Nucleic acid-based bioactive substances have recently emerged as a new class of nextgeneration therapeutics, but their development has been limited by their relatively weakdelivery into target cells. Cationic liposome...Nucleic acid-based bioactive substances have recently emerged as a new class of nextgeneration therapeutics, but their development has been limited by their relatively weakdelivery into target cells. Cationic liposomes have been studied as a means to enhance thestability of nucleic acid therapeutics in the bloodstream and improve their cellular delivery.As nucleic acid therapeutics, siRNA and plasmid DNA have been extensively tested fordelivery using cationic liposomes. This review discusses recent progress in the applicationof cationic liposomes for the delivery of nucleic acid therapeutics.展开更多
Metabolic engineering of the tumor microenvironment has emerged as a new strategy.Lactate dehydrogenase A(LDHA)is a prominent target for metabolic engineering.Here,we designed a cationic lipid nanoparticle formulation...Metabolic engineering of the tumor microenvironment has emerged as a new strategy.Lactate dehydrogenase A(LDHA)is a prominent target for metabolic engineering.Here,we designed a cationic lipid nanoparticle formulation for LDHA gene editing.The 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.The 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/F3.The lipoplex including GFP-encoding plasmid DNA provided gene editing in HeLa-GFP cells.Treatment of B16F10 tumor cells with pCas9-sgLDHA/F3 yielded editing of the LDHA gene and increased the pH of the culture medium.pCas9-sgLDHA/F3 treatment activated the interferon-gamma and granzyme production of T cells in culture.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 mice.This study suggests that combining metabolic engineering of the tumor microenvironment with immune checkpoint inhibition could be a valuable antitumor strategy.展开更多
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 tes...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.展开更多
Despite the progress of conventional vaccines,improvements are clearly required due to concerns about the weak immunogenicity of these vaccines,intrinsic instability in vivo,toxicity,and the need for multiple administ...Despite the progress of conventional vaccines,improvements are clearly required due to concerns about the weak immunogenicity of these vaccines,intrinsic instability in vivo,toxicity,and the need for multiple administrations.To overcome such problems,nanotechnology platforms have recently been incorporated into vaccine development.Nanocarrier-based delivery systems offer an opportunity to enhance the humoral and cellular immune responses.This advantage is attributable to the nanoscale particle size,which facilitates uptake by phagocytic cells,the gut-associated lymphoid tissue,and the mucosa-associated lymphoid tissue,leading to efficient antigen recognition and presentation.Modifying the surfaces of nanocarriers with a variety of targeting moieties permits the delivery of antigens to specific cell surface receptors,thereby stimulating specific and selective immune responses.In this review,we introduce recent advances in nanocarrierbased vaccine delivery systems,with a focus on the types of carriers,including liposomes,emulsions,polymer-based particles,and carbon-based nanomaterials.We describe the remaining challenges and possible breakthroughs,including the development of needlefree nanotechnologies and a fundamental understanding of the in vivo behavior and stability of the nanocarriers in nanotechnology-based delivery systems.展开更多
We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F...We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate 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/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/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 preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.展开更多
Cancer immunotherapy has been intensively investigated in both preclinical and clinical studies.Whereas chemotherapies use cytotoxic drugs to kill tumor cells,cancer immunotherapy is based on the ability of the immune...Cancer immunotherapy has been intensively investigated in both preclinical and clinical studies.Whereas chemotherapies use cytotoxic drugs to kill tumor cells,cancer immunotherapy is based on the ability of the immune system to fight cancer.Tumors are intimately associated with the immune system:they can suppress the immune response and/or control immune cells to support tumor growth.Immunotherapy has yielded promising results in clinical practice,but some patients show limited responses.This may reflect the complexities of the relationship between a tumor and the immune system.In 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 tissues.Although extensive studies have examined the use of immune checkpoint-based immunotherapy,rather less work has focused on manipulating the innate immune cells.This review examines the recent approaches and challenges in the use of nanomaterials to modulate innate immune cells.展开更多
