RESUMO
The frequent mutations of influenza A virus (IAV) have led to an urgent need for the development of innovative antiviral drugs. Glycopolymers offer significant advantages in biomedical applications owing to their biocompatibility and structural diversity. However, the primary challenge lies in the design and synthesis of well-defined glycopolymers to precisely control their biological functionalities. In this study, functional glycopolymers with sulfated fucose and 6'-sialyllactose were successfully synthesized through ring-opening metathesis polymerization and a postmodification strategy. The optimized heteropolymer exhibited simultaneous targeting of hemagglutinin and neuraminidase on the surface of IAV, as evidenced by MU-NANA assay and hemagglutination inhibition data. Antiviral experiments demonstrated that the glycopolymer displayed broad and efficient inhibitory activity against wild-type and mutant strains of H1N1 and H3N2 subtypes in vitro, thereby establishing its potential as a dual-targeted inhibitor for combating IAV resistance.
Assuntos
Antivirais , Fucose , Vírus da Influenza A Subtipo H1N1 , Lactose , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Lactose/análogos & derivados , Lactose/química , Lactose/farmacologia , Fucose/química , Fucose/análogos & derivados , Fucose/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Farmacorresistência Viral/efeitos dos fármacos , Humanos , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Células Madin Darby de Rim Canino , Animais , Cães , Polímeros/farmacologia , Polímeros/químicaRESUMO
The entry of coronaviruses is initiated by spike recognition of host cellular receptors, involving proteinaceous and/or glycan receptors. Recently, TMPRSS2 was identified as the proteinaceous receptor for HCoV-HKU1 alongside sialoglycan as a glycan receptor. However, the underlying mechanisms for viral entry remain unknown. Here, we investigated the HCoV-HKU1C spike in the inactive, glycan-activated, and functionally anchored states, revealing that sialoglycan binding induces a conformational change of the NTD and promotes the neighboring RBD of the spike to open for TMPRSS2 recognition, exhibiting a synergistic mechanism for the entry of HCoV-HKU1. The RBD of HCoV-HKU1 features an insertion subdomain that recognizes TMPRSS2 through three previously undiscovered interfaces. Furthermore, structural investigation of HCoV-HKU1A in combination with mutagenesis and binding assays confirms a conserved receptor recognition pattern adopted by HCoV-HKU1. These studies advance our understanding of the complex viral-host interactions during entry, laying the groundwork for developing new therapeutics against coronavirus-associated diseases.
Assuntos
Serina Endopeptidases , Glicoproteína da Espícula de Coronavírus , Internalização do Vírus , Humanos , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Polissacarídeos/metabolismo , Polissacarídeos/química , Células HEK293 , Ligação Proteica , Receptores Virais/metabolismo , Receptores Virais/química , Coronavirus/metabolismo , Modelos MolecularesRESUMO
In recent years, most studies on the gut microbiome have primarily focused on feces samples, leaving the microbial communities in the intestinal mucosa relatively unexplored. To address this gap, our study employed shotgun metagenomics to analyze the microbial compositions in normal rectal mucosa and matched feces from 20 patients with colonic polyps. Our findings revealed a pronounced distinction of the microbial communities between these two sample sets. Compared with feces, the mucosal microbiome contains fewer genera, with Burkholderia being the most discriminating genus between feces and mucosa, highlighting its significant influence on the mucosa. Furthermore, based on the microbial classification and KEGG Orthology (KO) annotation results, we explored the association between rectal mucosal microbiota and factors such as age, gender, BMI, and polyp risk level. Notably, we identified novel biomarkers for these phenotypes, such as Clostridium ramosum and Enterobacter cloacae in age. The mucosal microbiota showed an enrichment of KO pathways related to sugar transport and short chain fatty acid metabolism. Our comprehensive approach not only bridges the knowledge gap regarding the microbial community in the rectal mucosa but also underscores the complexity and specificity of microbial interactions within the human gut, particularly in the Chinese population. IMPORTANCE: This study presents a system-level map of the differences between feces and rectal mucosal microbial communities in samples with colorectal cancer risk. It reveals the unique microecological characteristics of rectal mucosa and its potential influence on health. Additionally, it provides novel insights into the role of the gut microbiome in the pathogenesis of colorectal cancer and paves the way for the development of new prevention and treatment strategies.
