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Nano-Micro Letters 2021年第2期13卷 180-206页

作者： Dongyoon Kim Yina Wu Qiaoyun Li yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul 08826Republic of Korea

We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic *** was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F/ANs),and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment,yielding aCD3/F/*** in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/***3/F/AN-treated T cells exhibited clear mitochondrial cristae,a higher membrane potential,and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle *** proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T *** of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor ***-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma *** vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor *** treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor *** findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.

关键词： Metabolic reprogramming T cells Fatty acid metabolism Immunometabolic therapy Mitochondrial function

Chemokine-mimetic plerixafor derivative for tumorspecific delivery of nanomaterials

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Nano Research 2018年第4期11卷 2159-2172页

作者： Seungbeom Ko Gayong Shim Jinyoung Kim yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University 1 Kwanak-ro Kwanak-gu Seoul 08826 Republic of Korea

Here, we report that chemokine-mimetic plerixafor derivatives could govern tumor-specific delivery and functional effects of nanomaterials. Reduced graphene oxide （rGO） nanosheets were used as a model functional nanomaterial, and plerixafor-conjugated lipid （PL/rGO） or a benzylcyclam derivative of plerixafor- conjugated lipid （BPL/rGO） was physically adsorbed onto the surface of rGO. The cellular uptake of surface-modified rGO was dependent on overexpression of the CXCR4 chemokine receptor on cancer cells. In KB cells, the binding affinity of BPL/rGO for CXCR4 was 6.8-fold greater than that of PL/rGO. Notably, cellular uptake patterns correlated with in vitro photothermal anticancer efficacy. The tumor distribution of BPL/rGO was higher than that of PL/rGO and plain rGO in mice bearing CXCR4-overexpressing tumors, whereas the distribution of the various rGO forms was similar in mice harboring CXCR4-negative tumors. Moreover, complete photothermal tumor ablation was observed in BPL/rGO- treated mice bearing CXCR4-positive KB cell tumors, but not in CXCR4-negative MCF-7 cell tumors. These results provide evidence that BPL can be used to enhance the delivery of nanomaterials to CXCR4-overexpressing tumors. Chemokine-mimetic BPL can be further applied for nanomaterial-based delivery of photosensitizers, anticancer drugs, or diagnostic tumor imaging agents in CXCR4-overexpressing cancer patients.

关键词： chemokine-mimetic plerixafor derivatives chemokine receptor nanomaterial photothermal therapy

Lipid nanoparticle-mediated CRISPR/Cas9 gene editing and metabolic engineering for anticancer immunotherapy

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Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 641-652页

作者： Hyemin Ju Dongyoon Kim yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul 08826Republic of Korea

Metabolic engineering of the tumor microenvironment has emerged as a new *** dehydrogenase A(LDHA)is a prominent target for metabolic ***,we designed a cationic lipid nanoparticle formulation for LDHA gene *** plasmid DNA delivery efficiency of our lipid nanoparticle formulations was screened by testing the fluorescence of lipid nanoparticles complexed to plasmid DNA encoding green fluorescence protein(GFP).The delivery efficiency was affected by the ratios of three components:a cationic lipid,cholesterol or its derivative,and a fusogenic *** lipid nanoparticle designated formulation F3 was complexed to plasmid DNA co-encoding CRISPR-associated protein 9 and LDHA-specific sgRNA,yielding the lipoplex,pCas9-sgLDHA/*** lipoplex including GFP-encoding plasmid DNA provided gene editing in HeLa-GFP *** of B16F10 tumor cells with pCas9-sgLDHA/F3 yielded editing of the LDHA gene and increased the pH of the culture ***9-sgLDHA/F3 treatment activated the interferon-gamma and granzyme production of T cells in *** vivo,combining pCas9-sgLDHA/F3 with immune checkpoint-inhibiting anti-PD-L1 antibody provided a synergistic antitumor effect and prolonged the survival of tumor model *** study suggests that combining metabolic engineering of the tumor microenvironment with immune checkpoint inhibition could be a valuable antitumor strategy.