Liposomes were selected as the theme topic of the memorable first special issue of Asian Journal of Pharmaceutical Sciences.Before the advent of nanomedicine era,liposomes have been studied and commercialized for drug...Liposomes were selected as the theme topic of the memorable first special issue of Asian Journal of Pharmaceutical Sciences.Before the advent of nanomedicine era,liposomes have been studied and commercialized for drug delivery systems.As compared to other emerging nanocarriers,liposomes have unparalleled high biocompatibility,the record of commer-cialization,and long history of clinical use.The versatile loading techniques,the variation of surface charges and lipid compositions contribute to the longevity of liposomes until now.展开更多
Cell membranes have recently emerged as a new source of materials for molecular delivery systems.Cell membranes have been extruded or sonicated to make nanoscale vesicles.Unlike synthetic lipid or polymeric nanopartic...Cell membranes have recently emerged as a new source of materials for molecular delivery systems.Cell membranes have been extruded or sonicated to make nanoscale vesicles.Unlike synthetic lipid or polymeric nanoparticles,cell membrane-derived vesicles have a unique multicomponent feature,comprising lipids,proteins,and carbohydrates.Because cell membrane-derived vesicles contain the intrinsic functionalities and signaling networks of their parent cells,they can overcome various obstacles encountered in vivo.Moreover,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 systems.Cell membrane-derived vesicles can carry therapeutic agents within their interior or can coat the surfaces of drug-loaded core nanoparticles.Cell membranes typically come from single cell sources,including red blood cells,platelets,immune cells,stem cells,and cancer cells.However,recent studies have reported hybrid sources from two different types of cells.This 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.展开更多
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...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 micelles.The 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.展开更多
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 t...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 antibody.Here,a molecular engineering technique was used for sitespecific conjugation of antibodies to nanoparticles.We 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 cys.The 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 cells.High binding of C-LPNs to CLDN3-overexpressing T47 D cells resulted in significantly higher temperature generation upon NIR irradiation and potent anticancer photothermal efficacy.Consistent 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 increases.Our results establish an accurate antibody-linking method and demonstrate the possibility of developing therapeutics using antibody-guided nanoparticles.展开更多
In immunotherapy,ex vivo stimulation of T cells requires significant resources and effort.Here,we report artificial dendritic cell-mimicking DNA microflowers(DM)for programming T cell stimulation in situ.To mimic dend...In immunotherapy,ex vivo stimulation of T cells requires significant resources and effort.Here,we report artificial dendritic cell-mimicking DNA microflowers(DM)for programming T cell stimulation in situ.To 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 used.Compared to PS-A,DM-AI showed significantly greater contact with T cell surfaces.DM-AI provided the highest ex vivo expansion of cytotoxic T cells.Local injection of DM-AI to tumor tissues induced the recruitment of T cells and expansion of cytotoxic T cells in tumor microenvironments.Unlike the other groups,model animals injected with DM-AI did not exhibit growth of primary tumors.Treatment of mice with DM-AI also protected against growth of a rechallenged distant tumor,and thus prevented tumor recurrence in this model.DM-AI has great potential for programmed stimulation of CD8+T cells.This concept could be broadly extended for the programming of specific T cell stimulation profiles.展开更多
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 nan...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.展开更多
基金This work was supported by Research Settlement Fund for the new faculty of Seoul National University,and grants from Ministry of Science,ICT and Future Planning(No.2013035166)from Business for Cooperative R&D between Industry,Academy,and Research Institute funded Korea Small and Medium Business Administration in 2012(No.C0010962).
文摘Nucleic acid-based bioactive substances have recently emerged as a new class of nextgeneration therapeutics, but their development has been limited by their relatively weakdelivery into target cells. Cationic liposomes have been studied as a means to enhance thestability of nucleic acid therapeutics in the bloodstream and improve their cellular delivery.As nucleic acid therapeutics, siRNA and plasmid DNA have been extensively tested fordelivery using cationic liposomes. This review discusses recent progress in the applicationof cationic liposomes for the delivery of nucleic acid therapeutics.
基金by grants from the National Research Foundation,Ministry of Science and ICT,Republic of Korea(NRF-2021R1A2B5B03002123,NRF-2018R1A5A2024425,NRF-2021K2A9A2A06044515,2022M3E5F1017919)Ministry of Education,Republic of Korea(NRF-2021R1A6A3A01086428)Korean Health Technology R&D Project(No.HI19C0664),Ministry of Health&Welfare,Republic of Korea.