Assuntos
Bactérias , Fezes , Microbioma Gastrointestinal , Mucosa Intestinal , Reto , Humanos , Fezes/microbiologia , Masculino , Mucosa Intestinal/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Pessoa de Meia-Idade , Reto/microbiologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Idoso , Adulto , Pólipos do Colo/microbiologia , Metagenômica , Neoplasias Colorretais/microbiologiaRESUMO
The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudo-steroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf)3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo- and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.
Assuntos
Anti-Inflamatórios , Glicosídeos , Esteroides , Glicosídeos/química , Glicosídeos/síntese química , Glicosídeos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/síntese química , Esteroides/química , Esteroides/farmacologia , Esteroides/síntese química , Camundongos , Animais , Humanos , Teoria da Densidade Funcional , Estrutura Molecular , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Macrófagos/efeitos dos fármacosRESUMO
ConspectusThe limited availability of structurally well-defined diverse glycans remains a major obstacle for deciphering biological functions as well as biomedical applications of carbohydrates. Despite tremendous progress that has been made in past decades, the synthesis of structurally well-defined complex glycans still represents one of the most challenging topics in synthetic chemistry. Chemical synthesis of glycans is a time-consuming and labor-intensive process that requires elaborate planning and skilled personnel. In contrast, glycosyltransferase-catalyzed enzymatic synthesis provides a more efficient, convenient, low-cost, and sustainable alternative to affording diverse and complex glycans. However, the existing methods are still insufficient to fulfill the increasing demand for specific synthetic glycan libraries necessary for functional glycomics research. This is mainly attributed to the inherent character of the glycan biosynthetic pathway. In nature, there are too many glycosyltransferases involved in the in vivo glycan synthesis, but only a small number of them are available for in vitro enzymatic synthesis. For instance, humans have over 200 glycosyltransferases, but only a few of them could be produced from the conventional bacterial expression system, and most of these membrane-associated enzymes could be overexpressed only in eukaryotic cells. Moreover, the glycan biosynthetic pathway is a nontemplate-driven process, which eventually ends up with heterogeneous glycan product mixtures. Therefore, it is not a practical solution for the in vitro enzymatic synthesis of complex glycans by simply copying the glycan biosynthetic pathway.In the past decade, we have tried to develop a simplified and transformable approach to the enzymatic modular assembly of a human glycan library. Despite the structural complexity of human glycans, the glycoinformatic analysis based on the known glycan structure database and the human glycosyltransferase database indicates that there are approximately 56 disaccharide patterns present in the human glycome and only 16 disaccharide linkages are required to account for over 80% of the total disaccharide fragments, while 35 disaccharide linkages are sufficient to cover over 95% of all disaccharide fragments of human glycome. Regardless of the substrate specificity, if one glycosyltransferase could be used for the synthesis of all of the same glycosidic linkages in human glycome, it will require only a few dozen glycosyltransferases for the assembly of entire human glycans. According to the glycobioinformatics analysis results, we rationally designed about two dozen enzyme modules for the synthesis of over 20 common glycosidic linkages in human glycome, in which each enzyme module contains a glycosyltransferase and a group of enzymes for the in situ generation of a nucleotide-activated sugar donor. By sequential glycosylation using orchestrated enzyme modules, we have completed the synthesis of over 200 structurally well-defined complex human glycans including blood group antigens, O-mannosyl glycans, human milk oligosaccharides, and others. To overcome the product microheterogeneity problem of enzymatic synthesis in the nontemplate-driven glycan biosynthetic pathway, we developed several substrate engineering strategies to control or manipulate the outcome of glycosyltransferase-catalyzed reactions for the precise synthesis of structurally well-defined isomeric complex glycans.
RESUMO
Glycosylation is one of the most common post-translational modifications of proteins, which plays essential roles in regulating the biological functions of proteins. Efficient and versatile methods for the synthesis of homogeneous and well-defined N- and O-glycans remain an urgent need for biological studies and biomedical applications. Despite their structural complexity, tremendous progress has been made in the synthesis of N- and O-glycans in recent years. This review discusses some recent advances in the enzymatic and chemoenzymatic synthesis of N- and O-glycans.
Assuntos
Polissacarídeos , Proteínas , Glicosilação , Polissacarídeos/química , Proteínas/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Human milk oligosaccharides (HMOs) have unique beneficial effects for infants and are considered as the new gold standard for premium infant formula. They are a collection of unconjugated glycans, and more than 200 distinct structures have been identified. Generally, HMOs are enzymatically produced by elongation and/or modification from lactose via stepwise glycosylation. Each glycosylation requires a specific glycosyltransferase (GT) and the corresponding nucleotide sugar donor. In this review, the typical HMO-producing GTs and the one-pot multienzyme modules for generating various nucleotide sugar donors are introduced, the principles for designing the enzyme cascade routes for HMO synthesis are described, and the important metabolic engineering strategies for mass production of HMOs are also reviewed. In addition, the future research directions in biotechnological production of HMOs were prospected.
Assuntos
Engenharia Metabólica , Leite Humano , Lactente , Humanos , Leite Humano/química , Oligossacarídeos/química , Glicosilação , Lactose/metabolismoRESUMO
Mitochondria targeting complexes are widely utilized as photosensitizers in photodynamic therapy. However, the mechanisms by which they regulate reactive oxygen species (ROS) production at the molecular level and their influence on intracellular mitochondrial signaling and ultrastructures remain rarely studied. Herein, we present two terpyridyl Zn(II) complexes with different side alkyl chain lengths (Zn-2C and Zn-6C) that lead to low and high ROS productivities in vitro, respectively. Both complexes could enter live cells effectively with minimal dark toxicity and accumulate preferably in the mitochondria. We also demonstrated that Zn-6C, with more efficient ROS productivity, could significantly downregulate the caspase signaling pathway but showed no evident influence on mitochondrial membrane proteins. We also highlighted and compared the mitochondrial ultrastructural variations during such a process by stimulated emission depletion (STED) super-resolution nanoscopy.
Assuntos
Mitocôndrias , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/metabolismo , Zinco/químicaRESUMO
Human milk oligosaccharides (HMOs) are structurally complex unconjugated glycans that are the third largest solid component in human milk. HMOs have drawn increasing attention because of their beneficial effects to infant health. Of the more than 200 HMOs, only less than 10 have been used in medical or food industries. Although HMO research has been becoming increasingly intensive and booming, the limited availability of HMOs still cannot meet the demand in health effect research and large-scale application. Therefore, efficient synthetic approaches and strategies for HMO production are urgently needed. The goal of this review is to highlight recent advances in microbial cell factory development for HMO biosynthesis. Key challenges in representative HMO production are also highlighted. The further perspectives in general HMO biosynthesis are discussed.
Assuntos
Engenharia Metabólica , Leite Humano , Humanos , OligossacarídeosRESUMO
Fucosylation is one of the most common modifications of oligo-N-acetyllactosamine (oligo-LacNAc) glycans. However, none of known fucosyltransferases (FucTs) could install the α1,3-linked fucose to the oligo-LacNAc substrates in a site-specific manner. Here, we report a facile and general redox-controlled substrate engineering strategy for the site-specific α1,3-fucosylation of complex glycans containing multiple LacNAc units. This strategy takes advantage of an operationally simple oxidation enzyme module by using galactose oxidase (GOase) to convert the LacNAc unit into oxidized C6'-aldehyde LacNAc sequence, which is not a good substrate for recombinant α1,3-FucT from Helicobacter pylori strain 26695 (Hpα1,3FucT), enabling the site-specific α1,3-fucosylation at intact LacNAc sites. The general applicability and robustness of this strategy were demonstrated by the synthesis of a variety of structurally well-defined fucosides of linear and branched O- and N-linked glycans.
