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OBJECTIVE: Endovascular thrombectomy (EVT) in patients with large infarct volume remains controversial. The aim of this study is to compare clinical outcomes between EVT and medical management in acute large vessel occlusion with infarct volumes larger than 70 mL on diffusion-weighted magnetic resonance imaging (DWI). METHODS: A prospective observational cohort study was conducted, including patients with anterior cerebral circulation occlusion due to ischemic stroke with infarct volumes larger than 70 mL within 24 h of onset between July 2018 and June 2023. Eligible patients were divided into two groups: the EVT group and the medical management (non-EVT) group. The main outcomes were functional independence and mortality at 90 days. To assess clinical endpoints, we selected variables including age, NIHSS score, infarct volume, and occlusion location for 1:1 propensity score (PS) matching and PS adjustment using inverse probability of treatment weighting (IPTW). RESULTS: Among the 131 identified patients (mean [SD] age, 69.9 [13.7] years; 58 female), the median infarct volume was 123.6 mL. Of these patients, 75 (57.3%) underwent EVT. After PS adjustment, EVT was not associated with functional independence (10.9% vs. 10.9%; p = 1.000) or mortality (43.5% vs. 47.8%; p = 0.675). Additionally, after PS adjustment using IPTW, EVT was also not associated with a functional independence (15.8% vs. 13.7%; p = 0.767) or mortality (46.8% vs. 44.0%; p = 0.762). CONCLUSION: This study provides real-world evidence regarding infarct volumes larger than 70 mL, indicating that EVT does not provide benefits compared to medical management alone when considering age, NIHSS score, infarct volume, and occlusion location.
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Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Trombectomía , Humanos , Femenino , Masculino , Trombectomía/métodos , Anciano , Persona de Mediana Edad , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Anciano de 80 o más Años , Estudios Prospectivos , Evaluación de Resultado en la Atención de Salud , Resultado del TratamientoRESUMEN
PURPOSE: The objective of this study was to evaluate the relationship between arterial transit artifact (ATA), arterial spin labeling (ASL) perfusion imaging, and the outcome of patients with acute ischemic stroke (AIS) due to occlusion of large vessels in anterior circulation after endovascular thrombectomy (EVT). METHODS: Patients with anterior circulation occlusion treated with EVT between October 2017 and December 2021 were enrolled in this retrospective study, and ATA was quantified by a 4-point scale. A favorable outcome was defined by modified Rankin Scale (mRS) scores of 0-2 at 3 months. To identify independent predictors of favorable outcome, age, sex, risk factors, baseline National Institutes of Health Stroke Scale (NIHSS) score, site of occlusion, cause of stroke, and early reperfusion were evaluated with univariate and multivariate analyses. Predictive accuracy was evaluated by calculating the area under the receiver operating characteristic (ROC) curve (AUC) for the model. RESULTS: In this study 187 patients (age, 65.0⯱ 12.5 years; men, 55%) were evaluated. Younger age (odds ratio, OR, 0.95; 95% confidence interval, CI, 0.92-0.98, pâ¯= 0.002), lower baseline NIHSS score (OR, 0.88; 95% CI, 0.82-0.94, pâ¯< 0.001), and lower ATA score (OR, 1.14; 95% CI, 1.06-1.22, pâ¯< 0.001) were independently associated with favorable outcomes in multivariate analysis. The ATA score has moderate to good accuracy in predicting favorable outcomes (AUC, 0.753). CONCLUSION: A high ATA score as a potential predictor, can help identify patients who may benefit from EVT.
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Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Masculino , Humanos , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/cirugía , Accidente Cerebrovascular Isquémico/etiología , Resultado del Tratamiento , Estudios Retrospectivos , Artefactos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/cirugía , Accidente Cerebrovascular/etiología , Trombectomía/métodos , Procedimientos Endovasculares/métodos , Isquemia Encefálica/etiologíaRESUMEN
Droplet impact behaviors are crucial in controlling infectious diseases, inkjet printing, and anti-icing applications. The wettability and microstructure of the material surface are critical factors in this regard. Compared to microstructures, submillimeter structures are more damage-resistant, thereby ensuring droplet impact behaviors' stability. Herein, submillimeter-structured PDMS surfaces with varying wetting properties were prepared to investigate droplet impact behaviors. Experimental results indicate that submillimeter-structured surfaces are more prone to droplet splashing than flat surfaces, which can be suppressed by increasing surface hydrophilicity. An increase in the submillimeter pillar height and a decrease in spacing result in an increased critical Weber number. Additionally, the capillary forces of the superhydrophilic surface lead to droplet impact, accompanied by deposition. This study supports the long-term stable use of the droplet impact effect to achieve fluid separation.
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INTRODUCTION: Based on real-world case data, this study intends to explore and analyze the impact of rescue conscious sedation (CS) on the clinical outcomes of patients with anterior circulation acute ischemic stroke (AIS) receiving mechanical thrombectomy (MT). METHODS: This retrospective study enrolled patients with anterior circulation AIS who received MT and were treated with either single local anesthesia (LA) or rescue CS during MT between January 2018 and October 2021. We used univariate and multivariate logistic regression methods to compare the impact of LA and CS on the clinical outcomes of patients with AIS who received MT, including the mRS at 90 days, the incidence of poststroke pneumonia (PSP), the incidence of symptomatic intracranial cerebral hemorrhage (sICH), and the mortality rate. RESULTS: We reviewed 314 patient cases with AIS who received MT. Of all patients, 164 met our search criteria. Eighty-nine patients received LA, and 75 patients received rescue CS. There was no significant difference between the two groups in the 90-day good prognosis (45.3% vs. 51.7%, p = 0.418) and mortality (17.3% vs. 22.5%, p = 0.414). Compared with the LA group, the incidence of postoperative pneumonia in the rescue CS group (44% vs. 25.8%, p = 0.015) was more significant. Multivariate stepwise logistic regression analysis revealed that intraoperative remedial CS was independently associated with PSP following MT. In a subgroup analysis, rescue CS was found to significantly increase the incidence of PSP in patients with dysphagia (OR = 7.307, 95% CI 2.144-24.906, p = 0.001). As the severity of the National Institutes of Health Stroke Scale (NIHSS) increased, intraoperative rescue CS was found to increase the risk of PSP (OR = 1.155, 95% CI 1.034-1.290, p = 0.011) by 5.1% compared to that of LA (OR = 1.104, 95% CI 1.013-1.204, p = 0.024). CONCLUSION: Compared to LA, rescue CS during MT does not significantly improve the 90 days of good prognosis and reduce the incidence of sICH and mortality in patients with anterior circulation AIS. However, it has a significantly increased risk of poststroke pneumonia (PSP), particularly in patients with dysphagia.
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Recently, laser polishing, as an effective post-treatment technology for metal parts fabricated by laser powder bed fusion (LPBF), has received much attention. In this paper, LPBF-ed 316L stainless steel samples were polished by three different types of lasers. The effect of laser pulse width on surface morphology and corrosion resistance was investigated. The experimental results show that, compared to the nanosecond (NS) and femtosecond (FS) lasers, the surface material's sufficient remelting realized by the continuous wave (CW) laser results in a significant improvement in roughness. The surface hardness is increased and the corrosion resistance is the best. The microcracks on the NS laser-polished surface lead to a decrease in the microhardness and corrosion resistance. The FS laser does not significantly improve surface roughness. The ultrafast laser-induced micro-nanostructures increase the contact area of the electrochemical reaction, resulting in a decrease in corrosion resistance.
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OBJECTIVE: The prognosis for patients presenting with a large ischemic core (LIC) following endovascular thrombectomy is relatively poor. This study aimed to construct and validate a nomogram for predicting 3-month unfavorable outcome in patients with anterior circulation occlusion-related LIC who underwent endovascular thrombectomy. METHODS: A retrospective training cohort and a prospective validation cohort of patients with a large ischemic core were studied. The diffusion weighted imaging related radiomic features and pre-thrombectomy clinical features were collected. After the selection of relevant features, a nomogram predicting modified Rankin Scale score of 3-6 as an unfavorable outcome was established. The discriminatory value of the nomogram was evaluated with a receiver operating characteristic curve. RESULTS: A total of 140 patients (mean age 66.3 ± 13.4 years, 35% female) were included in this study, consisting of a training cohort (n = 95) and a validation cohort (n = 45). The percentage of patients with an mRS scores of 0-2 was 30%, 0-3 was 40.7%, and 32.9% were dead. Age, National Institute of Health Stroke Scale (NIHSS) score, and two radiomic features, Maximum2DDiameterColumn and Maximum2DDiameterSlice, were identified as factors associated with unfavorable outcome in the nomogram. The nomogram demonstrated an area under the curve of 0.892 (95% confidence interval [CI], 0.812-0.947) in the training dataset and 0.872 (95% CI, 0.739-0.953) in the validation dataset. INTERPRETATION: This nomogram, which includes age, NIHSS score, Maximum2DDiameterColumn, and Maximum2DDiameterSlice, may predict the risk of unfavorable outcome in patients with LIC caused by anterior circulation occlusion.
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Imagen de Difusión por Resonancia Magnética , Nomogramas , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Estudios Retrospectivos , Curva ROC , Trombectomía/efectos adversosRESUMEN
Background and purpose: Distinguishing between intracranial atherosclerosis-related occlusion (ICAS-O) and non-ICAS-O can benefit strategies of identifying the need for surgical plans prior to thrombectomy. We investigated the association between vertebrobasilar artery calcification (VBAC) and ICAS-O in acute ischemic stroke patients undergoing thrombectomy. Methods: Patients were recruited from a prospective single-center registration study who had undergone thrombectomy between October 2017 and October 2021. The enrolled patients were divided into ICAS-O and non-ICAS-O, as determined by the intraarterial therapy process. The occurrences of VBAC were recorded on intracranial non-contrast computed tomography (NCCT) scans before thrombectomy. The association between VBAC and ICAS-O was assessed using binary logistic regression. Results: A total of 2732 patients who had undergone digital subtraction angiography were reviewed, and 314 thrombectomy patients (mean age: 65.4 years, 36.6% female) with NCCT were enrolled in this study. VBAC was detected before thrombectomy in 113 (36%) out of 314 patients. Age, hypertension, and diabetes were associated with VBAC, and a higher frequency of VBAC was identified in patients presenting posterior circulation. ICAS-O accounts for 43% (135/314) in eligible patients. From multivariable analyses, VBAC was identified as an independent predictor of ICAS-O (adjusted odds ratio, 6.16 [95% CI, 2.673-14.217], P < 0.001). Meanwhile, the (VBAC[+] atrial fibrillation[-]) group displayed higher rates of ICAS-O than the (VBAC[-] atrial fibrillation [-]) group (P < 0.001). Conclusions: We demonstrated that VBAC is an independent risk factor for ICAS-O in patients who underwent thrombectomy. Patients free of atrial fibrillation with VBAC have more trend to be ICAS-O.
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Background and Purpose: This study aimed to analyze the association between hyperattenuated lesions (HALs) and postoperative intracranial hemorrhage (IH) and predict perioperative IH through quantitative analysis of HALs in acute ischemic stroke (AIS) with anterior large vessel occlusion (LVO) after endovascular therapy (ET). Materials and Methods: This retrospective, propensity-matched study enrolled AIS who received ET from a single-center registry study between August 2017 and May 2020. The enrolled patients were divided into two groups: IH and non-IH, by follow-up postoperative CT. The occurrences of HALs on immediate CT after ET were also recorded. The association between IH and HALs after propensity score matching (PSM) was determined by binary logistic regression models. The receiver operating characteristic (ROC) curve was used to determine the predictive value of the highest CT Hounsfield units (HU) value on immediate CT. Results: Initially, 1,418 patients who underwent digital subtraction angiography were reviewed and 114 AIS patients with immediate postoperative CT and follow-up CT after ET were enrolled. Forty-nine out of the 114 patients developed IH after therapy. After PSM analysis, patients with IH were more likely to have HALs on immediate CT (Odds Ratio, OR 11.9, P = 0.002, and 95% CI: 2.485-57.284). For 80 patients with HALs, ROC analysis of the highest CT value in the HALs territory showed that the cut-off value was 97 HU, the sensitivity was 70.21%, and the specificity was 81.82%. Conclusions: Patients with HALs after ET are more likely to have perioperative IH. The highest CT value in the HALs area might be used to predict IH.
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In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as lack of potency of tumor penetration. In this work, we developed actively tumor-targeting micelles with pH-sensitive linker as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable poly(ethylene glycol)-poly(aspartate) polymers, in which paclitaxel can be covalently conjugated to pAsp via an acid-labile acetal bond to form pH-responsive structures. In vitro drug release studies showed that these structures were stable in physiological condition, whereas collapsed once internalized into cells due to the mildly acidic environment in endo/lysosomes, resulting in facilitated intracellular paclitaxel release. In addition, dehydroascorbic acid and guanidinopropyl methacrylamide polymers were decorated on the surface of micelles to achieve specific tumor accumulation and tumor penetration. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.
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Acrilamidas/química , Ácido Aspártico/química , Ácido Deshidroascórbico/química , Polietilenglicoles/química , Polímeros/química , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Ratones Desnudos , Micelas , Paclitaxel/química , Paclitaxel/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
With Two-photon absorption laser-induced fluorescence(TALIF) technology, leads pulse laser in pure high-enthply flow field from the direction of perpendicular to flow field, and obtains the two-dimension atom O fluorescent signal with ICCD setting outside of test section on the vertical direction of flat made with flow field and laser, this signal reflects the relative concentration of atom O. In paper, given the experimental environment and experimental equipment, to ensure that excitation laser wavelength in experiment is the best one, different angular quantum number on ground state of atom O are tested; finally, it is determined that J=2, wavelength 225.584 nm shall be experimental excitation laser wavelength. To make sure that the obtaining atom O fluorescent signal is in unsaturated linear region, in same condition, changing the excitation laser energy from small to large to test fluorescent signal, ultimately acquiring laser energy linear region is below 3.4 mJ. To record ICCD fluorescent image clearly with optimum contrast, Nikon f=105 mm F/2.8 lens is chosen as experimental lens, and the results are got with an accumulation of 50 times exposure. By analyzing the experimental fluorescent signal, we can get two peak positions on left and right of central line about ±50 mm wide which are generated with compressional wave in supersonic flow field, and atom O concentration has 60 mm wide uniform area in central zone of subsonic flow field, the concentration decreases dramatically. This phenomenon is consistent with flow characteristics of wind tunnel, so the method can be applied to flow parameters measurement in the future.
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Compared with peripheral tumors, glioma is very difficult to treat, not only because it has general features of tumor but also because the therapy has been restricted by the brain-blood barrier (BBB). The two main features of tumor growth are angiogenesis and proliferation of tumor cells. RNA interference (RNAi) can downregulate VEGF overexpression to inhibit tumor neovascularization. Meanwhile, doxorubicin (DOX) has been used for cytotoxic chemotherapy to kill tumor cells. Thus, combining RNAi and chemotherapy has been regarded as a potential strategy for cancer treatment. However, the BBB limits the shVEGF-DOX codelivery system to direct into glioma. Here, a smart drug delivery system modified with a dual functional peptide was established, which could target to transferrin receptor (TfR) overexpressing on both the BBB and glioma. It showed that the dual-targeting delivery system had high tumor targeting efficiency in vitro and in vivo.
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Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Nanopartículas/administración & dosificación , Péptidos/administración & dosificación , Animales , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Glioma/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Interferencia de ARN/efectos de los fármacos , Receptores de Transferrina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Multifunctional nanocarriers are increasingly promising for disease treatment aimed to regulate multiple pathological dysfunctions and overcome barriers in drug delivery. Here we develop a multifunctional nanocarrier for Alzheimer's disease (AD) treatment by achieving therapeutic gene and peptide co-delivery to brain based on PEGylated dendrigraft poly-l-lysines (DGLs) via systemic administration. The dendritic amine-rich structure of DGLs provides plenty reaction sites and positive charge for drug loading. Successful co-delivery of drugs overcoming the blood-brain barrier by brain-targeted ligand modification was demonstrated both in vitro and in vivo. The pharmacodynamics study of the system following multiple-dosing treatment was verified in transgenic AD mice. Down-regulation of the key enzyme in amyloid-ß formation was achieved by delivering non-coding RNA plasmid. Simultaneous delivery of the therapeutic peptide into brain leads to reduction of neurofibrillary tangles. Meanwhile, memory loss rescue in AD mice was also observed. Taken together, the multifunctional nanocarrier provides an excellent drug co-delivery platform for brain diseases.
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Enfermedad de Alzheimer/terapia , Encéfalo/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Técnicas de Transferencia de Gen , Nanopartículas/química , Péptidos/uso terapéutico , Plásmidos/uso terapéutico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Péptidos beta-Amiloides/metabolismo , Animales , Secuencia de Bases , Encéfalo/metabolismo , Encéfalo/patología , Portadores de Fármacos/química , Terapia Genética , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Péptidos/administración & dosificación , Péptidos/química , Péptidos/farmacocinética , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Plásmidos/administración & dosificación , Plásmidos/genética , Plásmidos/farmacocinética , Polietilenglicoles/química , Polilisina/análogos & derivados , Polilisina/química , ARN no Traducido/genéticaRESUMEN
Ligand-mediated polymeric micelles have enormous potential for improving the efficacy of glioma therapy. Linear-dendritic drug-polymer conjugates composed of doxorubicin (DOX) and polyethylene glycol (PEG) were synthesized with or without modification of choline derivate (CD). The resulting MeO-PEG-DOX8 and CD-PEG-DOX8 could self-assemble into polymeric micelles with a nanosized diameter around 30 nm and a high drug loading content up to 40.6 and 32.3%, respectively. The optimized formulation 20% CD-PEG-DOX8 micelles had superior cellular uptake and antitumor activity against MeO-PEG-DOX8 micelles. The subcellular distribution using confocal study revealed that 20% CD-PEG-DOX8 micelles preferentially accumulated in the mitochondria. Pharmacokinetic study showed area under the plasma concentration-time curve (AUC0-t) and Cmax for 20% CD-PEG-DOX8 micelles and DOX solution were 1336.58 ± 179.43 mg/L·h, 96.35 ± 3.32 mg/L and 1.40 ± 0.19 mg/L·h, 1.15 ± 0.25 mg/L, respectively. Biodistribution study showed the DOX concentration of 20% CD-PEG-DOX8 micelles treated group at 48 h was 2.37-fold higher than that of MeO-PEG-DOX8 micelles treated group at 48 h and was 24 fold-higher than that of DOX solution treated group at 24 h. CD-PEG-DOX8 micelles (20%) were well tolerated with reduced cardiotoxicity, as evaluated in the body weight change and HE staining studies, while they induced most significant antitumor activity with longest media survival time in an orthotopic mouse model of U87-luci glioblastoma model as displayed in the bioluminescence imaging and survival curve studies. Our findings consequently indicated that 20% CD-PEG-DOX8 micelles are promising drug delivery system for glioma chemotherapy.
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Neoplasias Encefálicas/tratamiento farmacológico , Colina/química , Glioma/tratamiento farmacológico , Micelas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Citometría de Flujo , Humanos , Ratones , Polietilenglicoles/química , Espectroscopía de Protones por Resonancia Magnética , Ratas Sprague-Dawley , Fracciones Subcelulares/metabolismo , Distribución Tisular/efectos de los fármacosRESUMEN
Existing limitations of common RNA interference (RNAi) oncotherapy severely compromised their therapeutic effects. In this study, a novel glioma-targeting RNAi system was developed. Single-component RNAi nanospheres were tactfully self-assembled in vitro, combining the carrier and cargo as a whole. An artificially synthesized polycation (pOEI) with redox-sensitive disulfides in structure condensed the RNAi nanospheres into more compacted nanoparticles. Then a novelly designed tumor-homing and penetrating cyclopeptide iNGR was further modified on the surface. iNGR modified RNAi nanoparticles demonstrated significantly enhanced accumulation in glioma site, remaining stable in circulation until the release of naked RNAi nanospheres were triggered off by the paranormal concentration of glutathione within glioma cells. Naked RNAi nanospheres were digested into abudant siRNA afterwards. Remarkable luciferase gene down-regulations have confirmed their outstanding RNAi effects. With specific design of sequences, the iNGR modified RNAi nanoparticles were supposed to be of great potential in safe and efficient glioma therapy in future.
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Neoplasias Encefálicas/terapia , Glioma/terapia , Nanopartículas , Oligopéptidos/química , Interferencia de ARN , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Oxidación-ReducciónRESUMEN
A new linear-dendritic copolymer composed of poly(ethylene glycol) (PEG) and all-trans-retinoic acid (ATRA) was synthesized as the anticancer drug delivery platform (PEG-G3-RA8). It can self-assemble into core-shell micelles with a low critical micelle concentration (CMC) at 3.48 mg/L. Paclitaxel (PTX) was encapsulated into PEG-G3-RA8 to form PEG-G3-RA8/PTX micelles for breast cancer treatment. The optimized formulation had high drug loading efficacy (20% w/w of drug copolymer ratio), nanosized diameter (27.6 nm), and narrow distribution (PDI = 0.103). Compared with Taxol, PEG-G3-RA8/PTX remained highly stable in the serum-containing cell medium and exhibited 4-fold higher cellular uptake. Besides, near-infrared fluorescence (NIR) optical imaging results indicated that fluorescent probe loaded micelle had a preferential accumulation in breast tumors. Pharmacokinetics and biodistribution studies (10 mg/kg) showed the area under the plasma concentration-time curve (AUC0-∞) and mean residence time (MRT0-∞) for PEG-G3-RA8/PTX and Taxol were 12.006 ± 0.605 mg/L h, 2.264 ± 0.041 h and 15.966 ± 1.614 mg/L h, 1.726 ± 0.097 h, respectively. The tumor accumulation of PEG-G3-RA8/PTX group was 1.89-fold higher than that of Taxol group 24 h postinjection. With the advantages like efficient cellular uptake and preferential tumor accumulation, PEG-G3-RA8/PTX showed superior therapeutic efficacy on MCF-7 tumor bearing mice compared to Taxol.
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Neoplasias de la Mama , Dendrímeros/química , Sistemas de Liberación de Medicamentos/métodos , Paclitaxel/química , Polietilenglicoles/química , Tretinoina/química , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Dendrímeros/administración & dosificación , Dendrímeros/metabolismo , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Paclitaxel/administración & dosificación , Paclitaxel/metabolismo , Polietilenglicoles/administración & dosificación , Polietilenglicoles/metabolismo , Ratas , Tretinoina/administración & dosificación , Tretinoina/metabolismoRESUMEN
In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as their serious systemic toxicity. In this work, we developed actively tumor-targeting trilayer micelles with microenvironment-sensitive cross-links as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable PEG-pLys-pPhe polymers, in which pLys could react with a disulfide-containing agent to form redox-responsive cross-links. In vitro drug release and pharmacokinetics studies showed that these cross-links were stable in physiological condition whereas cleaved once internalized into cells due to the high level of glutathione, resulting in facilitated intracellular doxorubicin release. In addition, dehydroascorbic acid (DHAA) was decorated on the surface of micelles for specific recognition of tumor cells via GLUT1, a member of glucose transporter family overexpressed on hepatocarcinoma cells. Moreover, DHAA exhibited a "one-way" continuous accumulation within tumor cells. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.