文摘Metabolic engineering of the tumor microenvironment has emerged as a new strategy.Lactate dehydrogenase A(LDHA)is a prominent target for metabolic engineering.Here,we designed a cationic lipid nanoparticle formulation for LDHA gene editing.The 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.The 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/F3.The lipoplex including GFP-encoding plasmid DNA provided gene editing in HeLa-GFP cells.Treatment of B16F10 tumor cells with pCas9-sgLDHA/F3 yielded editing of the LDHA gene and increased the pH of the culture medium.pCas9-sgLDHA/F3 treatment activated the interferon-gamma and granzyme production of T cells in culture.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 mice.This study suggests that combining metabolic engineering of the tumor microenvironment with immune checkpoint inhibition could be a valuable antitumor strategy.
文摘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.
基金This work was supported by grants from the Korean Health Technology R&D project,Ministry of Health and Welfare(Grant No.A092010)from Ministry of Science,ICT and Future Planning(No.2014023227)from Business for Cooperative R&D between Industry,Academy,and Research Institute funded Korea Small and Medium Business Administration(No.C0010962).
文摘Despite the progress of conventional vaccines,improvements are clearly required due to concerns about the weak immunogenicity of these vaccines,intrinsic instability in vivo,toxicity,and the need for multiple administrations.To overcome such problems,nanotechnology platforms have recently been incorporated into vaccine development.Nanocarrier-based delivery systems offer an opportunity to enhance the humoral and cellular immune responses.This advantage is attributable to the nanoscale particle size,which facilitates uptake by phagocytic cells,the gut-associated lymphoid tissue,and the mucosa-associated lymphoid tissue,leading to efficient antigen recognition and presentation.Modifying the surfaces of nanocarriers with a variety of targeting moieties permits the delivery of antigens to specific cell surface receptors,thereby stimulating specific and selective immune responses.In this review,we introduce recent advances in nanocarrierbased vaccine delivery systems,with a focus on the types of carriers,including liposomes,emulsions,polymer-based particles,and carbon-based nanomaterials.We describe the remaining challenges and possible breakthroughs,including the development of needlefree nanotechnologies and a fundamental understanding of the in vivo behavior and stability of the nanocarriers in nanotechnology-based delivery systems.
基金supported by grants from the Ministry of Science and ICT,Republic of Korea(NRF-2018R1A2A1A05019203,NRF-2018R1A5A2024425)the Korean Health Technology R&D Project(No.HI15C2842,HI18C2177,HI19C0664),Ministry of Health&Welfare,Republic of Korea.
文摘We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate 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/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/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 preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.
基金funded by research grants from the Ministry of Science and Future Planning,Republic of Korea(NRF2018R1A2A1A05019203NRF-2018R1A5A2024425)the Korean Health Technology R&D Project(No.HI15C2842),Ministry of Health&Welfare,Republic of Korea。
文摘Cancer immunotherapy has been intensively investigated in both preclinical and clinical studies.Whereas chemotherapies use cytotoxic drugs to kill tumor cells,cancer immunotherapy is based on the ability of the immune system to fight cancer.Tumors are intimately associated with the immune system:they can suppress the immune response and/or control immune cells to support tumor growth.Immunotherapy has yielded promising results in clinical practice,but some patients show limited responses.This may reflect the complexities of the relationship between a tumor and the immune system.In 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 tissues.Although extensive studies have examined the use of immune checkpoint-based immunotherapy,rather less work has focused on manipulating the innate immune cells.This review examines the recent approaches and challenges in the use of nanomaterials to modulate innate immune cells.
文摘Liposomes were selected as the theme topic of the memorable first special issue of Asian Journal of Pharmaceutical Sciences.Before the advent of nanomedicine era,liposomes have been studied and commercialized for drug delivery systems.As compared to other emerging nanocarriers,liposomes have unparalleled high biocompatibility,the record of commer-cialization,and long history of clinical use.The versatile loading techniques,the variation of surface charges and lipid compositions contribute to the longevity of liposomes until now.