关键词： Gene editing Lipid nanoparticle Metabolic engineering Lactate dehydrogenase A Tumor microenvironment

Safety and photochemotherapeutic application of poly(γ-glutamic acid)-based biopolymeric nanoparticle

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Acta Pharmaceutica Sinica B 2019年第3期9卷 565-574页

作者： Dongyoon Kim Quoc-Viet Le Young Bong Kim yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul08826Republic of Korea Department of Biomedical Engineering Konkuk UniversitySeoul05029Republic of Korea

The safety of nanomaterials, a crucial consideration for clinical translation, is enhanced by using building blocks that are biologically nontoxic. Here, we used poly(γ-glutamic acid)(γ-PGA) and dopamine as building blocks of polymeric nanomaterials for carrying hydrophobic anticancer drugs. The introduction of phenylalanine onto γ-PGA enabled the resulting amphiphilic derivative of γ-PGA acid to self-assemble in the presence of the anticancer drug paclitaxel(PTX) to form PTX-encapsulated *** surfaces of PTX-loaded micelles were then coated with polymerized dopamine(PDA). The PDAcoated, amphiphilic γ-PGA-based micelles(AM) carrying PTX(PDA/AM/P) exerted near-infraredresponsive photothermal effects. Near-infrared irradiation of cancer cells treated with PDA/AM/P nanoparticles produced a greater anticancer effect than that observed in other treatment groups, indicating a synergistic effect. Intravenous administration of PDA/AM/P completely ablated tumors and prevented their recurrence. Notably, the in vivo safety profile of PDA/AM/P nanoparticles allowed PTX to be delivered at a 3.6-fold higher dose than was possible with PTX solubilized in surfactant, and circumvented the side effects of the surfactant. These results support the multifunctional potential of PDA/AM for the delivery of various hydrophobic drugs and imaging dyes for safe translation of nanomaterials into the clinic.

关键词： Safety Photochemotherapy Biopolymeric nanoparticle Poly(γ-glutamic acid) Polymerized dopamine Paclitaxel

Cell membrane-derived vesicles for delivery of therapeutic agents

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Acta Pharmaceutica Sinica B 2021年第8期11卷 2096-2113页

作者： Quoc-Viet Le Jaiwoo Lee Hobin Lee Gayong Shim yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul 08826Republic of Korea School of Systems Biomedical Science Soongsil UniversitySeoul 06978Republic of Korea

Cell membranes have recently emerged as a new source of materials for molecular delivery *** membranes have been extruded or sonicated to make nanoscale *** synthetic lipid or polymeric nanoparticles,cell membrane-derived vesicles have a unique multicomponent feature,comprising lipids,proteins,and *** cell membrane-derived vesicles contain the intrinsic functionalities and signaling networks of their parent cells,they can overcome various obstacles encountered in ***,the different natural combinations of membranes from various cell sources expand the range of cell membrane-derived vesicles,creating an entirely new category of drug-delivery *** membrane-derived vesicles can carry therapeutic agents within their interior or can coat the surfaces of drug-loaded core *** membranes typically come from single cell sources,including red blood cells,platelets,immune cells,stem cells,and cancer ***,recent studies have reported hybrid sources from two different types of *** review will summarize approaches for manufacturing cell membrane-derived vesicles and treatment applications of various types of cell membrane-derived drug-delivery systems,and discuss challenges and future directions.

关键词： Cell membrane-derived vesicles Membrane engineering Drug-delivery systems Blood cells Immune cells Stem cells Cancer cells Manufacturing

Surface-modified liposomes for syndecan 2-targeted delivery of edelfosine

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Asian Journal of Pharmaceutical Sciences 2016年第5期11卷 596-602页

作者： Gayong Shim Yong Hee yu Soondong Lee Jinyoung Kim yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University

