved using " reconstituted" micelle/pDNA/bPEI1.8kDa complexes were 3.6-fold lower than control " fresh" bPEI25kDa/pDNA (N/P 5) complexes, transfection levels were 39-fold higher than " reconstituted" bPEI25kDa/pDNA (N/P 5) complexes. The micelle/pDNA/bPEI1.8kDa system showed very low cytotoxicity in MCF7 cells even with pDNA doses up to 20 μg, and transfection levels increased linearly with increasing pDNA dose. These results indicate that this PLGA-b-bPEI polymeric micelle-based system is well suited as a reconstitutable gene delivery system, and has high potential for use as a delivery system for gene therapy applications. © 2011 Elsevier Ltd.

Tian L.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Colloids and Surfaces B: Biointerfaces | Year: 2012

Tumors have been a highlight in the research of nanomedicine for decades. Despite all the efforts in the decoration of the nano systems, tumor specific targeting is still an issue due to the heterogeneous nature of tumors. Hypoxia is frequently observed in solid tumors. The consequent acidification of tumor extracellular matrices may bring new insight to tumor targeting. In this review, we present the polymeric nano systems that target tumor extracellular pH (pH e). © 2011 Elsevier B.V.

Kang H.C.,Catholic University of Korea | Cho H.,Catholic University of Korea | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Molecular Pharmaceutics | Year: 2015

Double helix nucleic acids were used as a combination drug carrier for doxorubicin (DOX), which physically intercalates with DNA double helices, and cisplatin (CDDP), which binds to DNA without an alkylation reaction. DNA interacting with DOX, CDDP, or both was complexed with positively charged, endosomolytic polymers. Compared with the free drug, the polyplexes (100-170 nm in size) delivered more drug into the cytosol and the nucleus and demonstrated similar or superior (up to a 7-fold increase) in vitro cell-killing activity. Additionally, the gene expression activities of most of the chemical drug-loaded plasmid DNA (pDNA) polyplexes were not impaired by the physical interactions between the nucleic acid and DOX/CDDP. When a model reporter pDNA (luciferase) was employed, it expressed luciferase protein at 0.7- to 1.4-fold the amount expressed by the polyplex with no bound drugs (a control), which indicated the fast translocation of the intercalated or bound drugs from the "carrier DNA" to the "nuclear DNA" of target cells. The proposed concept may offer the possibility of versatile combination therapies of genetic materials and small molecule drugs that bind to nucleic acids to treat various diseases. © 2015 American Chemical Society.

Park H.,University of Utah | Cho S.,University of Utah | Han Y.H.,University of Utah | Janat-Amsbury M.M.,University of Utah | And 3 more authors.
Journal of Controlled Release | Year: 2015

The combinatorial peptidergic therapy of islet amyloid polypeptide (IAPP) and leptin (LEP) analogues was once an optimistic option in treating obese animals and patients. However, the need for frequent administrations and its negative side effects prevent it from being a viable choice. Here, we developed a combinatorial gene therapy of IAPP and LEP, where two genes are inserted into a single plasmid with self-cleaving furin and 2A sites to treat diet-induced obese (DIO) mice. The developed plasmid DNA (pDNA) individually produced both IAPP and LEP peptides in vitro and in vivo. The pDNA was delivered with a non-viral polymeric carrier, and its once-a-week administrations demonstrated a synergistic loss of body weight and significant reductions of fat mass, blood glucose, and lipid levels in DIO mice. The results suggest that the combinatorial gene therapy would have higher potential than the peptidergic approach for future translation due to its improved practicability. © 2015 Elsevier B.V.All rights reserved.

Park H.,University of Utah | Cho S.,University of Utah | Janat-Amsbury M.M.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
Biomaterials | Year: 2015

Thermogenic program (also known as browning) is a promising and attractive anti-obesity approach. Islet amyloid polypeptide (IAPP) and irisin have emerged as potential browning hormones that hold high potential to treat obesity. Here, we have constructed a dual browning gene system containing both IAPP and irisin (derived from fibronectin type III domain containing 5; FNDC5) combined with 2A and furin self-cleavage sites. Intraperitoneal administration of the construct complexed with a linear polyethylenimine into diet-induced obese mice demonstrated the elevation of anti-obesogenic effects characterized as the decreased body weight, adiposity, and levels of glucose and insulin. In addition, the construct delivery increased energy expenditure and the expression of core molecular determinants associated with browning. The additional advantages of the dual browning gene construct delivery compared to both single gene construct delivery and dual peptide delivery can be emphasized on efficacy and practicability. Hence, we have concluded that dual browning gene delivery makes it therapeutically attractive for diet-induced obesity treatment. © 2015 Elsevier Ltd.

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