Papers by Dongin (Donoven) Kim
The ketone bodies b-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival duri... more The ketone bodies b-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP1. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet2. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown2–6. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the
G protein–coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome–mediated interleukin (IL)-1b and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1
activation and IL-1b secretion in mouse models of NLRP3-mediated diseases such as Muckle–Wells syndrome, familial cold autoinflammatory syndrome and urate crystal–induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome
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Journal of Bioactive and Compatible Polymers
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International journal of pharmaceutics, Jan 24, 2008
A doxorubicin (DOX)-carrier micellar system consisting of poly(histidine)(5K)-b-poly(ethylene gly... more A doxorubicin (DOX)-carrier micellar system consisting of poly(histidine)(5K)-b-poly(ethylene glycol)(2K) and poly(l-lactic acid)(3K)-b-PEG(2K)-folate has been developed targeting the early endosomal pH and it have been convincingly proved that intracellular high dose strategy using such micelles is effective in overcoming multidrug resistance (MDR) of cancer cells. Due to the low DOX concentrations in the micelle solution obtained by dialysis and the lack of long-term stability of the micelles, stable and lyophilized micelle formulations were the subject of investigation reported here by using excipients of sucrose, PEG or Pluronic. The reconstituted micelle solutions were examined by particle size, pH sensitivity, and cytotoxicity for MDR cells and the results were compared with the non-lyophilized micelles. Among tested excipients, Pluronic F127 (33 wt%) added to the polymer/drug solution prior to dialysis resulted in a reconstituted product stable for a week and presented equiva...
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International journal of pharmaceutics, Jan 25, 2014
Multimeric grain-marked micelles consisting of an inner core micelle (for Fe3O4 encapsulation) an... more Multimeric grain-marked micelles consisting of an inner core micelle (for Fe3O4 encapsulation) and outer multi-grain micelles (for chlorin e6 (Ce6, a model drug) encapsulation) were fabricated using a micelle-to-micelle conjugation method. Grain micelles (mono-thiol functionalized micelles) were chemically linked to the surface of the core micelle (multi-maleimide functionalized micelle). These micelles enable discrete compartments for Ce6 and iron oxide (Fe3O4) that enable a significantly increased in vivo photodynamic tumor inhibition while preserving high contrast magnetic resonance (MR) imaging of the tumor in vivo.
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Pharmaceutical Perspectives of Cancer Therapeutics, 2009
ABSTRACT Chemotherapy together with debulking surgery is a major treatment for cancer. There are,... more ABSTRACT Chemotherapy together with debulking surgery is a major treatment for cancer. There are, however, major limitations of conventional cytotoxic drugs that result from their nonspecific toxicity (e.g., the lack of selectivity) in the body and the intrinsic or acquired multidrug resistance (MDR) of cancer cells. To this end, polymeric drug carriers have been developed to address this nonspecificity and MDR [1]. It is believed that these drug carriers alter the biodistribution and increase the bioavailability of incorporated anticancer agents to the target cells [2].
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ABSTRACT Printout. Thesis (M.S.)--University of Florida, 2002. Vita. Includes bibliographical ref... more ABSTRACT Printout. Thesis (M.S.)--University of Florida, 2002. Vita. Includes bibliographical references.
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Nature Nanotechnology, 2014
Clinical translation of cell therapies requires strategies that can manufacture cells efficiently... more Clinical translation of cell therapies requires strategies that can manufacture cells efficiently and economically. One promising way to reproducibly expand T cells for cancer therapy is by attaching the stimuli for T cells onto artificial substrates with high surface area. Here, we show that a carbon nanotube-polymer composite can act as an artificial antigen-presenting cell to efficiently expand the number of T cells isolated from mice. We attach antigens onto bundled carbon nanotubes and combined this complex with polymer nanoparticles containing magnetite and the T-cell growth factor interleukin-2 (IL-2). The number of T cells obtained was comparable to clinical standards using a thousand-fold less soluble IL-2. T cells obtained from this expansion were able to delay tumour growth in a murine model for melanoma. Our results show that this composite is a useful platform for generating large numbers of cytotoxic T cells for cancer immunotherapy.
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Nature Nanotechnology, 2014
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Biomaterials, 2014
Here, we report a self-assembled polymeric micellar immunomodulator (SPI) for enhanced cancer tre... more Here, we report a self-assembled polymeric micellar immunomodulator (SPI) for enhanced cancer treatment based on cationic amphiphilic polymers. To obtain the cationic amphiphilic polymer, the hydrophobic all-trans-retinoic acid (ATRA) was conjugated with a hydrophilic low-molecular-weight PEI (LowPEI, Mn = 1.8 kDa). The ATRA-LowPEI conjugates could self-assemble in aqueous media, forming micelles with a strong positive charge (∼+40 mV) and particle sizes of ~70 nm. Compared to conventional therapeutic agents (e.g., cisplatin), the SPI exhibited enhanced anti-cancer activity regardless of drug resistance. After mechanistic in vitro cell death studies, we revealed that the mechanical disruptive force generated by the cationic charge of SPI primarily induced necrotic cell death. Furthermore, the organelle fragments induced by the necrotic cell death triggered antitumoral immune responses. Therefore, SPI induced synergistic effects of the cationic charge-induced necrosis and antitumoral...
