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OBJECTIVE: To prepare chitosan-loaded nanoparticles (NPs) that enhance the oral bioavailability of puerarin (Pur) and render it responsive to reactive oxygen species (ROS). SIGNIFICANCE: This research makes substantial progress towards the theory of intelligent drug delivery, offering a new reference for combining Pur with other natural medicinal active ingredients. METHODS: The acylation reaction between chitosan and ROS-sensitive 3-carboxyphenylboronic acid (PBA) was used to synthesise ROS-sensitive phenylboronylated chitosan (PBACS). Subsequently, PBACS-PBA-Pur-NPs and PBACS-TPP-Pur-NPs were prepared via ion gelation after the addition of PBA and sodium tripolyphosphate(TPP), respectively. The physicochemical and functional properties of both NPs were compared, and their differences were preliminarily studied through molecular docking. RESULTS: Reactive oxygen species-sensitive PBACS was successfully synthesised. Of the two NPs prepared, PBACS-TPP-Pur-NPs had a size of 127.2 ± 0.80 nm, polydispersity index (PDI) of 0.129 ± 0.0008, and an encapsulation rate of 95.75 ± 0.387%, whereas PBACS-PBA-Pur-NPs had a size of 149.8 ± 0.1414 nm, PDI of 0.389 ± 0.0012, and an encapsulation rate of 91.77 ± 0.279%. The micromorphology of the PBACS-TPP-Pur-NPs exhibited better physical properties. However, PBACS-PBA-Pur-NPs demonstrated a faster in vitro release and more significant in vitro anti-inflammatory effects. Pharmacokinetically, the AUC0-24, Tmax, and Cmax of PBACS-PBA-Pur-NPs were 3.485, 2.117, and 3.339 times higher, respectively, than those of Pur. The AUC0-24, Tmax, and Cmax of PBACS-TPP-Pur-NPs were 2.41, 1.33, and 2.03 times higher, respectively, than those of Pur. Molecular simulation revealed that the binding energy of PBACS-PBA-Pur -NPs was approximately -4.34 kcal/mol and that of PBACS-TPP-Pur-NPs was even lower, approximately -5.93 kcal/mol, suggesting that the NPs prepared with TPP are more densely packed than those designed with PBA, resulting in slower and reduced drug release. CONCLUSION: The NPs constructed in this study effectively reduced inflammatory factors at the disease site, providing a theoretical and experimental basis for the application of nano drugs in inflammatory disease models. In addition, the molecular docking study of the two NPs offered insights into the relationship between the release and structure of subsequent nano drugs.
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INTRODUCTION: Nonstationary, nonlinear mass transfer in traditional Chinese medicine (TCM) extraction poses challenges to correlating process characteristics with quality parameters, particularly in defining clear parameter ranges for the process. OBJECTIVES: The aim of the study was to provide a solution for quality consistency analysis in TCM preparation processes. MATERIALS AND METHODS: Salvia miltiorrhiza was taken as an example for 15 batches of standard decoction. Using aqueous extract, alcoholic extract, and the content of salvianolic acid B as herb material key quality attributes, multiple nonlinear regression, Gaussian process regression, and artificial neural network models were employed to predict the key quality attributes including the paste yield, the content of salvianolic acid B, and the transfer rate. The evaluation criteria were root mean square error, mean absolute percentage error, and R2. RESULTS: The Gaussian process regression model had the best prediction effect on the paste yield, the content of salvianolic acid B, and the transfer rate, with R2 being 0.918, 0.934, and 0.919, respectively. Utilizing Gaussian process regression model confidence intervals, along with Shewhart control and intervals optimized through process capability index analysis, the quality control range of the standard decoction was determined as follows: paste yield, 25.14%-33.19%; salvianolic acid B content, 2.62%-4.78%; and transfer rate, 56.88%-64.80%. CONCLUSION: This study combined the preparation process of standard decoction with the Gaussian process regression model, accurately predicted the key quality attributes, and determined the quality parameter range by using process analysis tools, providing a new idea for the quality consistency standard of TCM processes.
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Benzofuranos , Medicamentos Herbarios Chinos , Salvia miltiorrhiza , Salvia miltiorrhiza/química , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/normas , Medicamentos Herbarios Chinos/análisis , Benzofuranos/análisis , Análisis de Regresión , Control de Calidad , Redes Neurales de la Computación , Distribución Normal , DepsidosRESUMEN
Single-atom nanozymes (SANzymes) emerge as promising alternatives to conventional enzymes. However, chemical instability limits their application. Here, a systematic synthesis of highly active and stable SANzymes is presented by leveraging noble metal-porphyrins. Four noble metal-porphyrins are successfully synthesized to mimic the active site of natural peroxidases through atomic metal-N coordination anchored to the porphyrin center. These noble metal-porphyrins are integrated into a stable and biocompatible Zr-based metal-organic framework (MxP, x denoting Ir, Ru, Pt, and Pd). Among these, MIrP demonstrates superior peroxidase-like activity (685.61 U mg-1 ), catalytic efficiency, and selectivity compared to horseradish peroxidase (267.71 U mg-1 ). Mechanistic investigations unveil heightened catalytic activity of MIrP arises from its robust H2 O2 adsorption capacity, unique rate-determining step, and low energy threshold. Crucially, MIrP exhibits remarkable chemical stability under both room temperature and high H2 O2 concentrations. Further, through modification with (-)-Epigallocatechin-3-Gallate, a natural ligand for Epstein-Barr virus (EBV)-encoded latent membrane protein 1, targeted SANzyme (MIrPHE) tailored for EBV-associated nasopharyngeal carcinoma is engineered. This study not only presents an innovative strategy for augmenting the catalytic activity and chemical stability of SANzymes but also highlights the substantial potential of MIrP as a potent nanomedicine for targeted catalytic tumor therapy.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo , Herpesvirus Humano 4 , Ingeniería , Catálisis , MetalesRESUMEN
Achieving effective drug delivery to traverse the blood-brain barrier (BBB) and target tumor cells remains the greatest challenge for brain tumor therapy. Importantly, the overexpressed membrane receptors on the brain endothelial cells, especially transferrin receptor 1 (TfR1), which mediate their ligands/antibodies to overcome the BBB by transcytosis, have been emerging as promising targets for brain tumor therapy. By employing ligands (e.g., transferrin, H-ferritin), antibodies or targeting peptides of TfR1 or aptamers, various functional nano-formulations have been developed in the last decade. These agents showed great potential for the treatment of brain diseases due to their ideal size, high loading capacity, controlled drug release and suitable pharmacokinetics. Herein, we summarize the latest advances on TfR1-targeted nanomedicine for brain tumor therapy. Moreover, we also discuss the strategies of improving stability, targeting ability and accumulation of nano-formulations in brain tumors for better outcomes. In this review, we hope to provide inspiration for the rational design of TfR1-targeted nanomedicine against brain tumors.
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Neoplasias Encefálicas , Células Endoteliales , Humanos , Células Endoteliales/metabolismo , Nanomedicina , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Receptores de Transferrina , Neoplasias Encefálicas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , TransferrinaRESUMEN
Nucleic acid-based therapy emerges as a powerful weapon for the treatment of tumors thanks to its direct, effective, and lasting therapeutic effect. Encouragingly, continuous nucleic acid-based drugs have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the tremendous progress, there are few nucleic acid-based drugs for brain tumors in clinic. The most challenging problems lie on the instability of nucleic acids, difficulty in traversing the biological barriers, and the off-target effect. Herein, nucleic acid-based therapy for brain tumor is summarized considering three aspects: (i) the therapeutic nucleic acids and their applications in clinical trials; (ii) the various administration routes for nucleic acid delivery and the respective advantages and drawbacks. (iii) the strategies and carriers for improving stability and targeting ability of nucleic acid drugs. This review provides thorough knowledge for the rational design of nucleic acid-based drugs against brain tumor.
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Neoplasias Encefálicas , Ácidos Nucleicos , Neoplasias Encefálicas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Humanos , Ácidos Nucleicos/uso terapéutico , Preparaciones Farmacéuticas , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Extensive efforts are devoted to refining metal sites for optimizing the catalytic performance of single-atom nanozymes (SANzymes), while the contribution of the defect environment of neighboring metal sites lacks attention. Herein, an iron-based SANzyme (Fe-SANzyme) is rationally designed by edge-site engineering, which intensively exposes edge-hosted defective Fe-N4 atomic sites anchored in hierarchical mesoporous structures. The Fe-SANzyme exhibits excellent catalase-like activity capable of efficiently catalyzing the decomposition of H2 O2 into O2 and H2 O, with a catalytic kinetic KM value superior to that of natural catalase and reported nanozymes. The mechanistic studies depict that the defects introduce notable charge transfer from the Fe atom to the carbon matrix, making the central Fe more activated to strengthen the interaction with H2 O2 and weaken the OO bond. By performing catalase-like catalysis, the Fe-SANzyme significantly scavenges reactive oxygen species (ROS) and alleviates oxidative stress, thus eliminating the pathological angiogenesis in animal models of retinal vasculopathies without affecting the repair of normal vessels. This work provides a new way to refine SANzymes by engineering the defect environment and geometric structure around metal sites, and demonstrates the potential therapeutic effects of the nanozyme on retinal vasculopathies.