Here, we report that the modification of liposome surfaces with AG73 peptides enhances delivery of the lipophilic anticancer drug, edelfosine, to tumor cells overexpressing the cellsurface receptor, syndecan 2. To test the effect of liposomal surface density of AG73 peptides on cellular uptake, we synthesized AG73 peptide-conjugated polyethylene glycol(MW 2000)lipid and incorporated it into fluorescence dye-labeled anionic liposomes with different ligand densities(1, 2, or 5 mol% of total lipids). Cellular uptake of AG73-peptide–modified liposomes gradually increased in proportion to the surface ligand density. The percentages of cells positive for AG73-modified, fluorescent-dye–labeled liposomes were 19.8 ± 2.0%, 23.1 ± 5.0%,and 99.2 ± 1.0%, for ligand mole percentages of 1, 2, and 5, respectively. The cell-targeting ability of AG73-modified liposomes was not significantly altered by the serum content of culture media. In keeping with the observed enhanced cellular uptake, AG73-peptide–modified liposomes entrapping edelfosine exhibited greater cancer cell-killing effects compared with unmodified liposomes. Following intravenous administration into tumor-bearing mice,AG73-peptide–modified liposomes showed 2.1-fold greater accumulation in tumors than unmodified liposomes. These results support the feasibility of using syndecan 2–directed liposomes for delivery of edelfosine.

关键词： Ligand density AG73 peptide Syndecan 2 Liposome Anticancer drug Edelfosine

Molecular engineering of antibodies for site-specific conjugation to lipid polydopamine hybrid nanoparticles

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Acta Pharmaceutica Sinica B 2020年第11期10卷 2212-2226页

作者： Hobin Yang Quoc-Viet Le Gayong Shim yu-kyoung oh Young Kee Shin Laboratory of Molecular Pathology and Cancer Genomics College of Pharmacy and Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoul 08826Republic of Korea College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul 08826Republic of Korea Bio-MAX Seoul National UniversitySeoul 08826Republic of Korea

Conjugation of antibodies to nanoparticles allows specific cancer targeting,but conventional conjugation methods generate heterogeneous conjugations that cannot guarantee the optimal orientation and functionality of the conjugated ***,a molecular engineering technique was used for sitespecific conjugation of antibodies to *** designed an anti-claudin 3(CLDN3)antibody containing a single cysteine residue,h4 G3 cys,then linked it to the maleimide group of lipid polydopamine hybrid nanoparticles(LPNs).Because of their negatively charged lipid coating,LPNs showed high colloidal stability and provided a functional surface for site-specific conjugation of h4 G3 *** activity of h4 G3 cys was tested by measuring the binding of h4 G3 cys-conjugated LPNs(C-LPNs)to CLDN3-positive tumor cells and assessing its subsequent photothermal effects.C-LPNsspecifically recognized CLDN3-overexpressing T47 D breast cancer cells but not CLDN3-negative Hs578 T breast cancer *** binding of C-LPNs to CLDN3-overexpressing T47 D cells resulted in significantly higher temperature generation upon NIR irradiation and potent anticancer photothermal *** with this,intravenous injection of C-LPNsin a T47 D xenograft mouse model followed by NIR irradiation caused remarkable tumor ablation compared with other treatments through high temperature *** results establish an accurate antibody-linking method and demonstrate the possibility of developing therapeutics using antibody-guided nanoparticles.

关键词： Molecular engineering Site-specific conjugation Lipid polydopamine hybrid nanoparticles Claudin 3 Photothermal therapy

DNA-based artificial dendritic cells for in situ cytotoxic T cell stimulation and immunotherapy

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Bioactive Materials 2022年第9期7卷 160-172页

作者： Quoc-Viet Le Jaiwoo Lee Junho Byun Gayong Shim yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University1 Gwanak-roGwanak-guSeoul08826Republic of Korea School of Systems Biomedical Science Soongsil UniversitySeoul06978Republic of Korea

In immunotherapy,ex vivo stimulation of T cells requires significant resources and ***,we report artificial dendritic cell-mimicking DNA microflowers(DM)for programming T cell stimulation in *** mimic dendritic cells,DNA-based artificial dendritic microflowers were constructed,surface-coated with polydopamine,and further modified with anti-CD3 and anti-CD28 antibodies to yield antibody-modified DM(DM-A).The porous structure of DM-A allowed entrapment of the T cell-stimulating cytokine,ineterleukin-2,yielding interleukin-2-loaded DM-A(DM-AI).For comparison,polystyrene microparticles coated with polydopamine and modified with anti-CD3 and anti-CD28 antibodies(PS-A)were *** to PS-A,DM-AI showed significantly greater contact with T cell ***-AI provided the highest ex vivo expansion of cytotoxic T *** injection of DM-AI to tumor tissues induced the recruitment of T cells and expansion of cytotoxic T cells in tumor *** the other groups,model animals injected with DM-AI did not exhibit growth of primary *** of mice with DM-AI also protected against growth of a rechallenged distant tumor,and thus prevented tumor recurrence in this ***-AI has great potential for programmed stimulation of CD8+T *** concept could be broadly extended for the programming of specific T cell stimulation profiles.