基金supported by grants from the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT(NRF-2021R1A2B5B03002123,NRF-2018R1A5A2024425,Republic of Korea)the Korea Medical Device Development Fund grant funded by the Korea government(the Ministry of Science and ICT,the Ministry of Trade,Industry and Energy,the Ministry of Health&Welfare,the Ministry of Food and Drug Safety+1 种基金NTIS Number:9991007273,Republic of Korea)the Korean Health Technology R&D Project(No.HI18C2177,HI19C0664,Republic of Korea),Ministry of Health&Welfare
文摘Cell membranes have recently emerged as a new source of materials for molecular delivery systems.Cell membranes have been extruded or sonicated to make nanoscale vesicles.Unlike synthetic lipid or polymeric nanoparticles,cell membrane-derived vesicles have a unique multicomponent feature,comprising lipids,proteins,and carbohydrates.Because cell membrane-derived vesicles contain the intrinsic functionalities and signaling networks of their parent cells,they can overcome various obstacles encountered in vivo.Moreover,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 systems.Cell membrane-derived vesicles can carry therapeutic agents within their interior or can coat the surfaces of drug-loaded core nanoparticles.Cell membranes typically come from single cell sources,including red blood cells,platelets,immune cells,stem cells,and cancer cells.However,recent studies have reported hybrid sources from two different types of cells.This 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.
基金supported by grants from the Ministry of Science and ICT, Republic of Korea (NRF-2018R1A2A1A05019203 and NRF-2018R1A5A2024425)from the Korean Health Technology R&D Project (Nos. HI15C2842 and HI18C2177)Ministry of Health & Welfare, Republic of Korea
文摘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 micelles.The 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.
基金funded by grants from the Global Core Research Center(GCRC,Grant No.2011-0030001)of the National Research Foundation(NRF),Ministry of Science and ICT(MSIT),Republic of Koreathe MSIT,Republic of Korea(NRF-2018R1A2A1A05019203+1 种基金NRF-2018R1A5A2024425)the Korean Health Technology R&D Project(No.HI19C0664),Ministry of Health&Welfare,Republic of Korea
文摘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 antibody.Here,a molecular engineering technique was used for sitespecific conjugation of antibodies to nanoparticles.We 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 cys.The 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 cells.High binding of C-LPNs to CLDN3-overexpressing T47 D cells resulted in significantly higher temperature generation upon NIR irradiation and potent anticancer photothermal efficacy.Consistent 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 increases.Our results establish an accurate antibody-linking method and demonstrate the possibility of developing therapeutics using antibody-guided nanoparticles.
基金supported by grants from the Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science and ICT,Republic of Korea(NRF-2021R1A2B5B03002123,NRF-2018R1A5A2024425),the Ministry of Education(NRF-2020R1I1A1A01070084,NRF-2020R1A6A3A01099750)the Korean Health Technology R&D Project(No.HI18C2177)Ministry of Health&Welfare,and a Korea Medical Device Development Fund grant funded by the Korean government(the Ministry of Science and ICT,the Ministry of Trade,Industry and Energy,the Ministry of Health&Welfare,the Ministry of Food and Drug Safety)(Project Number:9991007273,KMDF_PR_20200901_0106),Republic of Korea.
文摘In immunotherapy,ex vivo stimulation of T cells requires significant resources and effort.Here,we report artificial dendritic cell-mimicking DNA microflowers(DM)for programming T cell stimulation in situ.To 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 used.Compared to PS-A,DM-AI showed significantly greater contact with T cell surfaces.DM-AI provided the highest ex vivo expansion of cytotoxic T cells.Local injection of DM-AI to tumor tissues induced the recruitment of T cells and expansion of cytotoxic T cells in tumor microenvironments.Unlike the other groups,model animals injected with DM-AI did not exhibit growth of primary tumors.Treatment of mice with DM-AI also protected against growth of a rechallenged distant tumor,and thus prevented tumor recurrence in this model.DM-AI has great potential for programmed stimulation of CD8+T cells.This concept could be broadly extended for the programming of specific T cell stimulation profiles.
文摘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.