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Activating the cGAS-STING pathway of circulating tumor cell clusters (CTC clusters) represents a promising strategy to mitigate metastases. To fully exploit the potential of cholesterol-regulating agents in activating CTCs' STING levels, we developed a nanoparticle (NP) composed of metal complex lipid (MCL). This design includes MCL-miriplatin to increase NP stiffness and loads lomitapide (lomi) modulating cholesterol levels, resulting in the creation of PLTs@Pt-lipid@lomi NPs. MCL-miriplatin not only enhances lomi's eliciting efficacy on STING pathway but also increases NPs' stiffness, thus a vital factor affecting the penetration into CTC clusters to further boost lomi's ability. Demonstrated by cy5 tracking experiments, PLTs@Pt-lipid@lomi NPs quickly attach to cancer cell via platelet membrane anchorage, penetrate deep into the spheres, and reach the subcellular endoplasmic reticulum where lomi regulates cholesterol. Additionally, these NPs have been shown to track CTCs in the bloodstream, a capability not demonstrated by the free drug. PLTs@Pt-lipid@lomi NPs more efficiently activate the STING pathway and reduce CTC stemness compared to free lomi. Ultimately, PLTs@Pt-lipid@lomi NPs reduce metastasis in a post-surgery animal model. While cholesterol-regulating agents are limited in efficacy when being repositioned as immunomodulatory agents, this MCL-composing NP strategy demonstrates the potential to effectively deliver these agents to target CTC clusters.
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More than 3 years into the global pandemic, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a significant threat to public health. Immunities acquired from infection or current vaccines fail to provide long term protection against subsequent infections, mainly due to their fast-waning nature and the emergence of variants of concerns (VOCs) such as Omicron. To overcome these limitations, SARS-CoV-2 Spike protein receptor binding domain (RBD)-based epitopes are investigated as conjugates with a powerful carrier, the mutant bacteriophage Qß (mQß). The epitope design is critical to eliciting potent antibody responses with the full length RBD being superior to peptide and glycopeptide antigens. The full length RBD conjugated with mQß activates both humoral and cellular immune systems in vivo, inducing broad spectrum, persistent, and comprehensive immune responses effective against multiple VOCs including Delta and Omicron variants, rendering it a promising vaccine candidate.
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Linfócitos B , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Linfócitos T , SARS-CoV-2/imunologia , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Linfócitos T/imunologia , Animais , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Linfócitos B/imunologia , Camundongos , Humanos , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/química , Mutação , Feminino , Allolevivirus/imunologia , Allolevivirus/química , Anticorpos Antivirais/imunologia , Domínios Proteicos , Camundongos Endogâmicos BALB C , Imunidade CelularRESUMO
The successful development of an anticancer vaccine will be a giant leap forward in cancer prevention and treatment. Herein, the bacteriophage MX1 coat protein virus-like particles (MX1 VLPs) have been conjugated with 9NHAc-GD2 (NHAcGD2) to obtain a MX1-NHAcGD2 conjugate. Intriguingly, vaccinating against this conjugate produced a robust anti-NHAcGD2 IgG response in mice, with an average IgG titer of over 3 million. More interestingly, antibodies induced by the MX1-NHAcGD2 conjugate bound well to IMR-32 neuroblastoma cells and had potent complement-dependent cytotoxic (CDC) effects on IMR-32 cells. Inspired by the superiority of the 9NHAc-GD2 antigen, we also designed another 9NHAc-modified ganglioside antigen, 9NHAc-GD3 (NHAcGD3), to overcome the hydrolytic instability of 9-O-acetylated-GD3. By coupling NHAcGD3 with MX1 VLP, the MX1-NHAcGD3 conjugate was constructed. Strikingly, vaccination of MX1-NHAcGD3 elicited high anti-NHAcGD3 IgG antibodies, which effectively recognized human malignant melanoma SK-MEL-28 cells and had a significant CDC effect against this cell line. This study provides novel MX1-NHAcGD2 and MX1-NHAcGD3 conjugates with broad clinical translational prospects as promising anticancer vaccines.
