Advanced Therapeutics Research Center

Yeonsu gu, South Korea

Advanced Therapeutics Research Center

Yeonsu gu, South Korea
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Denison T.A.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Advanced Therapeutics Research Center
Journal of Controlled Release | Year: 2012

Evidence continues to accumulate that patient tumors contain heterogeneous cell populations, each of which may contribute differently in extent and mechanism to the progression of malignancy. However, the field of tumor drug delivery research, while continually presenting new and innovative approaches, in many ways continues to operate on the premise that essentially all tumor cells are identical. In some in vivo models, xenograft tumors using cell lines may actually be comparatively homogeneous, and thus result in overly encouraging results when a particular drug or delivery system is reported to successfully treat tumors in mice. It is well known, however, that many drugs that show success in preclinical studies will fail in clinical trials. Tumor heterogeneity is possibly one of the most significant factors that most treatment methods fail to address sufficiently. While a particular drug may exhibit initial success, the eventual relapse of tumor growth is due in many cases to subpopulations of cells that are either not affected by the drug mechanism, possess or acquire a greater drug resistance, or have a localized condition in their microenvironment that enables them to evade or withstand the drug. These various subpopulations may include cancer stem cells, mutated clonal variants, and tumor-associated stromal cells, as well as cells experiencing a spatially different condition such as hypoxia within a diffusion-limited tumor region. This review briefly discusses some of the many aspects of tumor heterogeneity and their potential implications for future drug design and delivery methods. © 2012 Elsevier B.V. All rights reserved.


Kang H.C.,Catholic University of Korea | Huh K.M.,Chungnam National University | Bae Y.H.,University of Utah | Bae Y.H.,Advanced Therapeutics Research Center
Journal of Controlled Release | Year: 2012

To deliver nucleic acids including plasmid DNA (pDNA) and short interfering RNA (siRNA), polymeric gene carriers equipped with various functionalities have been extensively investigated. The functionalities of these polymeric vectors have been designed to overcome various extracellular and intracellular hurdles that nucleic acids and their carriers encounter during their journey from injection site to intracellular target site. This review briefly introduces known extracellular and intracellular issues of nucleic acid delivery and their solution strategies. We examine significant yet overlooked factors affecting nucleic acid delivery (e.g., microenvironmental pH, polymer/siRNA complexation, and pharmaceutical formulation) and highlight our reported approaches to solve these problems. © 2012 Elsevier B.V.


Choi J.-W.,Hanyang University | Jung S.-J.,Hanyang University | Kasala D.,Hanyang University | Hwang J.K.,Hanyang University | And 4 more authors.
Journal of Controlled Release | Year: 2015

Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH 6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and-negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH 6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH 7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX. © 2015 Elsevier B.V. All rights reserved.


Kang H.C.,University of Utah | Samsonova O.,University of Utah | Samsonova O.,University of Marburg | Bae Y.H.,University of Utah | Bae Y.H.,Advanced Therapeutics Research Center
Biomaterials | Year: 2010

While multidrug resistance (MDR) has been a significant issue in cancer chemotherapy, delivery resistance to various anti-cancer biotherapeutics, including genes, has not been widely recognized as a property of MDR. This study aims to provide a better understanding of the transfection characteristics of drug-sensitive and drug-resistant cells by tracing microenvironmental pHs of two representative polymer vectors: poly(l-lysine) and polyethyleneimine. Drug-sensitive breast MCF7 cells had four- to seven-times higher polymeric transfection efficiencies than their counterpart drug-resistant MCF7/ADR-RES cells. Polyplexes in MCF7/ADR-RES cells after endocytosis were exposed to a more acidic microenvironment than those in MCF7 cells; the MDR cells show faster acidification rates in endosomes/lysosomes than the drug-sensitive cells after endocytosis (in the case of PLL/pDNA complexes, ∼ pH 5.1 for MCF7/ADR-RES cells vs. ∼ pH 6.8 for MCF7 cells at 0.5 h post-transfection). More polyplexes were identified trapped in acidic subcellular compartments of MCF7/ADR-RES cells than in MCF7 cells, suggesting that they lack endosomal escaping activity. These findings demonstrate that the design of polymer-based gene delivery therapeutics should take into account the pH of subcellular compartments. © 2010 Elsevier Ltd. All rights reserved.


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.,Advanced Therapeutics Research Center
Journal of Materials Chemistry | Year: 2012