Assuntos
Fucose , Fucosiltransferases , Fucosiltransferases/genética , Fucosiltransferases/metabolismo , Glicosilação , Polissacarídeos , Oxirredução , Especificidade por SubstratoRESUMO
Conventional photosensitizers (PSs) often have shorter excitation wavelengths and poor cancer cell targeting, resulting in a limited tissue penetration depth and increased biotoxicity, which are significant barriers to ensuring effective photodynamic therapy (PDT) in vivo. In this work, a cyclometallated iridium(III) complex (Ir-Biotin) with a long excitation wavelength and effective cancer cell targeting was designed and synthesized. The initial in vitro assessment indicated that Ir-Biotin shows excellent PDT activity with a high singlet-oxygen (1O2) generation yield (0.19) due to the facilitated intersystem crossing process. Further study shows that Ir-Biotin shows good biocompatibility, has specific selectivity for cancer cells, and can induce apoptosis under laser irradiation. Furthermore, Ir-Biotin can be applied for imaging-guided PDT using an in vivo imaging system, and showed significant anti-tumour effects (tumour growth inhibition value: 87.66%). These results reveal the importance of long excitation wavelengths of photosensitizers for efficient PDT and suggest a promising strategy for developing effective photosensitizers.
Assuntos
Neoplasias , Fotoquimioterapia , Biotina , Humanos , Irídio/farmacologia , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio SingleteRESUMO
Human milk oligosaccharides (HMOs) are the second most abundant carbohydrates in colostrum. In this study, we performed a quantitative analysis of 13 oligosaccharides in 99 colostrum samples obtained from mothers living in Northwest China. The analysis combined liquid chromatography-mass spectrometry (LC-MS) with 2-amino-N-(2-aminoethyl)benzamide (AEAB) labeling and nonsecretors accounted for 17%. Compared with healthy secretor mothers, those with gestational diabetes mellitus presented lower levels of sialylated oligosaccharides, especially 3'-sialyllactose. Colostrum from mothers with pregnancy-induced hypertension had higher levels of fucosylated oligosaccharides, but the difference was not significant, and hypothyroidism appeared to have no effect on HMOs. Most HMOs (especially 6'-sialyllactose) were more abundant in colostrum from mothers who underwent vaginal delivery than a C-section. These findings show that the concentration of total or individual HMOs is affected by multiple factors. These findings provide a reference for evaluating variations in HMO expression among different populations and potential guidance for providing personalized clinical nutrition.
Assuntos
Leite Humano , Oligossacarídeos , Cromatografia Líquida , Colostro/química , Feminino , Humanos , Leite Humano/química , Mães , Oligossacarídeos/química , GravidezRESUMO
Typhoid toxin is an A2B5 protein toxin and an important virulence factor for the human-adapted bacterial pathogen Salmonella enterica serovar Typhi, the causative agent of typhoid fever. Typhoid toxin contains two enzymatic subunits, PltA and CdtB, which dock onto a pentameric delivery platform composed of the protein PltB. It was recently reported that the same enzymatic subunits can assemble with a different delivery platform composed of the protein PltC, forming a distinct version of typhoid toxin. However, the differences in structure and receptor specificity between the PltC and PltB typhoid toxins remain unknown. Here, we determined atomic-level structures of the pentameric PltC subunit, the fully assembled PltC typhoid toxin, and the PltC pentamers in complex with glycan receptors. Biochemical and structural analyses indicate that PltB and PltC are unable to form heteromeric delivery complexes due to electrostatic repulsion at the subunit interface and thus form separate toxins only. We further observed that, despite low sequence similarity between PltB and PltC, they interact with PltA in a similar manner but that PltC exhibits stronger electrostatic interactions with PltA, enabling it to outcompete PltB in toxin assembly. The ligand-bound atomic structures of PltC show an additional glycan binding site not found in PltB and glycan array analysis indicates that PltB and PltC exhibit significant differences in glycan binding specificity. Collectively, this study offers atomic-level insights into how S. Typhi produces two distinct versions of typhoid toxin, thereby generating functional diversity in this key virulence factor. IMPORTANCE Typhoid fever is a devastating disease that kills more than 115,000 people every year and is caused by Salmonella Typhi. Typhoid toxin, exclusively produced by S. Typhi, was demonstrated to be responsible for the pathogenesis of typhoid fever. Typhoid toxin consists of a pentameric delivery B subunit to transport the catalytic A subunits into the host cell through binding of the glycan receptors. Recent study shows that S. Typhi encodes two homologous delivery B subunits that are able to associate with the same active subunits to produce alternative toxins with distinct functional characteristics. Here, we show that the two delivery subunits can form only homopentameric delivery platforms that compete to associate with typhoid toxin's active subunits and that the two resulting toxins have distinct glycan-binding properties that confer distinct functional traits. These findings highlight the unique assembly and functional diversification of typhoid toxins.
Assuntos
Toxinas Bacterianas , Febre Tifoide , Humanos , Febre Tifoide/microbiologia , Toxinas Bacterianas/metabolismo , Salmonella typhi , Fatores de Virulência/metabolismo , Polissacarídeos/metabolismoRESUMO
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.
Assuntos
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 enzymatic synthesis of hybrid Lewis antigens including KH-1 (Lewis y-Lewis x-Lactose, Ley-Lex-Lac), Lewis a-Lewis x-Lactose (Lea-Lex-Lac), and Lewis b-Lewis x-Lactose (Leb-Lex-Lac) has been achieved using a facile enzymatic modular assembly strategy. Starting from a readily available tetrasaccharide, 3 complex hybrid Lewis antigens were achieved in over 40% total yields in less than 5 linear steps of sequential enzymatic glycosylation using 6 enzyme modules. The regio-selective fucosylation was achieved by simply controlling the donor-acceptor ratio. This strategy provides an easy access to these biologically important complex hybrid Lewis antigens at preparative scales.
Assuntos
Antígenos do Grupo Sanguíneo de LewisRESUMO
Siglecs that binds cell surface sialoglycans are a family of immunomodulatory receptors, of which, Siglec-7 expressed on natural killer (NK) cells promotes tumor immunoevation while the role of Siglec-1 expressed on macrophages on tumor development remains largely unexplored. Herein, we selectively introduced high affinity sialoside ligands of Siglec-1 and Siglec-7 to tumor cell surface via in vivo Strain-promoted Azide-Alkyne cyclization of TCCSiaα2,3-Lactose or FITCSiaα2,6-Lactose with 9-azido sialic acid (AzSia) metabolically installed on tumor cell surface. We found that TCCSiaα2,3-Lactose conjugated on tumor surface moderately inhibited tumor growth while FITCSiaα2,6-Lactose promote tumor growth. These results suggest high-affinity ligand of Siglec-1 dispalyed on tumors surface provide a new perspective for tumor immunotherapy.