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Camptothecin (CPT) is an attractive natural drug for cancer chemotherapy. However, the poor water solubility, non-targeting feature, and adverse side effects of CPT are significant obstacles to developing an effective anticancer drug. Here, for the first time, 9-thiol-sialic acid (9-SH-Sia) is coupled to CPT by forming a disulfide releasable carbonate linkage, resulting in a novel CPT prodrug (CPT-ss-Sia) that self-assembles into nanostructures in an aqueous solution. Strikingly, CPT-ss-Sia exhibited excellent in vitro properties, including enhanced water solubility, glutathione (GSH)-triggered CPT release, and increased E-lactone ring stability. Furthermore, CPT-ss-Sia had good cancer cell-killing ability comparable to CPT. Intravenous administration of CPT-ss-Sia significantly inhibited the growth of multiple types of tumors. Histological analysis showed that CPT-ss-Sia treatment significantly reduced lesions in tumor-bearing mice compared to CPT treatment. Notably, CPT-ss-Sia treatment did not adversely affect the body weight of the mice. This is the first report of the 9-SH-Sia conjugate-based prodrug. Overall, CPT-ss-Sia has broad clinical application prospects.
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Antineoplásicos , Nanopartículas , Neoplasias , Pró-Fármacos , Camundongos , Animais , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Camptotecina/química , Ácido N-Acetilneuramínico , Nanopartículas/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Neoplasias/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Developing safe, high-quality theranostic agents for cancer treatment is of great clinical value. In this work, for the first time, the clinical indocyanine green (ICG) is coupled with the biocompatible poly(styrene-alt-maleic anhydride) (PSMAn) to obtain the PSMAn-ICG polymer. The self-assembly of its hydrolyzed product in water results in ICG-conjugated poly(styrene-alt-maleic acid) nanoparticles (PSMA-ICG NPs). Intriguingly, the NPs have many advantages, including good solubility and stability in aqueous solutions, high photostability and decreased hemolytic damage to red blood cells, highlighting the importance of PSMA coupling. More interestingly, PSMA-ICG NPs significantly promote tumor targeting and enable long-term imaging of tumors. Furthermore, the administration of PSMA-ICG NPs in combination with near-infrared laser irradiation provides superior potency in the photothermal therapy of tumors. Furthermore, 9-amino-sialic acid (Sia)-coated PSMA-ICG NPs are fabricated, further enhancing tumor imaging and phototherapy. This is the first report of PSMA-NIR conjugates achieving tumor reduction in mice. Overall, this study provides novel phototheranostic agents with broad clinical transformation prospects.
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Nanopartículas , Neoplasias , Animais , Camundongos , Verde de Indocianina/farmacologia , Verde de Indocianina/uso terapêutico , Estireno/uso terapêutico , Nanomedicina Teranóstica , Fototerapia/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Nanopartículas/uso terapêuticoRESUMO
Correction for 'High-throughput computational screening of hypothetical metal-organic frameworks with open copper sites for CO2/H2 separation' by Mengmeng Li et al., Phys. Chem. Chem. Phys., 2022, 24, 18764-18776, https://doi.org/10.1039/D2CP01139E.
