You Han Bae

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

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Publications (223)1215.88 Total impact

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    ABSTRACT: In recent years, advances in biotechnology and protein engineering have enabled the production of large quantities of proteins and peptides as important therapeutic agents. Various researchers have used biocompatible functional polymers to prepare oral dosage forms of proteins and peptides for chronic use and for easier administration to enhance patient compliance. However, there is a need to enhance their safety and effectiveness further. Most macromolecules undergo severe denaturation at low pH and enzymatic degradation in the gastrointestinal tract. The macromolecules' large molecular size and low lipophilicity cause low permeation through the intestinal membrane. The major strategies that have been used to overcome these challenges (in oral drug carrier systems) can be classified as follows: enteric coating or encapsulation with pH-sensitive polymers or mucoadhesive polymers, co-administration of protease inhibitors, incorporation of absorption enhancers, modification of the physicochemical properties of the macromolecules, and site-specific delivery to the colon. This review attempts to summarize the various advanced oral delivery carriers, including nanoparticles, lipid carriers, such as liposomes, nano-aggregates using amphiphilic polymers, complex coacervation of oppositely charged polyelectrolytes, and inorganic porous particles. The particles were formulated and/or surface modified with functional polysaccharides or synthetic polymers to improve oral bioavailability of proteins and peptides. We also discuss formulation strategies to overcome barriers, therapeutic efficacies in vivo, and potential benefits and issues for successful oral dosage forms of the proteins and peptides.
    Current pharmaceutical design 05/2015; · 3.29 Impact Factor
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    ABSTRACT: 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. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Controlled Release 03/2015; 207. DOI:10.1016/j.jconrel.2015.03.016 · 7.26 Impact Factor
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    ABSTRACT: 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 pH6.4, 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 pH6.4, 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 pH7.4, 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. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 01/2015; 205. DOI:10.1016/j.jconrel.2015.01.005 · 7.26 Impact Factor
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    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.
    12/2014; 6(4). DOI:10.1039/C4PY01380H
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    ABSTRACT: Limited drug distribution is partially responsible for the efficacy gap between preclinical and clinical studies of nano-sized drug carriers for cancer therapy. In this study, we examined the transport behavior of cationic micelles formed from a triblock copolymer of poly(D,L-lactide-co-glycolide)-block-branched polyethyleneimine-block-poly(D,L-lactide-co-glycolide) using a unique in vitro tumor model composed of a multilayered cell culture (MCC) and an Ussing chamber system. The Cy3-labeled cationic micelles showed remarkable Cy3 distribution in the MCC whereas charge-shielded micelles with a poly(ethylene glycol) surface accumulated on the surface of the MCC. Penetration occurred against convectional flow caused by a hydraulic pressure gradient. The study using fluorescence resonance energy transfer (FRET) showed that the cationic micelles dissociate at the interface between the culture media and the MCC or possibly inside of the first-layer cells and penetrates into the MCC as unimers. The penetration and distribution were energy-dependent and suppressed by various endocytic inhibitors. These suggest that cationic unimers mainly utilized clathrin-mediated endocytosis and macropinocytosis for cellular entry and a significant fraction were exocytosed by an unknown mechanism.
    Nano Today 12/2014; 9(6):695-704. DOI:10.1016/j.nantod.2014.10.003 · 18.43 Impact Factor
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    ABSTRACT: A potent synthetic methodology is introduced to generate a useful intermediate for the preparation of ‘smart’ polymeric pro-drugs. Herein, living anionic block polymerization of ethylene oxide (EO) and N-phenylmaleimide (N-PMI), as well as the Gabriel process, are introduced. Hydrazinolysis of the resulting poly(ethylene oxide)-block-poly(N-PMI) (PEO-b-PN-PMI) using hydrazine under acidic conditions leads to the production of PEO-based frameworks with hydrazide (HZ) groups. The HZ groups are found to effect the formation of an acid-sensitive bond in reactions with medicines or drugs under neutral conditions (pH 7.2). The PEO-HZ intermediate, which shows a strong triplet splitting patterned chemical shift in the range δ = 6.5–8.5 ppm, represents the most powerful material employed for mass production of smart polymeric pro-drugs while controlling the drug-loading yield. Water-soluble “smart” polymeric pro-drugs, such as poly(ethylene oxide)-doxorubicin (PEO-HZ-Dox), poly(ethylene oxide)-methotrexate (PEO-HZ-MTX), and poly(ethylene oxide)-folate (PEO-HZ-FA) conjugates, show excellent acid-sensitive release profiles in water or alcohol at pH 4.5.
    Macromolecular Chemistry and Physics 11/2014; 216(3). DOI:10.1002/macp.201400457 · 2.45 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 10/2014; 14(10). DOI:10.1002/mabi.201400145 · 3.65 Impact Factor
  • Eun Seong Lee, Kun Na, You Han Bae
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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. DOI:10.1016/j.jconrel.2014.07.012 · 7.26 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; 15(10). DOI:10.1021/bm500843r · 5.79 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 07/2014; 3(7). DOI:10.1002/adhm.201400008 · 4.88 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 06/2014; 14(6). DOI:10.1002/mabi.201300432 · 3.65 Impact Factor
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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 05/2014; 25(5). DOI:10.1002/pat.3269 · 1.96 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; 190. DOI:10.1016/j.jconrel.2014.03.057 · 7.26 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; 21(1). DOI:10.1089/ten.TEC.2014.0040 · 4.64 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; DOI:10.1016/j.jconrel.2013.12.034 · 7.26 Impact Factor
  • Joseph W. Nichols, You Han Bae
    Journal of Controlled Release 01/2014; · 7.26 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. DOI:10.1016/j.colsurfb.2013.12.041 · 4.29 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; 35(1). DOI:10.1016/j.biomaterials.2013.10.004 · 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; 172(3). DOI:10.1016/j.jconrel.2013.09.026 · 7.26 Impact Factor

Publication Stats

13k Citations
1,215.88 Total Impact Points

Institutions

  • 1990–2015
    • 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
      • Department of Pharmaceutical Sciences
      Boston, Massachusetts, United States
  • 2006
    • Catholic University of Korea
      • Department of Biotechnology
      Sŏul, Seoul, South Korea
  • 2003–2004
    • 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
      • • Department of Biomedical Engineering
      Seoul, Seoul, South Korea
  • 1994
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 1992–1993
    • Universiteit Twente
      • Group of Polymer Chemistry and Biomaterials (PBM)
      Enschede, Overijssel, Netherlands