Assuntos
Macrófagos/fisiologia , Polissacarídeos/química , Polissacarídeos/metabolismo , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Animais , Extensões da Superfície Celular , Imunoterapia , Células Matadoras Naturais , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/químicaRESUMO
Campylobacter jejuni is the leading cause of human diarrheal diseases and has been designated as one of highly resistant pathogens by the World Health Organization. The C. jejuni capsular polysaccharides feature broad existence of uncommon 6dHepp residues and have proven to be potential antigens to develop innovative antibacterial glycoconjugation vaccines. To address the lack of synthetic methods for rare 6dHepp architectures of importance, we herein describe a novel and efficient approach for the preparation of uncommon d-/l-6dHepp fluorides that have power as glycosylating agents. The synthesis is achieved by a C1-to-C5 switch strategy relying on radical decarboxylative fluorination of uronic acids arising from readily available allyl d-C-glycosides. To further showcase the application of this protocol, a structurally unique hexasaccharide composed of â3)-ß-d-6didoHepp-(1â4)-ß-d-GlcpNAc-(1â units, corresponding to the capsular polysaccharide of C. jejuni strain CG8486 has been assembled for the first time. The assembly is characterized by highly efficient construction of the synthetically challenging ß-(1,2-cis)-d-ido-heptopyranoside by inversion of the C2 configuration of ß-(1,2-trans)-d-gulo-heptopyranoside, which is conveniently obtained by anchimerically assisted stereoselective glycosylation of the orthogonally protected 6dgulHepp fluoride. Ready accessibility of 6dHepp fluorides and the resulting glycans could serve as a rational starting point for the further development of synthetic vaccines fighting Campylobacter infection.
Assuntos
Campylobacter jejuni/química , Fluoretos/síntese química , Polissacarídeos Bacterianos/química , Piranos/síntese química , Configuração de Carboidratos , Fluoretos/química , Glicosilação , Piranos/químicaRESUMO
The exploitation of effective strategies to develop materials bearing deep tissue focal fluorescence imaging capacity and excellent reactive oxygen species (ROS) generation ability is of great interest to address the high-priority demand of photodynamic therapy (PDT). Therefore, we use a rational strategy to fabricate a two-photon-active metal-organic framework via a click reaction (PCN-58-Ps). Moreover, PCN-58-Ps is capped with hyaluronic acid through coordination to obtain cancer cell-specific targeting properties. As a result, the optimized composite PCN-58-Ps-HA exhibits considerable two-photon activity (upon laser excitation at a wavelength of 910 nm) and excellent light-triggered ROS (1O2 and O2â¢-) generation ability. In summary, the interplay of these two critical factors within the PCN-58-Ps-HA framework gives rise to near-infrared light-activated two-photon PDT for deep tissue cancer imaging and treatment, which has great potential for future clinical applications.
Assuntos
Antineoplásicos/farmacologia , Estruturas Metalorgânicas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Benzotiazóis/efeitos da radiação , Química Click , Células HEK293 , Células HeLa , Humanos , Ácido Hialurônico/análogos & derivados , Ácido Hialurônico/farmacologia , Ácido Hialurônico/efeitos da radiação , Raios Infravermelhos , Estruturas Metalorgânicas/síntese química , Estruturas Metalorgânicas/efeitos da radiação , Fotoquimioterapia , Fótons , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismoRESUMO
Multiphoton materials are in special demand in the field of photodynamic therapy and multiphoton fluorescence imaging. However, rational design methodology for these brands of materials is still nascent. This is despite transition-metal complexes favoring optimized nonlinear-optical (NLO) activity and heavy-atom-effected phosphorescent emission. Here, three four-photon absorption (4PA) platinum(II) complexes (Pt1-Pt3) are achieved by the incorporation of varied functionalized C^N^C ligands with high yields. Pt1-Pt3 exhibit triplet metal-to-ligand charge-transfer transitions at â¼460 nm, which are verified multiple times by transient absorption spectra, time-dependent density functional theory calculations, and low-temperature emission spectra. Further, Pt1-Pt3 undergo 4PA. Notably, one of the complexes, Pt2, has maximum 4PA cross-sectional values of up to 15.2 × 10-82 cm8 s3 photon-3 under excitation of a 1600 nm femtosecond laser (near-IR II window). The 4PA cross sections vary when Pt2 is binding to lecithin and when it displays its lysosome-specific targeting behavior. On the basis of the excellent 4PA property of Pt2, we believe that those 4PA platinum(II) complexes have great potential applications in cancer theranostics.