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Major diseases, such as cancer and COVID-19, are frightening global health problems, and sustained action is necessary to develop vaccines. Here, for the first time, ethoxy acetalated dextran nanoparticles (Ace-Dex-NPs) are functionalized with 9-N-(4H-thieno[3,2-c]chromene-2-carbamoyl)-Siaα2-3Galß1-4GlcNAc (TCC Sia-LacNAc) targeting macrophages as a universal vaccine design platform. First, azide-containing oxidized Ace-Dex-NPs are synthesized. After the NPs are conjugated with ovalbumin (OVA) and resiquimod (Rd), they are coupled to TCC Sia-LacNAc-DBCO to produce TCC Sia-Ace-Dex-OVA-Rd, which induce a potent, long-lasting OVA-specific cytotoxic T-lymphocyte (CTL) response and high anti-OVA IgG, providing mice with superior protection against tumors. Next, this strategy is exploited to develop vaccines against infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the main target for neutralizing antibodies. The TCC Sia-Ace-Dex platform is preferentially used for designing an RBD-based vaccine. Strikingly, the synthetic TCC Sia-Ace-Dex-RBD-Rd elicited potent RBD-neutralizing antibodies against live SARS-CoV-2 infected Vero E6 cells. To develop a universal SARS-CoV-2 vaccine, the TCC Sia-Ace-Dex-N-Rd vaccine carrying SARS-CoV-2 nucleocapsid protein (N) is also prepared, which is highly conserved among SARS-CoV-2 and its variants of concern (VOCs), including Omicron (BA.1 to BA.5); this vaccine can trigger strong N-specific CTL responses against target cells infected with SARS-CoV-2 and its VOCs.
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COVID-19 , Vacinas , Animais , Humanos , Camundongos , Vacinas contra COVID-19 , Ligantes , SARS-CoV-2 , Ovalbumina , Anticorpos NeutralizantesRESUMO
It is challenging to identify the optimal metal-organic framework (MOF) adsorbents for gas adsorption and membrane-based separation from the large-scale material databases. The high-throughput computational screening (HTCS) method was adopted to discover the optimal materials for CO2/H2 separation from thousands of MOFs. First, a hierarchical strategy was used to select 1092 MOFs from 13 512 MOFs, and their adsorption capacity towards the equimolar CO2/H2 mixture at 298 K and 10 bar was further calculated using the grand canonical Monte Carlo (GCMC) simulations. The results show that those MOFs with lvtb topology and organic linker 1,2,4,5-tetrazine are conducive to exhibiting high performance CO2/H2 adsorption separation among top-100 MOFs with high performance. The MOFs with pore limited diameter (PLD), largest cavity diameter (LCD), gravimetrical surface area (GSA), and void fraction in the range of 4-12 Å, 5-12 Å, 5500-6500 m2 g-1 and 0.80-0.85, respectively, have high adsorption capacity towards CO2. Second, the dynamic adsorption properties of the top-4 MOFs were simulated by the breakthrough curves of the binary (CO2/H2) and quinary (CO2/H2/CH4/CO/N2) mixtures in the fixed adsorption bed. MOF-4641 exhibits a high breakthrough time of 130 for the quinary mixture. Finally, the adsorption mechanism of CO2 in the top-4 MOFs was investigated by the radial distribution function (RDF), the mass center probability density distribution, etc. The atomic insights from HTCS and breakthrough curve predictions in this work will be helpful in developing novel porous materials and obtaining superior CO2 separation performance.
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Vaccines are critical tools to treat and prevent diseases. For an effective conjugate vaccine, the carrier is crucial, but few carriers are available for clinical applications. In addition, a drawback of current protein carriers is that high levels of antibodies against the carrier are induced by the conjugate vaccine, which are known to interfere with the immune responses against the target antigen. To overcome these challenges, we obtained the near atomic resolution crystal structure of an emerging protein carrier, i.e., the bacteriophage Qß virus like particle. On the basis of the detailed structural information, novel mutants of bacteriophage Qß (mQß) have been designed, which upon conjugation with tumor associated carbohydrate antigens (TACAs), a class of important tumor antigens, elicited powerful anti-TACA IgG responses and yet produced lower levels of anticarrier antibodies as compared to those from the wild type Qß-TACA conjugates. In a therapeutic model against an aggressive breast cancer in mice, 100% unimmunized mice succumbed to tumors in just 12 days even with chemotherapy. In contrast, 80% of mice immunized with the mQß-TACA conjugate were completely free from tumors. Besides TACAs, to aid in the development of vaccines to protect against COVID-19, the mQß based conjugate vaccine has been shown to induce high levels of IgG antibodies against peptide antigens from the SARS-CoV-2 virus, demonstrating its generality. Thus, mQß is a promising next-generation carrier platform for conjugate vaccines, and structure-based rational design is a powerful strategy to develop new vaccine carriers.