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Journal of Materials Chemistry B, 2014
ABSTRACT We developed novel photosensitizing drug-carrying worm-like micelles using a pH-sensitiv... more ABSTRACT We developed novel photosensitizing drug-carrying worm-like micelles using a pH-sensitive AB2 miktoarm block copolymer consisting of one methoxy-poly(ethylene glycol) (mPEG) block (A) and two 3-diethylaminopropylated poly(L-lysine) [poly(Lys-DEAP)] blocks (B2). In particular, the Y-shaped AB2 miktoarm block copolymer structure mimicking the phospholipid structure enabled the facile prepartion of worm-like micelles. The unique feature of pH-responsive DEAP as a hydrophobic moiety (non-protonated DEAP) at pH 7.4 and a hydrophilic moiety (protonated DEAP) at pH 6.8 modulated acidic pH-activated micellar disintegration. These worm-like micelles serve as a basic transformer whose assembled conformation disintegrates in the acidic milieu (~ pH 6.8) of solid tumors, resulting in improved phototoxicity due to triggered drug release from disintegrated micelles at acidic tumor sites and high-yield generation of cytotoxic singlet oxygen from the photosensitizing drug. As a result, the tumor volume in the nude mice treated with these worm-like micelles was approximately 5.2 times smaller than those treated with free drug. We anticipate that this system will provide great potential for tumor therapy.
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Small, 2008
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Polymers for Advanced Technologies, 2008
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Polymers for Advanced Technologies, 2013
ABSTRACT In this study, a novel drug-carrying micelle composed of methoxy poly(ethylene glycol) (... more ABSTRACT In this study, a novel drug-carrying micelle composed of methoxy poly(ethylene glycol) (mPEG)-b-poly(L-lactic acid) (PLLA) with gas-forming carbonate linkage was fabricated. Here, the gas-forming carbonate linkage was formed by the chemical coupling of the terminal hydroxyl group of the PLLA block and benzyl chloroformate (BC). mPEG-b-PLLA-BC was self-organized in aqueous solution: the PEG block on the hydrophilic outer shell and the PLLA-BC block in the hydrophoboic innor core. The cleavage of carbonate linkage by hydrolysis and formation of carbon dioxide nanobubbles in the micellar core enabled an accelerated release of the encapsulated anticancer drug (doxorubicin: DOX) from the mPEG-b-PLLA-BC micelles. The amount of drug (DOX) released from the mPEG-b-PLLA-BC micelle was higher than that from the conventional mPEG-b-PLLA micelle, which allowed for increased in vitro toxicity against KB tumor cells. Copyright © 2013 John Wiley & Sons, Ltd.
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Pharmaceutical Research, 2008
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Organic Letters, 2010
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Nature Materials, 2011
The diagnosis of bacterial infections remains a major challenge in medicine. Although numerous co... more The diagnosis of bacterial infections remains a major challenge in medicine. Although numerous contrast agents have been developed to image bacteria, their clinical impact has been minimal because they are unable to detect small numbers of bacteria in vivo, and cannot distinguish infections from other pathologies such as cancer and inflammation. Here, we present a family of contrast agents, termed maltodextrin-based imaging probes (MDPs), which can detect bacteria in vivo with a sensitivity two orders of magnitude higher than previously reported, and can detect bacteria using a bacteria-specific mechanism that is independent of host response and secondary pathologies. MDPs are composed of a fluorescent dye conjugated to maltohexaose, and are rapidly internalized through the bacteria-specific maltodextrin transport pathway, endowing the MDPs with a unique combination of high sensitivity and specificity for bacteria. Here, we show that MDPs selectively accumulate within bacteria at millimolar concentrations, and are a thousand-fold more specific for bacteria than mammalian cells. Furthermore, we demonstrate that MDPs can image as few as 10(5) colony-forming units in vivo and can discriminate between active bacteria and inflammation induced by either lipopolysaccharides or metabolically inactive bacteria.
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Molecular Pharmaceutics, 2009
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Magnetic Resonance in Medicine, 2013
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Papers by Dongin (Donoven) Kim
G protein–coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome–mediated interleukin (IL)-1b and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1
activation and IL-1b secretion in mouse models of NLRP3-mediated diseases such as Muckle–Wells syndrome, familial cold autoinflammatory syndrome and urate crystal–induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome
G protein–coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome–mediated interleukin (IL)-1b and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1
activation and IL-1b secretion in mouse models of NLRP3-mediated diseases such as Muckle–Wells syndrome, familial cold autoinflammatory syndrome and urate crystal–induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome