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O-linked-N-acetylglucosaminylation (O-GlcNAcylation) plays a key role in hepatocellular carcinoma (HCC) development, and the inhibition of O-GlcNAcylation has therapeutic potential. To decrease the systemic adverse events and increase targeting, we used sialic acid (SA)-decorated liposomes loaded with OSMI-1, an inhibitor of the O-GlcNAcylation, to further improve the anti-HCC effect. Fifty pairs of HCC tissue samples and the cancer genome atlas database were used to analyze the expression of O-GlcNAc transferase (OGT) and its effects on prognosis and immune cell infiltration. OSMI-1 cells were treated with SA and liposomes. Western blotting, immunofluorescence, cell proliferation assay, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and tumorigenicity assays were used to investigate the antitumor effect of SA-modified OSMI-1 liposomes in vitro and in vivo. OGT was highly expressed in HCC tissues, negatively correlated with the degree of tumor infiltration of CD8+ and CD4+T cells and prognosis, and positively correlated with the degree of Treg cell infiltration. SA-modified OSMI-1 liposome (OSMI-1-SAL) was synthesized with stable hydrodynamic size distribution. Both in vitro and in vivo, OSMI-1-SAL exhibited satisfactory biosafety and rapid uptake by HCC cells. Compared to free OSMI-1, OSMI-1-SAL had a stronger capacity for suppressing the proliferation and promoting the apoptosis of HCC cells. Moreover, OSMI-1-SAL effectively inhibited tumor initiation and development in mice. OSMI-1-SAL also promoted the release of damage-associated molecular patterns, including anticalreticulin, high-mobility-group protein B1, and adenosine triphosphate, from HCC cells and further promoted the activation and proliferation of the CD8+ and CD4+T cells. In conclusion, the OSMI-1-SAL synthesized in this study can target HCC cells, inhibit tumor proliferation, induce tumor immunogenic cell death, enhance tumor immunogenicity, and promote antitumor immune responses, which has the potential for clinical application in the future.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Camundongos , Animais , Carcinoma Hepatocelular/genética , Lipossomos/farmacologia , Neoplasias Hepáticas/metabolismo , Ácido N-Acetilneuramínico , Proliferação de CélulasRESUMO
OBJECTIVES: To investigate whether baseline 18F-sodium fluoride (NaF) and 18F-choline PET activity is associated with metastatic castration-resistant prostate cancer (mCRPC) global and individual bone metastases' DWI MR imaging response to radium-223 treatment. METHODS: Thirty-six bone-only mCRPC patients were prospectively recruited from three centers. Whole-body (WB)-MRI with DWI and 18F-NaF and 18F-choline PET/CT were performed at therapy baseline and 8-week intervals. In each patient, bone disease median global (g)ADC change between baseline and follow-up was calculated. Additionally, up to five bone target lesions per patient were delineated and individual median ADC change recorded. An ADC increase > 30% defined response per-patient and per-lesion. For the same targets, baseline 18F-NaF and 18F-choline PET SUVmax were recorded. Mean SUVmax across patient targets was correlated with gADC change and lesion SUVmax with per-lesion ADC change. RESULTS: A total of 133 lesions in 36 patients (14 responders) were analyzed. 18F-NaF PET per-patient mean SUVmax was significantly higher in responders (median = 56.0 versus 38.7 in non-responders; p = 0.008), with positive correlation between SUVmax and gADC increase (rho = 0.42; p = 0.015). A 48.7 SUVmax threshold identified responders with 77% sensitivity and 75% specificity. Baseline 18F-NaF PET per-lesion SUVmax was higher in responding metastases (median = 51.6 versus 31.8 in non-responding metastases; p = 0.001), with positive correlation between baseline lesion SUVmax and ADC increase (rho = 0.39; p < 0.001). A 36.8 SUVmax threshold yielded 72% sensitivity and 63% specificity. No significant association was found between baseline 18F-choline PET SUVmax and ADC response on a per-patient (p = 0.164) or per-lesion basis (p = 0.921). CONCLUSION: 18F-NaF PET baseline SUVmax of target mCRPC bone disease showed significant association with response to radium-223 defined by ADC change. CLINICAL RELEVANCE STATEMENT: 18F-sodium fluoride PET/CT baseline maximum SUV of castration-resistant prostate cancer bone metastases could be used as a predictive biomarker for response to radium-223 therapy. KEY POINTS: ⢠18F-sodium fluoride PET baseline SUVmax of castration-resistant prostate cancer bone metastases showed significant association with response to radium-223. ⢠Baseline 18F-sodium fluoride PET can improve patient selection for radium-223 therapy. ⢠Change in whole-body DWI parameters can be used for response correlation with baseline 18F-sodium fluoride PET SUVmax in castration-resistant prostate cancer bone metastases.