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COVID-19 , Neoplasias , Camundongos , Animais , Vacinas Conjugadas , SARS-CoV-2 , Allolevivirus/química , Antígenos Glicosídicos Associados a Tumores , Imunoglobulina G , Neoplasias/terapiaRESUMO
Cancer is a multifaceted global health problem that requires continuous action to develop next-generation cancer theranostics. Inspired by the emerging use of indocyanine green (ICG), the only clinically approved near-infrared (NIR) dye for cancer phototherapy, here we synthesized two ICG conjugate theranostics by coupling ICG to sialic acid (Sia) through the C2 and C9 positions of Sia, respectively, referred to as Sia-C2-ICG and Sia-C9-ICG. Encouragingly, Sia-C2/C9-ICGs show superior in vitro properties, including enhanced stability, reduced non-specific binding to serum proteins, and improved blood compatibility, highlighting the benefits of Sia coupling. Notably, in vivo NIR imaging shows that Sia-C9-ICG significantly promotes tumor targeting and effectively prolongs the circulation time in the body, while Sia-C2-ICG is superior to ICG but inferior to Sia-C9-ICG in targeting tumors. Furthermore, Sia-C9-ICG combined with NIR laser irradiation can lead to excellent photothermal and photodynamic therapies for cancer cells, resulting in superior solid tumor ablation. To our knowledge, this is the first report of Sia-NIR conjugates achieving significant tumor reduction in vivo. Together, these advances render Sia-C9-ICG an attractive lead as next-generation cancer theranostics that can be translated clinically to treat human patients.
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Neoplasias , Fotoquimioterapia , Humanos , Verde de Indocianina/química , Verde de Indocianina/farmacologia , Ácido N-Acetilneuramínico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fototerapia/métodos , Medicina de PrecisãoRESUMO
Cytotoxic T-lymphocytes (CTLs) are central for eliciting protective immunity against malignancies and infectious diseases. Here, for the first time, partially oxidized acetalated dextran nanoparticles (Ox-AcDEX NPs) with an average diameter of 100 nm are fabricated as a general platform for vaccine delivery. To develop effective anticancer vaccines, Ox-AcDEX NPs are conjugated with a representative CTL peptide epitope (CTLp) from human mucin-1 (MUC1) with the sequence of TSAPDTRPAP (referred to as Mp1) and an immune-enhancing adjuvant R837 (referred to as R) via imine bond formation affording AcDEX-(imine)-Mp1-R NPs. Administration of AcDEX-(imine)-Mp1-R NPs results in robust and long-lasting anti-MUC1 CTL immune responses, which provides mice with superior protection from the tumor. To verify its universality, this nanoplatform is also exploited to deliver epitopes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to prevent coronavirus disease 2019 (COVID-19). By conjugating Ox-AcDEX NPs with the potential CTL epitope of SARS-CoV-2 (referred to as Sp) and R837, AcDEX-(imine)-Sp-R NPs are fabricated for anti-SARS-CoV-2 vaccine candidates. Several epitopes potentially contributing to the induction of potent and protective anti-SARS-CoV-2 CTL responses are examined and discussed. Collectively, these findings shed light on the universal use of Ox-AcDEX NPs to deliver both tumor-associated and virus-associated epitopes.
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Ganglioside GD2 is an attractive tumor-associated carbohydrate antigen for anti-cancer vaccine development. However, its low immunogenicity and the significant side effects observed with anti-GD2 antibodies present significant obstacles for vaccines. To overcome these, a new GD2 derivative bearing an N-acetamide (NHAc) at its non-reducing end neuraminic acid (9NHAc-GD2) has been designed to mimic the 9-O-acetylated-GD2 (9OAc-GD2), a GD2 based antigen with a restricted expression on tumor cells. 9NHAc-GD2 was synthesized efficiently via a chemoenzymatic method and subsequently conjugated with a powerful carrier bacteriophage Qß. Mouse immunization with the Qß-9NHAc-GD2 conjugate elicited strong and long-lasting IgG antibodies, which were highly selective toward 9NHAc-GD2 with little cross-recognition of GD2. Immunization of canines with Qß-9NHAc-GD2 showed the construct was immunogenic in canines with little adverse effects, paving the way for future clinical translation to humans.
