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Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.
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Terapia Molecular Dirigida , Neoplasias de la Próstata , Radioisótopos , Radiofármacos , Animales , Humanos , Masculino , Ratones , Antígenos de Superficie/química , Antígenos de Superficie/metabolismo , Línea Celular Tumoral , Fluoruros/química , Fluoruros/metabolismo , Glutamato Carboxipeptidasa II/química , Glutamato Carboxipeptidasa II/metabolismo , Ligandos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/química , Terapia Molecular Dirigida/métodos , Proyectos Piloto , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Radioisótopos/uso terapéutico , Radiofármacos/química , Radiofármacos/uso terapéutico , Radiofármacos/metabolismo , Radiofármacos/farmacocinética , Compuestos de Azufre/química , Compuestos de Azufre/metabolismo , Tirosina/metabolismo , Tirosina/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Boramino acids are a class of amino acid biomimics that replace the carboxylate group with trifluoroborate and can achieve the 18F-labeled positron emission tomography (PET) and boron neutron capture therapy (BNCT) with identical chemical structure. METHODS: This study reports a trifluoroborate-derived boronophenylalanine (BBPA), a derived boronophenylalanine (BPA) for BNCT, as a promising PET tracer for tumor imaging. RESULTS: Competition inhibition assays in cancer cells suggested the cell accumulation of [18F]BBPA is through large neutral amino acid transporter type-1 (LAT-1). Of note, [18F]BBPA is a pan-cancer probe that shows notable tumor uptake in B16-F10 tumor-bearing mice. In the patients with gliomas and metastatic brain tumors, [18F]BBPA-PET shows good tumor uptake and notable tumor-to-normal brain ratio (T/N ratio, 18.7 ± 5.5, n = 11), higher than common amino acid PET tracers. The [18F]BBPA-PET quantitative parameters exhibited no difference in diverse contrast-enhanced status (P = 0.115-0.687) suggesting the [18F]BBPA uptake was independent from MRI contrast-enhancement. CONCLUSION: This study outlines a clinical trial with [18F]BBPA to achieve higher tumor-specific accumulation for PET, provides a potential technique for brain tumor diagnosis, and might facilitate the BNCT of brain tumors.
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Compuestos de Boro , Neoplasias Encefálicas , Radioisótopos de Flúor , Fenilalanina , Tomografía Computarizada por Tomografía de Emisión de Positrones , Trazadores Radiactivos , Animales , Femenino , Humanos , Ratones , Compuestos de Boro/análisis , Compuestos de Boro/metabolismo , Compuestos de Boro/farmacocinética , Terapia por Captura de Neutrón de Boro , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Radioisótopos de Flúor/análisis , Radioisótopos de Flúor/metabolismo , Radioisótopos de Flúor/farmacocinética , Voluntarios Sanos , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Imagen por Resonancia Magnética , Melanoma Experimental , Ratones Endogámicos C57BL , Sondas Moleculares/análisis , Sondas Moleculares/metabolismo , Sondas Moleculares/farmacocinética , Fenilalanina/análogos & derivados , Fenilalanina/análisis , Fenilalanina/metabolismo , Fenilalanina/farmacocinética , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The toxicity of nanoparticles to freshwater microalgae is of significant importance in maintaining the overall stability of aquatic ecosystems. However, the transport mechanism and toxicity response of microalgae towards nanoplastics (NPs) remain to be further investigated. In this study, we examined the toxicity and internalization mechanisms of polystyrene nanoplastics (PS-NPs) in the microalga Chlorella sorokiniana. The results revealed that the PS-NPs inhibited algal cells' growth and disrupted cell integrity upon contact, leading to cell shrinkage or rupture. Moreover, amino-modified PS-NPs (Nano-PS-NH2) exhibited greater toxicity to C. sorokiniana than carboxyl-modified PS-NPs (Nano-PS-COOH). Furthermore, significant inhibition of PS-NPs internalization was observed when four different endocytosis-related inhibitors were used, indicating that internalized PS-NPs can enter algal cells through endocytic pathways. More importantly, C. sorokiniana exposed to Nano-PS-NH2 responded to the reduction in carbon sources and energy resulting from the suppression of photosynthesis by regulating the metabolism of carbohydrates. These findings elucidate the effects of PS-NPs on C. sorokiniana, including their impact on cell morphology and metabolism, while shedding light on the internalization mechanisms of NPs by C. sorokiniana which deepen our understanding of the toxicity of nanoplastics on algae and provide important theoretical support for solving such aquatic ecological environment problems.
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Chlorella , Microalgas , Nanopartículas , Contaminantes Químicos del Agua , Microplásticos/toxicidad , Poliestirenos/toxicidad , Ecosistema , Contaminantes Químicos del Agua/toxicidad , Nanopartículas/toxicidadRESUMEN
Numerous cardiovascular disorders have atherosclerosis as their pathological underpinning. Numerous studies have demonstrated that, with the aid of pattern recognition receptors, cytokines, and immunoglobulins, innate immunity, represented by monocytes/macrophages, and adaptive immunity, primarily T/B cells, play a critical role in controlling inflammation and abnormal lipid metabolism in atherosclerosis. Additionally, the finding of numerous complement components in atherosclerotic plaques suggests yet again how heavily the immune system controls atherosclerosis. Therefore, it is essential to have a thorough grasp of how the immune system contributes to atherosclerosis. The specific molecular mechanisms involved in the activation of immune cells and immune molecules in atherosclerosis, the controversy surrounding some immune cells in atherosclerosis, and the limitations of extrapolating from relevant animal models to humans were all carefully reviewed in this review from the three perspectives of innate immunity, adaptive immunity, and complement system. This could provide fresh possibilities for atherosclerosis research and treatment in the future.
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Aterosclerosis , Animales , Humanos , Inmunidad Innata , Inmunidad Adaptativa , Inflamación , Leucocitos/patologíaRESUMEN
Transmissible gastroenteritis virus (TGEV) could cause diarrhea, vomiting, dehydration and even death in piglets, miRNA played an important role in the interaction between virus and cell. The study aimed to investigate the impact of miR-17 on the polysaccharide of Polygonum Cillinerve (PCP) in combating TGEV. miR-17 was screened and transfection validation was performed by Real-time PCR. The function of miR-17 on PK15 cells infected with TGEV and treated with PCP was investigated by DCFH-DA loading probe, JC-1 staining and Hoechst fluorescence staining. Furthermore, the effect of miR-17 on PCP inhibiting TGEV replication and apoptosis signaling pathways during PCP against TGEV infection was measured through Real-time PCR and Western blot. The results showed that miR-17 mimic and inhibitor could be transferred into PK15 cells and the expression of miR-17 significantly increased and decreased respectively compared with miR-17 mimic and inhibitor (P < 0.05). A total 250 µg/mL of PCP could inhibit cells apoptosis after transfection with miR-17. PCP (250 µg/mL and 125 µg/mL) significantly inhibited the decrease in mitochondrial membrane potential induced by TGEV after transfection with miR-17 (P < 0.05). After transfection of miR-17 mimic, PCP at concentrations of 250 µg/mL and 125 µg/mL significantly promoted the mRNA expression of P53, cyt C and caspase 9 (P < 0.05). Compared with the control group, the replication of TGEV gRNA and gene N was significantly inhibited by PCP at concentrations of 250 µg/mL and 125 µg/mL after transfection of both miR-17 mimic and inhibitor (P < 0.05). PCP at 62.5 µg/mL significantly inhibited the replication of gene S following transfection with miR-17 inhibitor (P < 0.05). These results suggested that PCP could inhibit the replication of TGEV and apoptosis induced by TGEV by regulating miR-17.