关键词： Artificial dendritic cell DNA microflower In situ T cell stimulation Programmed T cell expansion Immunotherapy

Cell membrane-coated mRNA nanoparticles for enhanced delivery to dendritic cells and immunotherapy

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Asian Journal of Pharmaceutical Sciences 2024年第6期19卷 123-137页

作者： Qiaoyun Li Junho Byun Dongyoon Kim Yina Wu Jaiwoo Lee yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National UniversitySeoul 08826Republic of Korea

Cationic polymers such as polyethylenimine have been considered promising carriers for mRNA ***,their application is hindered by their inherent toxicity and a lack of targeted delivery *** issues need to be addressed to develop effective cancer *** this study,we investigated whether dendritic cell membrane-coated polyethylenimine/mRNA nanoparticles(DPN)could effectively deliver mRNA to dendritic cells and induce immune *** comparison,we employed red blood cell membrane-coated polyethylenimine/mRNA(RPN)and plain polyethylenimine/mRNA polyplex(PN).The dendritic cell membrane coating altered the zeta potential values and surface protein patterns of *** demonstrated significantly higher uptake in dendritic cells compared to PN and RPN,and it also showed greater mRNA expression within these ***,carrying mRNA encoding luciferase,enhanced green fluorescent protein,or ovalbumin(OVA),exhibited higher protein expression in dendritic cells than the other ***,DPN exhibited favorable mRNA escape from lysosomes post-internalization into dendritic ***,subcutaneous administration of DPN containing ovalbumin mRNA(DPN_(OVA))elicited higher titers of anti-OVA IgG antibodies and a greater population of OVA-specific CD8^(+)T cells than the other *** a B16F10-OVA tumor model,DPNOVA treatment resulted in the lowest tumor growth among the treated ***,the population of OVA-specific CD8^(+)T cellswas the highest in the DPNOVA-treated *** we demonstrated DPN’s feasibility as an mRNA delivery system in a tumor model,the potential of DPN can be broadly extended for immunotherapeutic treatments of various diseases through mRNA delivery to antigen-presenting cells.

关键词： Cell membrane coating Dendritic cells mRNA delivery Immune response Antitumor effect

Nanomaterials for modulating innate immune cells in cancer immunotherapy

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Asian Journal of Pharmaceutical Sciences 2019年第1期14卷 16-29页

作者： Quoc-Viet Le Geon Yang Yina Wu Ho Won Jang Mohammadreza Shokouhimehr yu-kyoung oh College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University1 Gwanak-roGwanak-guSeoul 08826Republic of Korea Department of Materials Science and Engineering Research Institute of Advanced MaterialsSeoul National UniversitySeoul 08826Republic of Korea

Cancer immunotherapy has been intensively investigated in both preclinical and clinical *** chemotherapies use cytotoxic drugs to kill tumor cells,cancer immunotherapy is based on the ability of the immune system to fight *** are intimately associated with the immune system:they can suppress the immune response and/or control immune cells to support tumor *** has yielded promising results in clinical practice,but some patients show limited *** may reflect the complexities of the relationship between a tumor and the immune *** an effort to improve the current immunotherapies,researchers have exploited nanomaterials in creating new strategies to cure tumors via modulation of the immune system in tumor *** extensive studies have examined the use of immune checkpoint-based immunotherapy,rather less work has focused on manipulating the innate immune *** review examines the recent approaches and challenges in the use of nanomaterials to modulate innate immune cells.

关键词： Cancer immunotherapy Nanomaterials Innate immune cells Tumor-associated macrophages