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Carbono , Hierro , Animales , Carbono/química , Catalasa/química , Catálisis , Hierro/química , Especies Reactivas de OxígenoRESUMEN
Idarubicin (IDA), an anthracycline antineoplastic drug, is commonly used in the treatment of acute myeloid leukemia (AML) with reasonable response rates and clinical benefits. However, some patients still relapse, or do not respond, and suffer high fatality rates. Recent studies have shown that overexpression of PARP-1 may represent an important risk factor in AML patients. The aim of the present study was to determine the underlying molecular mechanisms by which the PARP-1 inhibitor Olaparib enhances the chemosensitivity of the leukemia cell line K562 and THP1 to IDA. Our data demonstrated that PARP-1 is upregulated in AML patients as well as in K562 and THP1 cells, and that the suppression of PARP-1 activity by Olaparib enhances the inhibitory effect of IDA. A mechanistic study revealed that Olaparib decreases the expressions of p-ATM, p-IκBα, XIAP and p65, and upregulates Bax, cleaved-Caspase-3 and γ-H2AX. Olaparib can enhance the induction of DNA damage by IDA, probably mediated by the inhibition of the ATM-related DNA damage response. Moreover, we also found that the nuclear translocation of p65 and the nuclear export of NEMO are inhibited when IDA and Olaparib are combined. Our results suggest that Olaparib attenuates the activity of the NF-κB pathway and decreases the DNA damage response induced by IDA. Therefore, we conclude that Olaparib is a potentially valuable chemosensitizer for leukemia patients.
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Leucemia Mieloide Aguda , FN-kappa B , Línea Celular Tumoral , Daño del ADN , Humanos , Idarrubicina/farmacología , Idarrubicina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , FN-kappa B/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
OBJECTIVE: The objective of this study is to describe the development of the Outpatient Experience Questionnaire (OPEQ) and to assess the validity and reliability of the scale. DESIGN: Literature review, patient interviews, Delphi method and Cross-sectional validation survey. SETTING: Six comprehensive public hospitals in China. PARTICIPANTS: The survey was carried out on a sample of 600 outpatients. MAIN OUTCOME MEASURE(S): Acceptability of the questionnaire was assessed according to the overall response rate, item non-response rate and the average completion time. Correlation coefficients and confirmatory factor analysis were used to test construct validity. Delphi method was used to assess the content validity of the questionnaire. Cronbach's coefficient alpha and split-half reliability coefficient were used to estimate the internal reliability of the questionnaire. RESULTS: The overall response rate was 97.2% and the item non-response rate ranged from 0% to 0.3%. The mean completion time was 6 min. The Spearman correlations of item-total score ranged from 0.466 to 0.765. The results of confirmatory factor analysis showed that all items had factor loadings above 0.40 and the dimension intercorrelation ranged from 0.449 to 0.773, the goodness of fit of the questionnaire was reasonable. The overall authority grade of expert consultation was 0.80 and Kendall's coefficient of concordance W was 0.186. The Cronbach's coefficients alpha of six dimensions ranged from 0.708 to 0.895, the split-half reliability coefficient (Spearman-Brown coefficient) was 0.969. CONCLUSIONS: The OPEQ is a promising instrument covering the most important aspects which influence outpatient experiences of comprehensive public hospital in China. It has good evidence for acceptability, validity and reliability.
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Pacientes Ambulatorios/psicología , Satisfacción del Paciente , Encuestas y Cuestionarios , China , Estudios Transversales , Análisis Factorial , Hospitales Públicos , Humanos , Psicometría , Reproducibilidad de los ResultadosRESUMEN
Poor patient experience may trigger serious doctor-patient conflicts in China. Health system challenges related to access and financing may cause frustration in patients, but inadequate health literacy is an additional factor. This letter argues from two aspects that patient education is an effective and feasible pathway to improve patient experience, but its effects are influenced by underlying systemic problems and contextual factors in China.