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The bacteriophage is an effective adjunct to existing antibiotic therapy; however, in the course of bacteriophage therapy, host bacteria will develop resistance to bacteriophages, thus affecting the efficacy. Therefore, it is important to describe how bacteria evade bacteriophage attack and the consequences of the biological changes that accompany the development of bacteriophage resistance before the bacteriophage is applied. The specific bacteriophage vB3530 of Pseudomonas aeruginosa (P. aeruginosa) has stable biological characteristics, short incubation period, strong in vitro cleavage ability, and absence of virulence or resistance genes. Ten bacteriophage-resistant strains (TL3780-R) were induced using the secondary infection approach, and the plaque assay showed that vB3530 was less sensitive to TL3780-R. Identification of bacteriophage adsorption receptors showed that the bacterial surface polysaccharide was probably the adsorption receptor of vB3530. In contrast to the TL3780 parental strain, TL3780-R is characterized by the absence of long lipopolysaccharide chains, which may be caused by base insertion of wzy or deletion of galU. It is also intriguing to observe that, in comparison to the parent strain, the bacteriophage-resistant strains TL3780-R mostly exhibited a large cost of fitness (growth rate, biofilm formation, motility, and ability to produce enhanced pyocyanin). In addition, TL3780-R9 showed increased susceptibility to aminoglycosides and chlorhexidine, which may be connected to the loss and down-regulation of mexX expression. Consequently, these findings fully depicted the resistance mechanism of P. aeruginosa to vB3530 and the fitness cost of bacteriophage resistance, laying a foundation for further application of bacteriophage therapy.IMPORTANCEThe bacteriophage is an effective adjunct to existing antibiotic therapy; However, bacteria also develop defensive mechanisms against bacteriophage attack. Thus, there is an urgent need to deeply understand the resistance mechanism of bacteria to bacteriophages and the fitness cost of bacteriophage resistance so as to lay the foundation for subsequent application of the phage. In this study, a specific bacteriophage vB3530 of P. aeruginosa had stable biological characteristics, short incubation period, strong in vitro cleavage ability, and absence of virulence or resistance genes. In addition, we found that P. aeruginosa may lead to phage resistance due to the deletion of galU and the base insertion of wzy, involved in the synthesis of lipopolysaccharides. Simultaneously, we showed the association with the biological state of the bacteria after bacteria acquire bacteriophage resistance, which is extremely relevant to guide the future application of therapeutic bacteriophages.
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Bacteriófagos , Infecciones por Pseudomonas , Humanos , Bacteriófagos/genética , Pseudomonas aeruginosa , Infecciones por Pseudomonas/terapia , Infecciones por Pseudomonas/microbiología , Antibacterianos/farmacología , VirulenciaRESUMEN
Addressing the challenge of accurately monitoring polycyclic aromatic hydrocarbons (PAHs) in aquatic systems, this study employed diffusive gradients in thin-films (DGT) technique to achieve methods detection limits as low as 0.02 ng L-1 to 0.05 ng L-1 through in situ preconcentration and determination of time-integrated concentrations. The efficacy of the developed DGT samplers was validated under diverse environmental conditions, demonstrating independence from factors such as pH (5.03-9.01), dissolved organic matter (0-20 mg L-1), and ionic strength (0.0001-0.6 M). Notably, the introduction of a novel theoretical approach to calculate diffusion coefficients based on solvent-accessible volume tailored for PAHs significantly enhanced the method's applicability, particularly for organic pollutants with low solubility. Field deployments in coastal zones validated the DGT method against traditional grab sampling, with findings advocating a 4 to 7-day optimal deployment duration for balancing sensitivity and mitigating lag time effects. These results provide a sophisticated, efficient solution to the persistent challenge of monitoring hydrophobic organic pollutants in aquatic environments, broadening the scope and applicability of DGT in environmental science and providing a robust tool for researchers.
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The continuous rise of multidrug-resistant (MDR) Gram-negative bacteria poses a severe threat to public health worldwide. Colistin(COL), employed as the last-line antibiotic against MDR pathogens, is now at risk due to the emergence of colistin-resistant (COL-R) bacteria, potentially leading to adverse patient outcomes. In this study, synergistic activity was observed when colistin and diclofenac sodium (DS) were combined and used against clinical COL-R strains of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa) both in vitro and in vivo. The checkerboard method and time-killing assay showed that DS, when combined with COL, exhibited enhanced antibacterial activity compared to DS and COL monotherapies. Crystal violet staining and scanning electron microscopy showed that COL-DS inhibited biofilm formation compared with monotherapy. The in vivo experiment showed that the combination of DS and COL reduced bacterial loads in infected mouse thighs. Synergistic activity was observed when COL and DS were use in combination against clinical COL-R strains of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa both in vitro and in vivo. The synergistic antibacterial effect of the COL-DS combination has been confirmed by performing various in vitro and in vivo experiments, which provides a new treatment strategy for infections caused by MDR bacteria.
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Antibacterianos , Colistina , Diclofenaco , Sinergismo Farmacológico , Bacterias Gramnegativas , Pruebas de Sensibilidad Microbiana , Colistina/farmacología , Animales , Antibacterianos/farmacología , Diclofenaco/farmacología , Ratones , Bacterias Gramnegativas/efectos de los fármacos , Biopelículas/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple , Acinetobacter baumannii/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Gramnegativas/microbiología , Klebsiella pneumoniae/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Humanos , Quimioterapia Combinada , FemeninoRESUMEN
Radiotherapy-induced prodrug activation provides an ideal solution to reduce the systemic toxicity of chemotherapy in cancer therapy, but the scope of the radiation-activated protecting groups is limited. Here we present that the well-established photoinduced electron transfer chemistry may pave the way for developing versatile radiation-removable protecting groups. Using a functional reporter assay, N-alkyl-4-picolinium (NAP) was identified as a caging group that efficiently responds to radiation by releasing a client molecule. When evaluated in a competition experiment, the NAP moiety is more efficient than other radiation-removable protecting groups discovered so far. Leveraging this property, we developed a NAP-derived carbamate linker that releases fluorophores and toxins on radiation, which we incorporated into antibody-drug conjugates (ADCs). These designed ADCs were active in living cells and tumour-bearing mice, highlighting the potential to use such a radiation-removable protecting group for the development of next-generation ADCs with improved stability and therapeutic effects.
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Profármacos , Profármacos/química , Profármacos/farmacología , Animales , Humanos , Ratones , Inmunoconjugados/química , Inmunoconjugados/farmacología , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacología , FemeninoRESUMEN
Synthetic musks (SMs) have gained widespread utilization in daily consumer products, leading to their widespread dissemination in aquatic environments through various pathways. Over the past few decades, the production of SMs has consistently risen, prompting significant concern over their potential adverse impacts on ecosystems and human health. Although several studies have focused on the development of analytical techniques for detecting SMs in biological samples and cosmetic products, a comprehensive evaluation of their global distribution in diverse aquatic media and biological matrices remains lacking. This review aims to provide an up-to-date overview of the occurrence of SMs in both aquatic and various biological matrices, investigating their worldwide distribution trends, assessing their ecological toxicity, and comparing different methodologies for processing and analysis of SMs. The findings underscore the prevalence of polycyclic musks as predominant SMs, with consumption of various products in different countries leading to contrasting distribution of contaminants. Furthermore, the migration of SMs from sediments to the water phase is investigated, indicating the role of solid-phase reservoirs. Incomplete degradation of SMs in the environment could contribute to their accumulation in aquatic systems, impacting the growth and oxidative stress of aquatic organisms, and having a possibility of genotoxicity to them. Human exposure data highlight substantial risks for vulnerable populations such as pregnant women and infants. Moreover, contemporary methods for SMs analysis are presented in this review, particularly focusing on advancements made in the last five years. Finally, research enhancement and critical questions regarding the analysis of SMs are provided, offering suggestions for future research endeavors.
