You Han Bae

University of Utah, Salt Lake City, Utah, United States

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Publications (219)1044.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study, a series of amphiphilic AB2-type 3-miktoarm copolymers consisting of hydrophilic poly(ethylene glycol) (PEG) as the A arm and hydrophobic poly(ε-caprolactone) (PCL) as the two B arms were synthesized through the ring-opening polymerization of ε-caprolactone (CL) using a PEG macroinitiator with a bi-arm structure. The self-assembly behaviors, drug-loading capacities, and controlled drug release features of the PEG-PCL2 miktoarm copolymers were compared with those of their linear diblock counterparts (PEG-PCL). The PEG-PCL2 miktoarm copolymer with a relatively short PCL arm length (PEG volume fraction, fPEG = 0.55) self-assembled in aqueous solution to form a spherical micelle structure. However, cylindrical micelles were observed for the miktoarm copolymers with long PCL arms (fPEG = 0.15–0.32), whereas the corresponding linear counterparts consistently formed spherical micelle structures regardless of the PCL arm lengths. Drug-loading using doxorubicin (DOX) as the model drug indicated that the PEG-PCL2 cylindrical micelles possessed superior drug-loading capacities compared with the spherical micelles of the corresponding diblock copolymers. Furthermore, although the DOX-loaded cylindrical micelles exhibited a slower release rate than the DOX-loaded spherical micelles, the former exhibited higher cellular uptake and improved cytotoxic effects than the latter. These findings demonstrate the useful morphological versatility of miktoarm-structured PEG-PCL block copolymers in comparison to the conventionally used linear diblock copolymers in the design of self-assembled nanocarriers for efficient drug delivery.
    Polym. Chem. 12/2014;
  • Macromolecular Chemistry and Physics 11/2014; · 2.39 Impact Factor
  • Eun Seong Lee, Kun Na, You Han Bae
    Journal of controlled release : official journal of the Controlled Release Society. 09/2014; 190:61-3.
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    ABSTRACT: To celebrate the success of the Journal of Controlled Release and the research covered in the journal, here we highlight some of the most cited research articles in the history of the journal. Based on the literature search in Google Scholar in July 2013, we identified ~30 research articles that have received most number of citations. Authors of these articles were invited to provide a commentary on these articles. This compilation of commentaries gives a historical perspective and current status of research covered in these articles.
    Journal of Controlled Release 09/2014; 190:29-74. · 7.63 Impact Factor
  • Hee Sook Hwang, Jun Hu, Kun Na, You Han Bae
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    ABSTRACT: Endosomal entrapment is one of the main barriers that must be overcome for efficient gene expression along with cell internalization, DNA release and nuclear import. Introducing pH-sensitive ionizable groups into the polycationic polymers to increase gene transfer efficiency has proven to be a useful method; however, effective methods of introducing equal numbers of ionizable groups in both polymer and monomer forms, has not been reported. In this paper, we prepared two types of histidine grafted Poly(L-lysine) (PLL), a stacking form of Poly(L-histidine) (PLL-g-PHis) and a mono- L-histidine (PLL-g-mHis) with same number of imidazole groups. These two types showed profound differences in hemolytic activity, cellular uptake, internalization and transfection efficiency. Cy3-labeled PLL-g-PHis showed strong fluorescence in the nucleus after internalization, and high hemolytic activity upon pH changes was also observed from PLL-g-PHis. The arrangement of imidazole groups from PHis also provided higher gene expression than mHis due to its ability to escape the endosome. mHis or PHis grafting reduced the cytotoxicity of PLL and changed the cellular uptake by changing the quantity of free ɛ-amines available for gene condensation. The sub-cellular localization of PLL-g-PHis/pDNA measured by YOYO1-pDNA intensity was highest inside the nucleus, and the lysotracker which stains the acidic compartments was lowest among polymers. Thus, the polymeric histidine arrangement demonstrate the ability to escape the endosome and trigger rapid release of polyplexes into the cytosol resulting in a greater amount of genes available for translocation to the nucleus and enhanced gene expression.
    Biomacromolecules 08/2014; · 5.37 Impact Factor
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    ABSTRACT: Branched-type hydrophilic polyethyleneimine derivatives (i.e., bPEI derivatives) are developed polymeric carriers for photodynamic therapy. Their chemical structures which contain pH-tunable hydrophobic/hydrophilic cavities enable efficient loading of hydrophobic drugs in basic pH environments. Intracellular stimuli trigger the release of the loaded drugs in bPEI derivatives. As expected, the hydrophobic photosensitizer known as pheophorbide A (PheoA) is solubilized by physical loading in the inner hydrophobic spaces of bPEI derivatives in environments with basic pH values. Interestingly, acidic pH environments induce aggregation, resulting in poor release of the loaded PheoA as well as in quenched photo-activity of the PheoA-loaded polymers. However, when reducible polycation derivatives of bPEI are used (i.e., RPC-bPEI), intracellular thiols degrade the disulfide linkages in the polymers, resulting in rapid PheoA release. Particularly, a RPC-bPEI containing 6 wt% PheoA (i.e., RPC-bPEI0.8kDa-PheoA6%) respond remarkably well to light exposure and display large differences between dark toxicity and light-induced toxicity. Cellular uptake of RPC-bPEI0.8kDa-PheoA6% is approximately sevenfold to ninefold lower than that of free PheoA. Nevertheless, the photo-toxicity of RPC-bPEI0.8kDa-PheoA6% was only two- to sixfold less potent than that of free PheoA. These results suggest that reducible bPEI materials may act as potential solubilizers and carriers for low-molecular-weight hydrophobic anti-cancer drugs.
    Macromolecular Bioscience 07/2014; · 3.74 Impact Factor
  • Joseph W Nichols, You Han Bae
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    ABSTRACT: The enhanced permeability and retention (EPR) of nanoparticles in tumors has long stood as one of the fundamental principles of cancer drug delivery, holding the promise of safe, simple and effective therapy. By allowing particles preferential access to tumors by virtue of size and longevity in circulation, EPR provided a neat rationale for the trend toward nano-sized drug carriers. Following the discovery of the phenomenon by Maeda in the mid-1980s, this rationale appeared to be well justified by the flood of evidence from preclinical studies and by the clinical success of Doxil®. Clinical outcomes from nano-sized drug delivery systems, however, have indicated that EPR is not as reliable as previously thought. Drug carriers generally fail to provide superior efficacy to free drug systems when tested in clinical trials. A closer look reveals that EPR-dependent drug delivery is complicated by high tumor interstitial fluid pressure (IFP), irregular vascular distribution, and poor blood flow inside tumors. Furthermore, the animal tumor models used to study EPR differ from clinical tumors in several key aspects that seem to make EPR more pronounced than in human patients. On the basis of this evidence, we believe that EPR should only be invoked on a case-by-case basis, when clinical evidence suggests the tumor type is susceptible.
    Journal of Controlled Release 04/2014; · 7.63 Impact Factor
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    ABSTRACT: Despite the development of a myriad of anticancer drugs that appeared promising in preclinical ovarian cancer animal models, they failed to predict efficacy in clinical testing. To improve the accuracy of preclinical testing of efficacy and toxicity including pharmacokinetic and pharmacodynamic evaluations a novel animal model was developed and characterized. In this study, murine ID8 (epithelial ovarian cancer; EOC) cells as injected cell suspensions (ICS) and as intact cultured monolayer cell sheets (CS) were injected or surgically grafted, respectively, into the left ovarian bursa of 6-8 week old, female C57BL/6 black mice and evaluated at 8 and 12 weeks after engraftment. Tumor volumes at 8 weeks were: 30.712±18.800 mm3 vs. 55.837±10.711 mm3 for ICS and CS, respectively, p=0.0990 (n=5). At 12 weeks tumor volumes were: 128.129±44.018 mm3 vs. 283.953±71.676 mm3 for ICS and CS, respectively, p=0.0112 (n=5). The ovarian weights at 8 weeks and 12 weeks were: 0.02138±0.01038 gm vs. 0.04954±0.00667 gm for ICS and CS, respectively (8 weeks), p=0.00602 (n=5); and 0.10594±0.03043 gm vs. 0.39264±0.09271 gm for ICS and CS respectively (12 weeks), p=0.0008 (n=5). These results confirm a significant accelerated tumorigenesis in CS-derived tumors compared to ICS-derived tumors when measured by tumor volume/time and ovarian weight/time. Furthermore, the CS-derived tumors closely replicated the metastatic spread found in human EOC and histopathologic identity with the primary tumor of origin.
    Tissue Engineering Part C Methods 04/2014; · 4.64 Impact Factor
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    ABSTRACT: This study investigates the potential of dexamethasone (Dex) to enhance the nuclear accumulation and subsequent gene expression of plasmid DNA (pDNA) delivered using a charged polymeric micelle-based gene delivery system. (PLGA)n -b-bPEI25kDa block copolymers are synthesized and used to prepare Dex-loaded cationic micelles (DexCM). After preparing DexCM/pDNA complexes, bPEI1.8kDa is coated on the complexes using a Layer-by-Layer (LbL) technique to construct DexCM/pDNA/bPEI1.8kDa complexes (i.e., LbL-DexCM polyplexes) that are 100-180 nm in diameter and have a zeta potential of 30-40 mV. In MCF7 cells, LbL-DexCM polyplexes cause 3-13-fold higher transfection efficiencies compared to LbL-CM polyplexes and show negligible cytotoxicity. LbL-DexCM3 polyplexes induce much higher nuclear delivery of pDNA compared to LbL-CM3 polyplexes. These results suggest that Dex-loaded polyplexes could be used in gene and drug delivery applications to increase nuclear accumulation of therapeutic payloads, further leading to a decrease in the dose of the drug and gene necessary to achieve equivalent therapeutic effects.
    Macromolecular Bioscience 02/2014; · 3.74 Impact Factor
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    ABSTRACT: Nontoxic endogenous nucleotides such as adenosine triphosphate and guanosine triphosphate have secondary phosphate groups, causing proton-buffering capacity and/or hemolytic activity in endolysosomal pH ranges. Nucleotides co-delivered in single polymeric pDNA nanocarrier induce highly enhanced transfection efficiency with negligible cytotoxicity due to their endosomolytic functions.
    Advanced Healthcare Materials 02/2014;
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    ABSTRACT: Bioreducible polymers have attracted intense attention as a gene carrier due to their low cell toxicity compared to other polymer-based gene delivery counterparts. We have synthesized low-molecular-weight spermine-originated bioreducible polyspermines (BPSs) to serve as a plasmid DNA (pDNA) carrier complex with low cytotoxicity and high transfection efficiency. Spermine is biogenic and ubiquitous and is of benefit to nucleic acid delivery in many respects. We found that the BPSs formed nano-sized, positively charged complexes with pDNA. In addition, they showed a high buffering capacity from the polyamine-based proton sponge effect which facilitates endosomal escape. With degradable characteristics in thiol-rich (intracellular) environments, BPSs exhibited significantly improved cell viability and suitable transfection efficiency across several cell lines in comparison to linear and branched polyethylenimine, the current gold standards of non-viral gene carriers. BPSs appear to be promising polymers for use as effective pDNA carriers. Copyright © 2014 John Wiley & Sons, Ltd.
    Polymers for Advanced Technologies 02/2014; · 1.64 Impact Factor
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    ABSTRACT: Oral delivery is the preferred route to deliver therapeutics via nanoparticles due to ease of administration and patient acceptance. Here, we report on the findings of the absorption pathway of taurocholic acid (TCA)-linked heparin and docetaxel (DTX) conjugate, which we refer to as HDTA. We studied the oral absorption of HDTA using a Caco-2 cell transport system and an animal model. We have also used other absorption enhancers, such as ethylene glycol tetraacetic acid (EGTA), or inhibitors, such as sodium azide, to compare the relative permeability of HDTA conjugates. In vivo comparative studies were conducted using free TCA as a pre-administration and exhibited the maximum absorption site of the organ after oral administration of HDTA conjugates. HDTA was found to be absorbed mainly in the ileum and Caco-2 cell monolayer through passive diffusion and bile acid transporters. High fluorescence intensity of HDTA in mice came from the ileum, and it was eliminated from the body through colon. This novel formulation could be further investigated by clinical trials to find the prospect of oral anti-cancer drug delivery through anti-angiogenic treatment strategies.
    Journal of Controlled Release 01/2014; · 7.63 Impact Factor
  • Joseph W. Nichols, You Han Bae
    Journal of Controlled Release 01/2014; · 7.63 Impact Factor
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    ABSTRACT: 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.
    Colloids and surfaces B: Biointerfaces 12/2013; 116C:128-137. · 4.28 Impact Factor
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    ABSTRACT: A cancer-recognizable MRI contrast agents (CR-CAs) has been developed using pH-responsive polymeric micelles. The CR-CAs with pH sensitivity were self-assembled based on well-defined amphiphilic block copolymers, consisting of methoxy poly(ethylene glycol)-b-poly(l-histidine) (PEG-p(l-His)) and methoxy poly(ethylene glycol)-b-poly(l-lactic acid)-diethylenetriaminopentaacetic acid dianhydride-gadolinium chelate (PEG-p(l-LA)-DTPA-Gd). The CR-CAs have a spherical shape with a uniform size of ∼40 nm at physiological pH (pH 7.4). However, in acidic tumoral environment (pH 6.5), the CR-CAs were destabilized due to the protonation of the imidazole groups of p(l-His) blocks, causing them to break apart into positively charged water-soluble polymers. As a result, the CR-CAs exhibit highly effective T1 MR contrast enhancement in the tumor region, which enabled the detection of small tumors of ∼3 mm(3)in vivo at 1.5 T within a few minutes.
    Biomaterials 10/2013; · 8.31 Impact Factor
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    ABSTRACT: With countless research papers using preclinical models and showing the superiority of nanoparticle design over current drug therapies used to treat cancers, it is surprising how deficient the translation of these nano-sized drug carriers into the clinical setting is. This review article seeks to compare the preclinical and clinical results for Doxil®, PK1, Abraxane®, Genexol-PM®, Xyotax™, NC-6004, Mylotarg®, PK2, and CALAA-01. While not comprehensive, it covers nano-sized drug carriers designed to improve the efficacy of common drugs used in chemotherapy. While not always available or comparable, effort was made to compare the pharmacokinetics, toxicity, and efficacy between the animal and human studies. Discussion is provided to suggest what might be causing the gap. Finally, suggestions and encouragement are dispensed for the potential that nano-sized drug carriers hold.
    Journal of Controlled Release 10/2013; · 7.63 Impact Factor
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    Jun Hu, Seiji Miura, Kun Na, You Han Bae
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    ABSTRACT: To address cancer cell heterogeneity while endowing tumor specificity, the approach of charge shielding/deshielding was tested in vitro and in vivo with a paclitaxel loaded cationic micelle from a block copolymer of poly(L-histidine) (3.7kDa) and short branched polyethyleneimine (1.8kDa). The cationic micelle surface was shielded by electrostatically complexing with a negatively charged mPEG (2kDa)-block-polysulfadimethoxine (4kDa) (mPEG-b-PSDM) at pH7.4. Unshielded micelle at pH7.4 and deshielded micelle at tumor extracellular pH were readily taken up by two wild types of human cancer cell lines, MCF-7 breast adenocarcinoma and SKOV-3 ovarian carcinoma, while the uptake of the shielded micelle at pH7.4 was minimal. The preliminary in vivo results from a mouse model xenografted with MCF-7 showed significant anticancer therapeutic efficacy and deep penetration of the micelle into tumor tissues after deshielding, supporting the unique pH-responsive mechanism to treat acidic cancer.
    Journal of Controlled Release 08/2013; · 7.63 Impact Factor
  • You Han Bae, David W Grainger
    Journal of Controlled Release 08/2013; · 7.63 Impact Factor
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    ABSTRACT: To enhance limited drug penetration that mediated drug resistance and heterogeneity within the tumour microenvironment, we designed a paclitaxel (PTX) loaded degradable cationic nanogel (DpNG) consisted with acetylated pullulan and low molecular weight polyethyleneimine (LowbPEI, 1.8 kDa). The restoration of cationic charge on the DpNG was achieved via HA degradation by hyaluronidase which is secreted in tumour. The size and surface charge of HA-coated DpNG loaded with PTX (HA/DpNG-PTX) was 200-250 nm and 0 mV, respectively. The DpNG-PTX was showed significant cytotoxicity in heterogeneous cancer cells. The IC50 value of DpNG-PTX was 100 times less than that of free PTX. The growth of heterogeneous tumour in Balb/c mice was inhibited via intravenous injection of HA/DpNG-PTX. Furthermore, the invasive distance and amount of HA/DpNG-PTX localised within the deep tissue regions were increased two times than that of PA-PTX. Therefore, the DpNG based drug delivery system could be useful for treatment of heterogeneous tumour.
    Biomaterials 07/2013; · 8.31 Impact Factor
  • Li Tian, Han Chang Kang, You Han Bae
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    ABSTRACT: 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-bPEI0.8 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.
    Biomacromolecules 07/2013; · 5.37 Impact Factor

Publication Stats

7k Citations
1,044.11 Total Impact Points

Institutions

  • 1989–2014
    • University of Utah
      • • Department of Pharmaceutics and Pharmaceutical Chemistry
      • • Department of BioEngineering
      • • Center for Controlled Chemical Delivery (CCCD)
      Salt Lake City, Utah, United States
  • 2010–2013
    • Utah Inha Drug Delivery Systems and Advanced Therapeutics Research Center
      Bucheon, Gyeonggi Province, South Korea
    • Massachusetts College of Pharmacy and Health Sciences
      Boston, Massachusetts, United States
  • 2006–2013
    • Catholic University of Korea
      • Department of Biotechnology
      Sŏul, Seoul, South Korea
  • 2005–2006
    • Ewha Womans University
      • Department of Chemistry Nano Science
      Sŏul, Seoul, South Korea
  • 2003–2005
    • Gwangju Institute of Science and Technology
      • School of Materials Science and Engineering
      Kwangju, Gwangju, South Korea
  • 1999–2004
    • Seoul National University
      • • Department of Materials Science and Engineering
      • • College of Dentistry
      • • Department of Biomedical Engineering
      Seoul, Seoul, South Korea
  • 2000
    • Chonnam National University
      Gwangju, Gwangju, South Korea
    • Sungkyunkwan University
      • School of Medicine
      Seoul, Seoul, South Korea
  • 1996–1999
    • Chonnam National University Hospital
      Sŏul, Seoul, South Korea
  • 1992–1994
    • Universiteit Twente
      • Group of Polymer Chemistry and Biomaterials (PBM)
      Enschede, Overijssel, Netherlands
  • 1991
    • Waseda University
      • Department of Applied Chemistry
      Edo, Tōkyō, Japan