Motivated by the limitations of liposomal drug delivery systems, we designed a novel histidine-based AB 2-miktoarm polymer (mPEG-b-(polyHis) 2) equipped with a phospholipid-mimic structure, low cytotoxicity, and pH-sensitivity. Using "core-first" click chemistry and ring-opening polymerization, mPEG 2kDa-b-(polyHis 29kDa) 2 was successfully synthesized with a narrow molecular weight distribution (1.14). In borate buffer (pH 9), the miktoarm polymer self-assembled to form a nano-sized polymersome with a hydrodynamic radius of 70.2 nm and a very narrow size polydispersity (0.05). At 4.2 μmol per mg polymer, mPEG 2kDa-b-(polyHis 29kDa) 2 strongly buffered against acidification in the endolysosomal pH range and exhibited low cytotoxicity on 5 days exposure. Below pH 7.4 the polymersome transitioned to cylindrical micelles, spherical micelles, and finally unimers as the pH was decreased. The pH-induced structural transition of mPEG 2kDa-b-(polyHis 29kDa) 2 nanostructures may be caused by the increasing hydrophilic weight fraction of mPEG 2kDa-b- (polyHis 29kDa) 2 and can help to disrupt the endosomal membrane through proton buffering and membrane fusion of mPEG 2kDa-b-(polyHis 29kDa) 2. In addition, a hydrophilic model dye 5(6)-carboxyfluorescein encapsulated into the aqueous lumen of the polymersome showed a slow, sustained release at pH 7.4 but greatly accelerated release below pH 6.8, indicating a desirable pH sensitivity of the system in the range of endosomal pH. Therefore, this polymersome that is based on a biocompatible histidine-based miktoarm polymer and undergoes acid-induced transformations could serve as a drug delivery vehicle for chemical and biological drugs. This journal is © The Royal Society of Chemistry.


Park W.,Catholic University of Korea | Park W.,University of Utah | Kim D.,University of Utah | Kang H.C.,Catholic University of Korea | And 3 more authors.
Biomaterials | Year: 2012

For long-term, sustained protein delivery, a new, star-shaped block copolymer composed of methoxy poly(ethylene glycol) (mPEG), branched oligoethylenimine (bOEI), and poly (l-histidine) (pHis) was synthesized via the multi-initiation and ring-opening polymerization (ROP) of His N-carboxy anhydride (NCA) on bOEI with a PEG conjugation. The resulting mPEG-bOEI-pHis (POH) had strong buffering capacity within the neutral-to-acidic pH range and was complexed with insulin (Ins) via an electrostatic attraction plus hydrophobic interactions, resulting in the formation of a dual-interaction complex (DIC, weight ratio 2) of approximately 30-60 nm in size. This DIC tolerated high salt concentrations without destabilization, supporting the existence of hydrophobic interactions, and protected Ins from the organic solvent/water interface. The DIC in poly(lactide-co-glycolide) microspheres (PLGA MS) as a long-term Ins delivery formulation was evenly distributed via a double-emulsion method. The DIC-loaded PLGA MS offered a higher Ins loading and a lower initial burst than Ins-loaded PLGA MS. This formulation possessed near zero-order release kinetics (for at least one month). In streptozotocin (STZ)-induced diabetic rats, a DIC-loaded PLGA MS formulation was able to maintain blood-glucose levels at 200-350 mg/dL for the first two weeks and even lower levels (100-200 mg/dL) for the next two weeks. Thus, a new POH polymer and its complex with a drug protein could have potential biological application as a long-term, sustained protein delivery system. © 2012 Elsevier Ltd.


Tian L.,University of Utah | Kang H.C.,Catholic University of Korea | Bae Y.H.,University of Utah | Bae Y.H.,Advanced Therapeutics Research Center
Biomacromolecules | Year: 2013

Despite the numerous vital functions of proteins in the cytosolic compartment, less attention has been paid to the delivery of protein drugs to the cytosol than to the plasma membrane. To address this issue and effectively deliver charged proteins into the cytoplasm, we used endosomolytic, thiol-triggered degradable polyelectrolytes as carriers. The cationic, reducible polyelectrolyte RPC-bPEI0.8 kDa2 was synthesized by the oxidative polymerization of thiolated branched polyethyleneimine (bPEI). The polymer was converted to the anionic, reducible polyelectrolyte RPA-bPEI0.8 kDa2 by introducing carboxylic acids. The two reducible polyelectrolytes (RPC-bPEI0.8 kDa2 and RPA-bPEI0.8 kDa2) were complexed with counter-charged model proteins (bovine serum albumin (BSA) and lysozyme (LYZ)), forming polyelectrolyte/protein complexes of less than 200 nm in size at weight ratios (WR) of ≥1. The resultant complexes maintained a proton buffering capacity nearly equivalent to that of the polyelectrolytes in the absence of protein complexation and were cytocompatible with MCF7 human breast carcinoma cells. Under cytosol-mimicking thiol-rich conditions, RPC-bPEI 0.8 kDa2/BSA and RPA-bPEI0.8 kDa2/LYZ complexes increased significantly in size and released the loaded protein, unlike the protein complexes with nonreducible polyelectrolytes (bPEI25 kDa and bPEI25 kDaCOOH). The polyelectrolyte/protein complexes showed cellular uptake similar to that of the corresponding proteins alone, but the former allowed more protein to escape into the cytosol from endolysosomes than the latter as a result of the endosomolytic function of the polyelectrolytes. In addition, the proteins in the polyelectrolyte/protein complexes kept their intrinsic secondary structures. In conclusion, the results show the potential of the designed endosomolytic, reducible polyelectrolytes for the delivery of proteins to the cytosol. © 2013 American Chemical Society.