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Cosméticos , Contaminantes Químicos del Agua , Embarazo , Humanos , Femenino , Ecosistema , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/análisis , Organismos AcuáticosRESUMEN
Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumor-selective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy for activating prodrugs using radiopharmaceuticals. This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals. [18F]FDG (2-[18F]-fluoro-2-deoxy-D-glucose), one of the most widely used radiopharmaceuticals in clinics, can trigger Pt(IV) complex for controlled release of axial ligands in tumors, it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide 18F. Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice. Of note, an OxaliPt(IV) linker is designed to construct an [18F]FDG-activated antibody-drug conjugate (Pt-ADC). Sequential injection of Pt-ADC and [18F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth. Radiotherapy is booming as a perturbing tool for prodrug activation, and we find that [18F]FDG is capable of deprotecting various radiotherapy-removable protecting groups (RPGs). Our results suggest that tumor-selective radiopharmaceutical may function as a trigger, for developing innovative prodrug activation strategies with enhanced tumor selectivity.
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Acinetobacter baumannii, which is predominantly responsible for hospital-acquired infections, presents a tremendous clinical challenge due to its increasing antibiotic resistance to colistin (COL), a last-line antibiotic. As a result, the combination of antimicrobial and non-antimicrobial agents is emerging as a more popular treatment approach against infections caused by COL-resistant A. baumannii. This study administered COL and verapamil (VER), that is an antihypertensive and antiarrhythmic agent. We found that the susceptibility of A. baumannii to COL was restored both in vitro and in vivo. Scanning electron microscope and Crystal violet staining showed inhibition of the VER/COL combination on bacterial biofilm formation. Cytotoxicity assay and haemolysis test were used to confirm in vitro safety evaluation. Further experiments using propidium iodide staining revealed that the VER/COL combination improved the therapeutic efficacy of COL by modifying the permeability of bacterial membranes. As demonstrated by reactive oxygen species experiments, the drug combination caused the accumulation of bacterial reactive oxygen species and their eventual death. Additionally, VER/COL treatment significantly reduced the efflux of Rhodamine 123 (Rh123). For the first time, this study identifies the anti-hypertensive drug VER as a COL potentiator against A. baumannii, providing a potential treatment approach against A. baumannii infections and improving patient outcomes.
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Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Biopelículas , Colistina , Pruebas de Sensibilidad Microbiana , Verapamilo , Acinetobacter baumannii/efectos de los fármacos , Colistina/farmacología , Antibacterianos/farmacología , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Biopelículas/efectos de los fármacos , Verapamilo/farmacología , Animales , Sinergismo Farmacológico , Especies Reactivas de Oxígeno/metabolismo , Humanos , Farmacorresistencia Bacteriana/efectos de los fármacos , Viabilidad Microbiana/efectos de los fármacosRESUMEN
Developing a mucosal vaccine against SARS-CoV-2 is critical for combatting the epidemic. Here, we investigated long-term immune responses and protection against SARS-CoV-2 for the intranasal vaccination of a triple receptor-binding domain (RBD) scaffold protein (3R-NC) adjuvanted with a flagellin protein (KFD) (3R-NC + KFDi.n). In mice, the vaccination elicited RBD-specific broad-neutralizing antibody responses in both serum and mucosal sites sustained at high level over a year. This long-lasting humoral immunity was correlated with the presence of long-lived RBD-specific IgG- and IgA-producing plasma cells, alongside the Th17 and Tfh17-biased T-cell responses driven by the KFD adjuvant. Based upon these preclinical findings, an open labeled clinical trial was conducted in individuals who had been primed with the inactivated SARS-CoV-2 (IAV) vaccine. With a favorable safety profile, the 3R-NC + KFDi.n boost elicited enduring broad-neutralizing IgG in plasma and IgA in salivary secretions. To meet the challenge of frequently emerged variants, we further designed an updated triple-RBD scaffold protein with mutated RBD combinations, which can induce adaptable antibody responses to neutralize the newly emerging variants, including JN.1. Our findings highlight the potential of the KFD-adjuvanted triple-RBD scaffold protein is a promising prototype for the development of a mucosal vaccine against SARS-CoV-2 infection.