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Vacinas Anticâncer/química , Gangliosídeos/síntese química , Vacinas Conjugadas/química , Acetamidas/química , Acetamidas/imunologia , Acetilação , Animais , Vacinas Anticâncer/imunologia , Configuração de Carboidratos , Gangliosídeos/química , Gangliosídeos/imunologia , Hidrólise , Camundongos , Ácidos Neuramínicos/química , Ácidos Neuramínicos/imunologia , Desenvolvimento de Vacinas , Vacinas Conjugadas/imunologiaRESUMO
The race is on for therapeutic agents that stop cancer. An effective vaccine offers a safe and promising approach for cancer immunotherapy. However, substantial barriers to immunotherapy in cancer vaccines include the low immunogenicity of cancer antigens and the immunosuppression commonly present in solid tumors, resulting in significant challenges for developing a clinically effective cancer vaccine. Here, the state of the art of synergistic therapy, which includes the photothermal effect combined with immunotherapy, was investigated to target tumors. For the first time, indocyanine green (ICG, referred to as I), imiquimod (R837, referred to as R) and a foreign cytotoxic T lymphocyte antigen peptide (CTL-Ap, referred to as Ap) with the sequence of SIINFEKL from ovalbumin (OVA) were encapsulated by acetalated dextran (AcDEX) to form nanoparticles (NPs) averaging 92 nm in diameter as an immunogen. Administration of the resulting multifunctional vaccine I-R-Ap-AcDEX NPs enhanced antitumor cytotoxic T lymphocyte (CTL) immunotherapy. On the one hand, subcutaneous immunization of the NPs allows foreign Ap to enter the major histocompatibility complex class I (MHC-I) cross-presentation pathway of antigen-presenting cells, thereby presenting Ap and eliciting high levels of Ap-specific CTLs. On the other hand, intratumor/intravenous injections of the NPs allow foreign Ap to enter tumor cells and present Ap through the MHC-I cross-presentation pathway. Ap-specific CTLs can kill Ap-presented tumor cells. Furthermore, the NPs generated near-infrared laser triggered the photothermal killing of tumor cells. To our knowledge, this is the first report of AcDEX NPs in antitumor photothermal therapy. Strikingly, systemic administration of the I-R-Ap-AcDEX NPs combined with near-infrared laser irradiation allowed for complete protection to mice from the tumors when applied to two non-OVA tumor models. This quite impressive result displays the great promise of synergistic therapy by the vaccine I-R-Ap-AcDEX NPs, an approach that harnesses the photothermal effect to boost antitumor immunotherapy.
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Vacinas Anticâncer , Nanopartículas , Neoplasias , Animais , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Imunoterapia , Camundongos , Neoplasias/terapia , FototerapiaRESUMO
MUC1 glycopeptides are attractive antigens for anti-cancer vaccine development. One potential drawback in using the native MUC1 glycopeptide for vaccine design is the instability of the O-glycosyl linkage between the glycan and the peptide backbone to glycosidase. To overcome this challenge, a MUC1 glycopeptide mimic has been synthesized with the galactose-galactosamine disaccharide linked with threonine (Thomsen-Friedenreich or Tf antigen) through an unnatural ß-glycosyl bond. The resulting MUC1-ß-Tf had a much-enhanced stability toward a glycosidase capable of cleaving the glycan from the corresponding MUC1 glycopeptide with the natural α-Tf linkage. The MUC1-ß-Tf was subsequently conjugated with a powerful carrier bacteriophage Qß. The conjugate induced high levels of IgG antibodies in clinically relevant human MUC1 transgenic mice, which cross-recognized not only the natural MUC1-α-Tf glycopeptide but also MUC1 expressing tumor cells, supporting the notion that a simple switch of the stereochemistry of the glycan/peptide linkage can be a strategy for anti-cancer vaccine epitope design for glycopeptides.