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Antineoplásicos/química , Portadores de Fármacos/química , Micelas , Nanoestructuras/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Ácido Deshidroascórbico/química , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Transportador de Glucosa de Tipo 1/antagonistas & inhibidores , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Polietilenglicoles/química , Polímeros/síntesis química , Polímeros/química , Ratas , Ratas Wistar , Espectroscopía Infrarroja Corta , Distribución Tisular , Trasplante Heterólogo , UltrasonografíaRESUMEN
Achieving effective gene therapy for glioma depends on gene delivery systems. The gene delivery system should be able to cross the blood-brain barrier (BBB) and further target glioma at its early stage. Active brain tumor targeted delivery can be achieved using the "Trojan horse" technology, which involves either endogenous ligands or extraneous substances that can recognize and bind to specific receptors in target sites. This method facilitates receptor-mediated endocytosis to cross the BBB and enter into glioma cells. Dendrigraft poly-l-lysines (DGLs), which are novel nonviral gene vectors, are conjugated to a peptide (sequence: EPRNEEK) derived from Streptococcus pneumonia, a pathogen causing meningitis. This process yields peptide-modified nanoparticles (NPs) after DNA loading. Cellular uptake and in vivo imaging results indicate that EPRNEEK peptide-modified NPs have a better brain tumor targeted effect compared with a pentapeptide derived from endogenous laminin after intravenous injection. The mechanism of this effect is further explored in the present study. Besides, EPRNEEK peptide-modified NPs also exhibited a prolonged median survival time. In conclusion, the EPRNEEK peptide-modified DGL NPs exhibit potential as a nonviral platform for efficient, noninvasive, and safe brain glioma dual-targeted gene delivery.
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Nanopartículas/química , Péptidos/química , Streptococcus pneumoniae/química , Animales , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Células Cultivadas , Técnicas de Transferencia de Gen , Humanos , Lisina/química , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
Malignant glioma, a highly aggressive tumor, is one of the deadliest types of cancer associated with dismal outcome despite optimal chemotherapeutic regimens. One explanation for this is the failure of most chemotherapeutics to accumulate in the tumors, additionally causing serious side effects in periphery. To solve these problems, we sought to develop a smart therapeutic nanodevice with cooperative dual characteristics of high tumor-targeting ability and selectively controlling drug deposition in tumor cells. This nanodevice was fabricated with a cross-linker, containing disulfide linkage to form an inner cellular microenvironment-responsive "-S-S-" barrier, which could shield the entrapped drug leaking in blood circulation. In addition, dehydroascorbic acid (DHA), a novel small molecular tumor-specific vector, was decorated on the nanodevice for tumor-specific recognition via GLUT1, a glucose transporter highly expressed on tumor cells. The drug-loaded nanodevice was supposed to maintain high integrity in the bloodstream and increasingly to specifically bind with tumor cells through the association of DHA with GLUT1. Once within the tumor cells, the drug release was triggered by a high level of intracellular glutathione. When these two features were combined, the smart nanodevice could markedly improve the drug tumor-targeting delivery efficiency, meanwhile decreasing systemic toxicity. Herein, this smart nanodevice showed promising potential as a powerful platform for highly effective antiglioma treatment.
Asunto(s)
Neoplasias Encefálicas/terapia , Portadores de Fármacos , Glioma/terapia , Nanoestructuras , Microambiente Tumoral , Animales , Xenoinjertos , Humanos , RatonesRESUMEN
This paper introduces the experiment technology for measuring the radiation of high temperature gas in the high frequency plasma wind tunnel. The infrared radiation of carbon dioxide at high temperature has been measured using this technology. We introduced the principium, flow field and the working gas of the high frequency plasma wind tunnel. The experiment condition, equipment, method of data processing and the analyse of the experiment results were introduced. We had measured the infrared radiation of carbon dioxide at four different temperatures between 1500 and 3000 K using this technology for measuring the radiation of high temperature gas which had been developed by ourselves. Measuring the spatial distribution of the infrared radiation of carbon dioxide using Able-transform were also introduced. We have analyzed the emission spectrum at 4.3 µm of carbon dioxide at high temperature. The conclusion had been obtained that the center wavelength of the emission spectrum moved to the long wave when the temperature risen. The authors also had analyzed and contrasted the experiment results and the data obtained from literatures.
RESUMEN
Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-L-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood-brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system.