Nadithe V.,University of Utah | Mishra D.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Advanced Therapeutics Research Center
Biotechnology and Bioengineering | Year: 2012

The objective of this study was to investigate the efficiency of multifunctional poly(ethylene glycol)-based hemoglobin conjugates crosslinked with antioxidant enzymes for their ability to protect an oxygen carrier (hemoglobin) and insulin secreting islets from the combination of hypoxic and free radical stress under simulated transplantation conditions. In this study, RINm5F cells and isolated pancreatic islets were challenged with oxidants (H2O2 or xanthine and xanthine oxidase) and incubated with conjugates (hemoglobin-hemoglobin or superoxide dismutase-catalase-hemoglobin) in normoxia (21% oxygen) or hypoxia (6% or 1% oxygen). Hemoglobin protection, intracellular free radical activity and cell viability in RINm5F cells measured by methemoglobin, dichlorofluorescein-diacetate, and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, respectively, showed that cells were better protected by conjugates containing antioxidant enzymes. Insulin secretion from islets and qualitative confocal evaluation of viability showed beta cells were protected by conjugates containing antioxidant enzymes when exposed to induced stress. Our study suggested that antioxidant enzymes play a significant role in hemoglobin protection and thus extended cell protection. © 2012 Wiley Periodicals, Inc..


Hwang H.S.,University of Utah | Kang H.C.,Catholic University of Korea | Bae Y.H.,University of Utah | Bae Y.H.,Advanced Therapeutics Research Center
Biomacromolecules | Year: 2013

Polyplex formation (complexation) and gene release from the polyplexes (decomplexation) are major events in polymeric gene delivery; however, the effect of the decomplexation rate on transfection has been rarely investigated. This study employed mixed polymers of poly(L-lysine) (PLL: MW ∼7.4 kDa) and reducible PLL (RPLL) (MW ∼6.7 kDa) to design decomplexation rate-controllable PLL100-xRPLLx/pDNA complexes (PRLx polyplexes). The transfection efficiency of a model gene (luciferase) in MCF7 and HEK293 cell lines increased with increasing x (RPLL content) in the PRLx polyplexes until peaking at x = 2.5 and 10, respectively, after which point transfection efficiency declined rapidly. In MCF7 cells, PRL2.5 polyplex produced 3 or 223 times higher gene expression than PLL or RPLL polyplexes, respectively. Similarly, the transfection efficiency of PRL10 polyplex-transfected HEK293 cells was 3.8 or 67 times higher than that of PLL or RPLL polyplexes, respectively. The transfection results were not apparently related to the particle size, surface charge, complexation/compactness, cellular uptake, or cytotoxicity of the tested polyplexes. However, the decomplexation rate varied by RPLL content in the polyplexes, which in turn influenced the gene transfection. The nuclear localization of pDNA delivered by PRLx polyplexes showed a similar trend to their transfection efficiencies. This study suggests that an optimum decomplexation rate may result in high nuclear localization of pDNA and transfection. Understanding in decomplexation and intracellular localization of pDNA may help develop more effective polyplexes. © 2012 American Chemical Society.


Chang Kang H.,University of Utah | Bae Y.H.,University of Utah | Bae Y.H.,Advanced Therapeutics Research Center
Biomaterials | Year: 2011

Cationic polymers are potential intracellular carriers for small interfering RNA (siRNA). The short and rigid nature of an siRNA chain often results in larger and more loosely packed particles compared to plasmid DNA (pDNA) after complexing with carrier polycations, and in turn, poor silencing effects are seen against the target mRNAs. A helper polyanion, pDNA, was incorporated along with siRNA to form compact nanosized polyplexes. At C/A (cation/anion) ratios of 2 and 5, poly(l-lysine) (PLL)/siRNA-pGFP and PLL/siRNA-pGFP-OSDZ (oligomeric sulfadiazine (OSDZ) for endosomolysis) complexes produced particles 90-150 nm in size with a 15-45 mV surface charge, while PLL/siRNA complexes yielded particles 1-2 μm in size at the same C/A ratios. The PLL/siRNA-pGFP (C/A 2) complexes showed significantly higher specific gene silencing (50-90% vs. 10-25%) than the complexes formed at C/A 5. PLL/siRNA-pGFP-OSDZ (C/A 2) complexes improved the specific gene silencing (90%) more dramatically than PLL/siRNA-pGFP (C/A 2) complexes (50%), demonstrating a potential role for OSDZ. PLL/siRNA-pGFP-OSDZ (C/A 2) complexes sustained higher specific gene silencing compared with PLL/siRNA-pGFP (C/A 2) complexes. Other oligomeric sulfonamides (OSA) with varying pKa used in PLL/siRNA-pGFP-OSA complexes also caused effective gene silencing. The pGFP in the PLL/siRNA-pGFP complexes successfully expressed GFP protein without interfering with the siRNA. In conclusion, this study demonstrates that long pDNA helps effectively form nanosized siRNA particles and that OSA enhances specific gene silencing. In a single nucleic acid carrier formulation, co-delivery of siRNA and pDNA is feasible to maximize therapeutic effects or to include therapeutic or diagnostic functionalities. © 2011 Elsevier Ltd.

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