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Antígenos Glicosídicos Associados a Tumores/química , Vacinas Anticâncer/química , Glicopeptídeos/química , Mucina-1/química , Animais , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dissacarídeos/química , Desenho de Fármacos , Galactosamina/química , Galactose/química , Humanos , Imunoglobulina G/química , Imunoglobulina G/farmacologia , Camundongos , Camundongos Transgênicos , Mucina-1/imunologiaRESUMO
For prevention of the coronavirus disease 2019 caused by the novel coronavirus SARS-CoV-2, an effective vaccine is critical. Herein, several potential peptide epitopes from the spike protein of SARS-CoV-2 have been synthesized and covalently linked with the cross-reactive material (CRM197). Immunization of mice with the resulting conjugates induced high titers of IgG antibodies against the spike protein. Importantly, the post-immune sera effectively neutralized SARS-CoV-2 pseudovirus, suggesting the epitopes identified are protective, and these conjugates are promising leads for anti-SARS-CoV-2 vaccine development.
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Vacinas contra COVID-19/síntese química , Vacinas contra COVID-19/imunologia , SARS-CoV-2/imunologia , Vacinas de Subunidades Antigênicas/síntese química , Vacinas de Subunidades Antigênicas/imunologia , Reações Cruzadas , Imunoglobulina G/imunologia , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
Cytotoxic T lymphocytes (CTLs) are an important tool for anticancer immunotherapy. To elicit powerful CTL activities, ultra-pH-sensitive nanoparticles (NPs) based on methoxy poly(ethylene glycol)-b-[poly(diisopropylamino)ethyl methacrylate] have been synthesized as a vaccine delivery platform. A representative CTL epitope, ovalbumin (OVA) peptide antigen, was covalently conjugated to the polymer backbone through an acid responsive carboxy-dimethylmaleic amide linker (CDM) resulting in polymer P-CDM-OVA. Interestingly, while the P-CDM-OVA released OVA peptide slowly in a pH 6.4 buffer, the addition of bovine serum albumin (BSA) mimicking proteins encountered in a cellular and/or in vivo environment significantly accelerated the release process. Successful cell surface presentation of OVA was observed when P-CDM-OVA based ultra-pH-sensitive particles were incubated with antigen presenting cells. These P-CDM-OVA NPs greatly enhanced CTL responses in vivo compared to the free peptide or the previously reported acetalated dextran particles encapsulating OVA. The P-CDM was also investigated for adjuvant conjugation, and the coadministration of P-CDM-OVA and the P-CDM-adjuvant conjugate NPs further improved CTL responses in vivo and effectively reduced tumor growth in mice. Thus, the CDM linked polymer presents a promising platform for anticancer immunotherapy.
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Adoptive transfer of immune cells is being actively pursued for cancer treatment. Natural killer (NK) cells, a class of cytotoxic immune cells, generally lack inherent selectivities toward cancer. To bestow tumor-targeting abilities and enhance anticancer efficacy, a new strategy is established to glycoengineer NK cells. Carbohydrate-based ligands for CD22, a marker for B cell lymphoma, are introduced onto NK cells through either metabolic engineering or glyco-polymer insertion. Such NK cells exhibited greatly enhanced cytotoxicities toward CD22+ lymphoma cells in a CD22-dependent manner. Importantly, both CD22+ lymphoma cell lines and primary lymphoma cells from human cancer patients can be effectively killed by the engineered NK cells. Furthermore, glycoengineered NK cells provided significant protection to tumor-bearing mice. Thus, NK cell glycoengineering is an exciting new approach for cancer treatment complementing the current immune cell genetic engineering strategy.