Assuntos
Neoplasias Ósseas , Colina/análogos & derivados , Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluoreto de Sódio/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Radioisótopos de Flúor , Neoplasias Ósseas/tratamento farmacológicoRESUMO
The structural investigation of amorphous pharmaceuticals is of paramount importance in comprehending their physicochemical stability. However, it has remained a relatively underexplored realm primarily due to the limited availability of high-resolution analytical tools. In this study, we utilized the combined power of X-ray pair distribution functions (PDFs) and solid-state nuclear magnetic resonance (ssNMR) techniques to probe the molecular packing of amorphous posaconazole and its amorphous solid dispersion at the molecular level. Leveraging synchrotron X-ray PDF data and employing the empirical potential structure refinement (EPSR) methodology, we unraveled the existence of a rigid conformation and discerned short-range intermolecular C-F contacts within amorphous posaconazole. Encouragingly, our ssNMR 19F-13C distance measurements offered corroborative evidence supporting these findings. Furthermore, employing principal component analysis on the X-ray PDF and ssNMR data sets enabled us to gain invaluable insights into the chemical nature of the intermolecular interactions governing the drug-polymer interplay. These outcomes not only furnish crucial structural insights facilitating the comprehension of the underlying mechanisms governing the physicochemical stability but also underscore the efficacy of synergistically harnessing X-ray PDF and ssNMR techniques, complemented by robust modeling strategies, to achieve a high-resolution exploration of amorphous structures.
Assuntos
Imageamento por Ressonância Magnética , Polímeros , Raios X , Espectroscopia de Ressonância Magnética/métodos , Polímeros/química , Preparações Farmacêuticas , Difração de Raios XRESUMO
BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease without effective treatment. The utilization of all trans-retinoic acid (TRA) and betamethasone (BT) for the treatment of psoriasis is still facing difficulties, due to their relatively poor stability, limited skin permeation, and systemic side effects. Flexible liposomes are excellent in deeper skin permeation and reducing the side effects of drugs, which is promising for effective treatment of skin disorders. This work aimed to establish dual-loaded flexible liposomal gel for enhanced therapeutic efficiency of psoriasis based on TRA and BT. RESULTS: Flexible liposomes co-loaded with TRA and BT were successfully prepared in our study. The characterization examination revealed that flexible liposomes featured nano-sized particles (around 70 nm), high drug encapsulation efficiency (> 98%) and sustained drug release behaviors. Flexible liposomes remarkably increased the drug skin permeation and retention as compared with free drugs. Results on HaCaT cells suggested that flexible liposomes were nontoxic, and its cellular uptake has a time-dependent manner. In vivo studies suggested the topical application of TRA and BT dual-loaded liposomal gel had the best ability to reduce the thickness of epidermal and the level of cytokines (TNF-α and IL-6), largely alleviating the symptoms of psoriasis. CONCLUSIONS: Flexible liposomal gel dual-loaded with TRA and BT exerted a synergistic effect, which is a promising topical therapeutic for the treatment of psoriasis.
Assuntos
Betametasona , Fármacos Dermatológicos , Lipossomos , Psoríase , Tretinoína , Animais , Betametasona/química , Betametasona/farmacocinética , Betametasona/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Fármacos Dermatológicos/química , Fármacos Dermatológicos/farmacocinética , Fármacos Dermatológicos/farmacologia , Fármacos Dermatológicos/toxicidade , Modelos Animais de Doenças , Géis , Células HaCaT , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Lipossomos/farmacologia , Lipossomos/toxicidade , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Maleabilidade , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Ratos , Ratos Sprague-Dawley , Tretinoína/química , Tretinoína/farmacocinética , Tretinoína/farmacologiaRESUMO
The spatial presentation of mechanical information is a key parameter for cell behavior. We have developed a method of polymerization control in which the differential diffusion distance of unreacted cross-linker and monomer into a prepolymerized hydrogel sink results in a tunable stiffness gradient at the cell-matrix interface. This simple, low-cost, robust method was used to produce polyacrylamide hydrogels with stiffness gradients of 0.5, 1.7, 2.9, 4.5, 6.8, and 8.2 kPa/mm, spanning the in vivo physiological and pathological mechanical landscape. Importantly, three of these gradients were found to be nondurotactic for human adipose-derived stem cells (hASCs), allowing the presentation of a continuous range of stiffnesses in a single well without the confounding effect of differential cell migration. Using these nondurotactic gradient gels, stiffness-dependent hASC morphology, migration, and differentiation were studied. Finally, the mechanosensitive proteins YAP, Lamin A/C, Lamin B, MRTF-A, and MRTF-B were analyzed on these gradients, providing higher-resolution data on stiffness-dependent expression and localization.
Assuntos
Acrilamida/química , Resinas Acrílicas/química , Movimento Celular/fisiologia , Hidrogéis/química , Mecanotransdução Celular/fisiologia , Células-Tronco/metabolismo , Adulto , Adesão Celular/fisiologia , Técnicas de Cultura de Células/métodos , Linhagem Celular , Módulo de Elasticidade/fisiologia , Humanos , PolimerizaçãoRESUMO
Multidrug resistance (MDR) is the largest obstacle to the success of chemotherapy. The development of innovative strategies and safe sensitizers is required to overcome MDR. Paclitaxel (PTX) is a widely used chemotherapeutic drug, the application of which has been learn to understand MDR. However, the application and use are severely restricted because of this MDR. Cyclodextrins (CDs) of many carriers, additionally have shown anti-cancer capability in MDR cancer cells. In this study, novel paclitaxel/hydroxypropyl-ß-cyclodextrin complex-loaded liposomes (PTXCDL) have been developed in an attempt to overcome MDR in a PTX-resistant human lung adenocarcinoma (A549/T) cell line. The in vitro application of PTXCDL exhibited pH-sensitive PTX release, potent cytotoxicity, and enhanced intracellular accumulation. In comparison to in vivo, PTXCDL also show a stronger inhibition of tumor growth. In comparison, these findings suggest that the PTXCDL provide a novel strategy for effective therapy of resistant cancers by overcoming the drug resistance.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Antineoplásicos/química , Ciclodextrinas/química , Lipossomos/química , Nanopartículas/química , Paclitaxel/química , 2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Concentração de Íons de Hidrogênio , Paclitaxel/farmacologia , Resultado do TratamentoRESUMO
Tumor metastasis is the most dangerous stage in tumorigenesis and its evolution, which causes about 80% clinical death. However, common therapies including chemotherapy may increase the risk of tumor metastasis while killing cancer cells. Tumor metastasis is closely related to many factors in the tumor microenvironment, especially hypoxia. As one of the characteristics of a malignant tumor microenvironment, hypoxia plays an important role in the growth, metabolism, and metastasis of tumors. Upregulation of the hypoxia-inducible factor (HIF) would stimulate the metastasis and migration of cancer cells. In this study, we developed an artificial oxygen carrier system, a hemoglobin-loaded liposome (Hb@lipo), which was capable of effectively delivering oxygen to tumor. The way of providing oxygen not only alleviated tumor hypoxia but also downregulated the expression of HIF, which is conducive to reducing tumor malignancy. Alleviating the tumor hypoxic microenvironment alone is not enough to inhibit tumor metastasis; thus, we prepared the liposome containing a chemotherapeutic agent cabazitaxel (CBZ@lipo). Our data indicated that the combination therapy of Hb@lipo and CBZ@lipo can efficiently kill cancer cells and inhibit tumor growth. At the same time, it can effectively entrap cancer cells in tumor sites by relieving the hypoxic microenvironment of tumors and reduce the metastasis of cancer cells during and after the chemotherapy. Our research may provide a clinical cancer chemotherapy reference that reduces the risk of cancer cell metastasis while inhibiting tumor growth.
Assuntos
Antineoplásicos/farmacologia , Metástase Neoplásica/tratamento farmacológico , Oxigênio/metabolismo , Hipóxia Tumoral/efeitos dos fármacos , Animais , Biomimética/métodos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células HT29 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lipossomos/química , Células MCF-7 , Melanoma Experimental , Camundongos , Camundongos Endogâmicos BALB C , Microambiente Tumoral/efeitos dos fármacosRESUMO
Skin damages are defined as one of most common lesions people suffer from, some of wounds are notoriously difficult to eradicate such as chronic wounds and deep burns. Existing wound therapies have been proved to be inadequate and far from satisfactory. The cutting-edge nanotechnology offers an unprecedented opportunity to revolutionize and invent new therapies or boost the effectiveness of current medical treatments. In particular, the nano-drug delivery systems anchor bioactive molecules to applied area, sustain the drug release and explicitly enhance the therapeutic efficacies of drugs, thus making a fine figure in field relevant to skin regeneration. This review summarized and discussed the current nano-drug delivery systems holding pivotal potential for wound healing and skin regeneration, with a special emphasis on liposomes, polymeric nanoparticles, inorganic nanoparticles, lipid nanoparticles, nanofibrous structures and nanohydrogel.
Assuntos
Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Fenômenos Fisiológicos da Pele , Cicatrização/efeitos dos fármacos , Animais , Liberação Controlada de Fármacos , Humanos , Hidrogéis/química , Lipídeos/química , Lipossomos/química , Polímeros/química , RegeneraçãoRESUMO
Mussel-inspired polydopamine (PDA) coatings have been broadly exploited for constructing functional membrane surfaces. One-step codeposition of PDA with antifouling polymers, especially zwitterionic polymers, has been regarded as a promising strategy for fabricating antifouling membrane surfaces. However, one challenge is that the codeposition is usually a slow process over 10 h or even several days. Herein, we report that CuSO4/H2O2 is able to notably accelerate the codeposition process of PDA with poly(sulfobetaine methacrylate) (PSBMA). In our case, PSBMA is facilely anchored to the polypropylene microporous membrane (PPMM) surfaces within 1 h with the assistance of PDA because of its strong interfacial adhesion. The PDA/PSBMA-coated PPMMs show excellent surface hydrophilicity, high water permeation flux (7506 ± 528 L/m2·h at 0.1 MPa), and an outstanding antifouling property. Moreover, the antifouling property is maintained after the membranes are treated with acid and alkali solutions as well as organic solvents. To recap, it provides a facile, universal, and time-saving strategy for exploiting high-efficiency and durable antifouling membrane surfaces.
Assuntos
Incrustação Biológica/prevenção & controle , Sulfato de Cobre/química , Peróxido de Hidrogênio/química , Indóis/química , Metacrilatos/química , Polímeros/química , Animais , Bovinos , Escherichia coli/química , Hemoglobinas/química , Interações Hidrofóbicas e Hidrofílicas , Indóis/síntese química , Lisina/química , Metacrilatos/síntese química , Polímeros/síntese química , Soroalbumina Bovina/química , Propriedades de SuperfícieRESUMO
To improve the gene transfection efficiency mediated by chitosan-g-stearic acid (CS) micelles, poly(ethylene glycol)-b-poly(γ-glutamic acid) (PG) was incorporated into a CS-based gene delivery system. CS/PG/pDNA complexes were prepared by ionic interaction. CS and PEGylated CS (PCS) micelles were introduced to prepare binary complexes for use as controls. CS/PG/pDNA complexes possessed similar sizes and presented as irregular spheroids in shape. The incorporation of PG into CS/pDNA complexes did not affect the ability of CS to compact pDNA and also showed a protective effect against DNase I based degradation of pDNA. Importantly, PG could increase gene transfection efficiency, which was also affected by the mixing methods used for the preparation of CS/PG/pDNA ternary complexes. The transfection efficiencies mediated by CS/PG/pDNA complexes against HEK293 and EC-1 cells reached up to 40.8% and 11.6%, respectively, which were much higher than those of CS/pDNA complexes (1.3% and 4.0%) and PCS/pDNA complexes (0.8% and 2.4%). In addition, the incorporation of PG into CS/pDNA complexes significantly enhanced cellular uptake in HEK293 and EC-1 cells and, additionally, improved endosomal escape and intracellular vector unpacking. However, the incorporation of PG reduced the cellular uptake of CS/PG/pDNA complexes in macrophages (RAW264.7 cells). It was further demonstrated that, in addition to a nonspecific charge-mediated binding to cell membranes, a γ-PGA-specific receptor-mediated pathway was involved in the internalization of CS/PG/pDNA complexes. These results indicated that PG played multiple important roles in enhancing the transfection efficiency of CS/PG/pDNA complexes.
Assuntos
Glicolipídeos/química , Micelas , Peptídeos/química , Polietilenoglicóis/química , Animais , Ânions , Quitosana/química , DNA/química , Eletroforese em Gel de Ágar , Endossomos/metabolismo , Técnicas de Transferência de Genes , Genes Reporter , Células HEK293 , Humanos , Macrófagos/metabolismo , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/química , Polímeros/química , Ácidos Esteáricos/química , TransfecçãoRESUMO
The amphiphilic graft copolymer poly (lactic-co-glycolic acid)-g-dextran (Dex-PLGA) was successfully synthesized to fabricate micelles for the delivery of paclitaxel with low critical micelle concentration (CMC). The sizes of paclitaxel-loaded Dex-PLGA (Dex-PLGA/PTX) micelles were kept below 100nm with a relatively narrow size distribution. This novel PTX nano-formulation was found to exhibit slightly stronger in vitro cytotoxicity against SKOV-3, OVCAR-8 and MCF-7 cells with Taxol®. However, it could overcome the drug resistance of multi-drug resistant human breast carcinoma cells (MCF-7/Adr cells). The maximum tolerated dose (MTD) of Dex-PLGA/PTX after a single dose was more than 200mg PTX/kg, which were 8-fold higher than that of Paclitaxel Injection. The in vivo antitumor activity results indicated that Dex-PLGA/PTX micelles treatments effectively suppressed the tumor growth and highly reduced the toxicity against animals than Taxol® and could eliminate the SKOV-3 tumor by highly increasing the drug dose. FROM THE CLINICAL EDITOR: Chemotherapy for cancer has always been hampered the toxic side effect of the drugs. Nanotechnology has helped to produce various drug delivery systems to minimize these side effects. In this article, the authors designed dextran-based micelles loaded with paclitaxel. They showed effective anti-tumor activity in both in vitro and in vivo experiments with significant lower systemic toxicity.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Dextranos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Láctico/farmacologia , Micelas , Paclitaxel/farmacologia , Ácido Poliglicólico/farmacologia , Animais , Neoplasias da Mama/patologia , Dextranos/química , Feminino , Ácido Láctico/química , Células MCF-7 , Camundongos , Paclitaxel/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Purpose: Fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and lockdown measures may have an impact on health care utilization particularly for people with chronic diseases. We investigated changes in outpatient utilization behavior in pandemic phases among people with selected chronic diseases in Germany. Methods: The nationwide population-based telephone surveys German Health Update (GEDA) 2019/2020 (April 2019 to September 2020) and GEDA 2021 (July to December 2021) covered 4 out of 7 pandemic phases from the pre-pandemic to the 4th pandemic wave. Data on hypertension, diabetes and major cardiovascular diseases (CVD) in the past 12 months and visiting a general practitioner (GP) or a specialist (excluding dentist) in the past 4 weeks was collected using a standardized questionnaire. Proportions and odds ratios were derived from logistic regression models adjusted for age, sex, education and federal states. Results: Among 27,967 participants aged ≥16 years, 8,449, 2,497 and 1,136 individuals had hypertension, diabetes and major CVD. Participants with these chronic diseases visited a GP or specialist significantly more often than the overall study population, irrespective of pandemic phases. Compared to the pre-pandemic phase, a significant reduction in specialist-visiting was found in the first pandemic wave among people with hypertension (34.3% vs 24.1%), diabetes (39.5% vs 25.5%) and major CVD (41.9% vs 25.6%). GP-visiting was lower only among people with hypertension (53.0% vs 46.0%). No difference in GP or specialist visiting was found in the 4th pandemic wave compared to the pre-pandemic phase. Conclusion: The observed decrease particularly in specialist utilization among people with the selected chronic diseases at the beginning of the pandemic was not observed for the second half of 2021 despite the ongoing pandemic. Further studies are required to examine whether the temporary changes in the utilization of ambulatory health care have affected the disease management of people with chronic diseases.
RESUMO
Formulation screening, essential for assessing the impact of physical, chemical, and mechanical stresses on protein stability, plays a critical role in biologics drug product development. This research introduces a Reciprocal Injection Device (RID) designed to accelerate formulation screening by probing protein stability under intensified stress conditions within prefilled syringes. This versatile device is designed to accommodate a broad spectrum of injection parameters and diverse syringe dimensions. A commercial drug product was employed as a model monoclonal antibody formulation. Our findings effectively highlight the efficacy of the RID in assessing concentration-dependent protein stability. This device exhibits significant potential to amplify the influences of interfacial interactions, such as those with buffer salts, excipients, air, metals, and silicone oils, commonly found in combination drug products, and to evaluate the protein stability under varied stresses.
Assuntos
Produtos Biológicos , Seringas , Óleos de Silicone , Injeções , Estabilidade de MedicamentosRESUMO
The aim of the present study was to evaluate the potential of PEGylated solid lipid nanoparticle (pSLN) as mucus penetrating particles (MPP) for oral delivery across gastrointestinal mucus. The SLN was prepared by an aqueous solvent diffusion method, subsequently modified with PEG2000-stearic acid (PEG2000-SA) as hydrophilic groups. Surface properties, cytotoxicity, cellular uptake, and transport across Caco-2/HT29 coculture cell monolayers, intestinal absorption, and pharmacokinetics of pSLN were studied compared with that of SLN. Quantitative cellular uptake showed that the internalization of SLN and pSLN was an active transfer process, which would be restrained by several inhibitors of cell activity. Compared with SLN, the permeation ability of pSLN decreased through Caco-2 cell monolayer while it increased through a mucus-secreting Caco-2/HT29 coculture cell monolayer, which indicated that the mucus layer has a significant impact on determining the efficiency of oral nanoformulations. In addition to increasing permeation ability, the stability of the nanoparticles in simulated intestinal fluids was also increased by the PEGylation. Moreover, in vitro everted gut sac technique and the ligated intestinal loops model in vivo also demonstrated that pSLN can rapidly penetrate mucus secretions, whereas the SLN were strongly trapped by highly viscoelastic mucus barriers. The pharmacokinetic studies presented that pSLN exhibited improved absorption efficiency and prolonged blood circulation times with a 1.99-fold higher relative bioavailability compared with SLN. In conclusion, PEGylated solid lipid nanoparticles had advantages in enhancing the bioavailability of oral administration.
Assuntos
Absorção Intestinal , Nanopartículas/administração & dosagem , Nanopartículas/química , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Técnicas de Cocultura , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Endocitose/efeitos dos fármacos , Células HT29 , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Lipídeos/química , Masculino , Nanopartículas/ultraestrutura , Polietilenoglicóis/química , Ratos , Ratos Sprague-DawleyRESUMO
AIMS: To explore differences in B-type natriuretic peptide (BNP) concentration and stability and evaluate BNP accuracy in different collection tubes. METHODS: BNP concentrations in heparin/glass, EDTA/glass, and EDTA/polyethylene terephthalate (PET) tubes were measured on the Mindray CL-6000i at 0.5, 1, 2, and 4 h after collection. Differences were evaluated using Wilcoxon's paired tests and Bland-Altman plots. BNP stability and measurement accuracies were estimated using Kruskal-Wallis H tests and recovery tests. RESULTS: BNP concentrations in EDTA/glass tubes were 31.4% higher than those in heparin/glass tubes and 3.04% lower than those in EDTA/PET tubes. BNP stability significantly decreased in the heparin/glass tube. BNP remained stable in EDTA/glass and EDTA/PET tubes at room temperature for 4 h. BNP recovery rates in heparin/glass, EDTA/glass, and EDTA/PET tubes were 77.46, 86.04, and 88.23%, respectively. CONCLUSIONS: Plasma in EDTA/glass and EDTA/PET tubes is suitable for BNP measurement on the Mindray CL-6000i.
Assuntos
Peptídeo Natriurético Encefálico , Polietilenotereftalatos , Humanos , Ácido Edético , HeparinaRESUMO
The field of biomaterials has experienced substantial evolution in recent years, driven by advancements in materials science and engineering. This has led to an expansion of the biomaterials definition to include biocompatibility, bioactivity, bioderived materials, and biological tissues. Consequently, the intended performance of biomaterials has shifted from a passive role wherein a biomaterial is merely accepted by the body to an active role wherein a biomaterial instructs its biological environment. In the future, the integration of bioinspired designs and dynamic behavior into fabrication technologies will revolutionize the field of biomaterials. This perspective presents the recent advances in the evolution of biomaterials in fabrication technologies and provides a brief insight into smart biomaterials.
Assuntos
Materiais Biocompatíveis , EngenhariaRESUMO
The two-signal model of T cell activation has helped shape our understanding of the adaptive immune response for over four decades. According to the model, activation of T cells requires a stimulus through the T cell receptor/CD3 complex (signal 1) and a costimulatory signal 2. Stimulation of activatory signals via T cell agonists has thus emerged. However, for a robust T cell activation, it necessitates not only the presence of both signal 1 and signal 2, but also a high signaling strength. Herein, we report a photo-activable nano-agonist for the two-signal model of T cell in vivo activation. A UV-crosslinkable polymer is coated onto upconversion nanoparticles with satisfactory NIR-to-UV light conversion efficiency. Then dual signal molecules, i.e., signal 1 and signal 2, are conjugated to the polymer end to yield the photo-activable T cell nano-agonist. In melanoma and breast cancer models, photo-activable nano-agonist could bind onto corresponding activatory receptors on the surface of T cells, but has limited activity without the application of NIR light (absence of photo-crosslinking of receptors and consequently a poor signaling strength). While when the NIR light is switched on locally, T cells in tumor are remarkably activated and kill tumor cells effectively. Moreover, we do not observe any detectable toxicities related to the photo-activable nano-agonist. We believe with two activatory signals being simultaneously strengthened by local photo-switched crosslinking, T cells realize a robust and selective activation in tumor and, consequently contribute to an enhanced and safe tumor immunotherapy.
Assuntos
Melanoma , Nanopartículas , Humanos , Imunoterapia , Ativação Linfocitária , PolímerosRESUMO
The incidence of chronic diabetic wounds is increasing with the growing number of diabetic patients, and conventional wound dressings have proven to be ineffective in treating them. To address this challenge, researchers have developed artificial dermal substitutes using collagen and hyaluronic acid, which are crucial extracellular matrices. However, these subsitiues lack precision and targeted treatment. To overcome this limitation, a gene liposome nanocomplex-loaded dermal substitute (GDS) has been developed as a potential solution. This innovative biomaterial combines the benefits of liposome nanocomplexes with dermal substitutes to offer a more accurate and effective treatment option for chronic diabetic wounds. The GDS has the ability to deliver genes and therapeutic agents specifically to the wound site, promoting angiogenesis and accelerating the wound healing process. Overall, the GDS presents a promising new approach for the clinical treatment of chronic diabetic wounds, offering a targeted and effective solution for this growing problem.
Assuntos
Diabetes Mellitus , Lipossomos , Ratos , Animais , Lipossomos/farmacologia , Cicatrização , Colágeno/farmacologia , Matriz ExtracelularRESUMO
The main objective of this study was aimed at tumor microenvironment-responsive vesicle for targeting delivery of the anticancer drug, doxorubicin (DOX). A glucolipid-like conjugate (CS) was synthesized by the chemical reaction between chitosan and stearic acid, and polyethylene glycol (PEG) was then conjugated with CS via a pH-responsive cis-aconityl linkage to produce acid-sensitive PEGylated CS conjugates (PCCS). The conjugates with a critical micelle concentration (CMC) of 181.8 µg/mL could form micelles in aqueous phase, and presented excellent DOX loading capacity with a drug encapsulation efficiency up to 87.6%. Moreover, the PCCS micelles showed a weakly acid-triggered PEG cleavage manner. In vitro drug release from DOX-loaded PCCS micelles indicated a relatively faster DOX release in weakly acidic environments (pH 5.0 and 6.5). The CS micelles had excellent cellular uptake ability, which could be significantly reduced by the PEGylation. However, the cellular uptake ability of PCCS was enhanced comparing with insensitive PEGylated CS (PCS) micelles in weakly acidic condition imitating tumor tissue. Taking PCS micelles as a comparative group, the PCCS drug delivery system was demonstrated to show much more accumulation in tumor tissue, followed by a relatively better performance in antitumor activity together with a security benefit on xenograft tumor model.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Glicolipídeos/administração & dosagem , Micelas , Neoplasias/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Animais , Antibióticos Antineoplásicos/química , Linhagem Celular Tumoral , Quitosana/química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Glicolipídeos/química , Glicolipídeos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/métodos , Neoplasias/metabolismo , Polietilenoglicóis/química , Ratos , Ácidos Esteáricos/químicaRESUMO
AIMS: We sought to describe quantitatively the distribution of rectally administered gels and seminal fluid surrogates using novel concentration-distance parameters that could be repeated over time. These methods are needed to develop rationally rectal microbicides to target and prevent HIV infection. METHODS: Eight subjects were dosed rectally with radiolabelled and gadolinium-labelled gels to simulate microbicide gel and seminal fluid. Rectal doses were given with and without simulated receptive anal intercourse. Twenty-four hour distribution was assessed with indirect single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and direct assessment via sigmoidoscopic brushes. Concentration-distance curves were generated using an algorithm for fitting SPECT data in three dimensions. Three novel concentration-distance parameters were defined to describe quantitatively the distribution of radiolabels: maximal distance (D(max) ), distance at maximal concentration (D(Cmax) ) and mean residence distance (D(ave) ). RESULTS: The SPECT/CT distribution of microbicide and semen surrogates was similar. Between 1 h and 24 h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (D(max) ), 10 cm (8.6-12) to 18 cm (13-26), distance at maximal concentration (D(Cmax) ), 3.8 cm (2.7-5.3) to 4.2 cm (2.8-6.3) and mean residence distance (D(ave) ), 4.3 cm (3.5-5.1) to 7.6 cm (5.3-11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT. CONCLUSIONS: Rectal microbicide surrogates migrated retrograde during the 24 h following dosing. Spatial kinetic parameters estimated using three dimensional curve fitting of distribution data should prove useful for evaluating rectal formulations of drugs for HIV prevention and other indications.