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Mucin-1 (MUC1) is a highly attractive antigenic target for anticancer vaccines. Naturally existing MUC1 can contain multiple types of O-linked glycans, including the Thomsen-Friedenreich (Tf) antigen and the Sialyl Thomsen-nouveau (STn) antigen. In order to target these antigens as potential anticancer vaccines, MUC1 glycopeptides SAPDT*RPAP (T* is the glycosylation site) bearing the Tf and the STn antigen, respectively, have been synthesized. The bacteriophage Qß carrier is a powerful carrier for antigen delivery. The conjugates of MUC1-Tf and -STn glycopeptides with Qß were utilized to immunize immune-tolerant human MUC1 transgenic (MUC1.Tg) mice, which elicited superior levels of anti-MUC1 IgG antibodies with titers reaching over 2 million units. The IgG antibodies recognized a wide range of MUC1 glycopeptides bearing diverse glycans. Antibodies induced by Qß-MUC1-Tf showed strongest binding, with MUC1-expressing melanoma B16-MUC1 cells, and effectively killed these cells in vitro. Vaccination with Qß-MUC1-Tf first followed by tumor challenge in a lung metastasis model showed significant reductions of the number of tumor foci in the lungs of immunized mice as compared to those in control mice. This was the first time that a MUC1-Tf-based vaccine has shown in vivo efficacy in a tumor model. As such, Qß-MUC1 glycopeptide conjugates have great potential as anticancer vaccines.
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Vacinas Anticâncer/uso terapêutico , Glicopeptídeos/uso terapêutico , Imunoconjugados/uso terapêutico , Mucina-1/imunologia , Fragmentos de Peptídeos/uso terapêutico , Proteínas Virais/uso terapêutico , Allolevivirus/química , Sequência de Aminoácidos , Animais , Antígenos Glicosídicos Associados a Tumores/imunologia , Vacinas Anticâncer/síntese química , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Feminino , Glicopeptídeos/síntese química , Glicopeptídeos/imunologia , Humanos , Imunoconjugados/imunologia , Imunoglobulina G/imunologia , Neoplasias Pulmonares/terapia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/imunologia , Proteínas Virais/síntese química , Proteínas Virais/imunologiaRESUMO
The adsorption separation of C6-C8 hydrocarbons in metal-organic frameworks (MOFs) has attracted extensive attention worldwide due to its technical feasibility and high energy efficiency in the petroleum industry. In this study, a large-scale computational screening of 13 512 MOFs with topological diversity was carried out to search optimal candidates for the simultaneous separation of two dimethyl butanes (DMB) from the quinary equimolar mixture of hexane isomers. We first screened out 841 MOFs according to their geometrical properties such as pore limited diameter (PLD) and volumetric surface area. Subsequently, high-performing MOFs were ranked out by an evaluation metric of adsorption performance score (APS), that is the product of the adsorption capacity of DMB and the selectivity of DMB over normal and mono-branched hexane isomers (N + M), on the basis of the predicted capacities by the grand canonical Monte Carlo (GCMC) simulations at 10 bar and 433 K. The structure-property relationships were established between APS and MOF descriptors such as density, PLD, etc. Among the screened 841 MOFs, the MOF with highest APS was MOF-163 because it provided an ideal pore topology with the 6.85 Å annular channel to distinguish DMB from the N + M isomers. The breakthrough predictions further demonstrated that the dimensionless residence time of 2,2-dimethylbutane (22DMB) was significantly different from that of n-hexane; this indicated that MOF-163 was a superior candidate for the dynamic separation of hexane isomers. Radial distribution function, adsorption equilibrium configurations and mass center probability density distributions were investigated to elucidate why MOF-163 could differentiate DBM from the N + M isomers. The molecular-level insights proposed in this study will facilitate the development of new MOFs for the separation of hydrocarbons in the petroleum industry.
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Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUC1 antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qß carrier with MUC1 glycopeptides containing 20-22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qß-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qß-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.