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BACKGROUND: Glioma is one of the deadliest human cancers. Although many therapeutic strategies for glioma have been explored, these strategies are seldom used in the clinic. The challenges facing the treatment of glioma not only involve the development of chemotherapeutic drugs and immunotherapeutic agents, but also the lack of a powerful platform that could deliver these two moieties to the targeted sites. Herein, we developed chemoimmunotherapy delivery vehicles based on C6 cell membranes and DC membranes to create hybrid membrane-coated DTX nanosuspensions (DNS-[C6&DC]m). RESULTS: Results demonstrated successful hybrid membrane fusion and nanosuspension functionalization, and DNS-[C6&DC]m could be used for different modes of anti-glioma therapy. For drug delivery, membrane coating could be applied to target the source cancer cells via a homotypic-targeting mechanism of the C6 cell membrane. For cancer immunotherapy, biomimetic nanosuspension enabled an immune response based on the professional antigen-presenting characteristic of the dendritic cell membrane (DCm), which carry the full array of cancer cell membrane antigens and facilitate the uptake of membrane-bound tumor antigens for efficient presentation and downstream immune n. CONCLUSION: DNS-[C6&DC]m is a multifunctional biomimetic nano-drug delivery system with the potential to treat gliomas through tumor-targeted drug delivery combined with immunotherapy, thereby presenting a promising approach that may be utilized for multiple modes of cancer therapy.
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Antineoplásicos , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Sistema de Administración de Fármacos con Nanopartículas , Nanopartículas , Animales , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Materiales Biomiméticos/química , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Membrana Celular/química , Membrana Celular/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Nanopartículas/química , Nanopartículas/metabolismo , Células RAW 264.7RESUMEN
Colchicine (COL), a widely used natural drug, has potent anti-inflammatory effects; however, as a narrow therapeutic index drug, its clinical application is limited by its serious gastrointestinal adverse effects, and only oral formulations are currently marketed worldwide. Recent studies have shown that transdermal, injection, and oral drug delivery are the three main delivery strategies for COL. This article elaborates on the research progress of different delivery strategies in terms of toxicity reduction and efficacy enhancement, depicting that the transdermal drug delivery route can avoid the first-pass effect and the traumatic pain associated with the oral and injection routes, respectively. Therefore, such a dosage form holds a significant promise that requires the development of further research to investigate effective COL delivery formulations. In addition, the permeation-promoting technologies utilized for transdermal drug delivery systems are briefly discussed. This article is expected to provide scientific ideas and theoretical guidance for future research and the exploration of COL delivery strategies.
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Gout is one of the most prevalent rheumatic diseases, globally. Colchicine (COL) is the first-line drug used for the treatment of acute gout. However, the oral administration of COL is restricted, owing to serious adverse reactions. Therefore, this study aimed to develop a drug-in-adhesive (DIA) patch to achieve transdermal delivery of COL. We investigated the solubility of COL in different pressure-sensitive adhesives (PSAs) using slide crystallization studies. The COL-DIA patches were optimized based on in vitro skin penetration studies and evaluated by in vivo pharmacokinetics and pharmacodynamics. The results showed that the optimized COL-DIA patch contained 10% COL, Duro-Tak 87-2516 as PSA, 5% oleic acid (OA) and 5% propylene glycol (PG) as permeation enhancer, exhibiting the highest in vitro cumulative penetration amount of COL (235.14 ± 14.47 µgâcm-2 over 48 h). Pharmacokinetic studies demonstrated that the maximum plasma drug concentration (Cmax) was 2.65 ± 0.26 ng/L and the mean retention time (MRT) was 37.47 ± 7.64 h of the COL-DIA patch, effectively reducing the drug side effects and prolonging drug activity. In addition, pharmacodynamic studies showed the patch significantly decreased the expression levels of inflammatory factors of gouty rats and reduced pathological damage in the ankle joint of rats, making it an attractive alternative to the administration of COL for the treatment of gout.
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Recent studies have demonstrated that ivermectin (IVM) exhibits antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19). However, the repurposing of IVM for the treatment of COVID-19 has presented challenges primarily due to the low IVM plasma concentration after oral administration, which was well below IC50. Here, a red blood cell (RBC)-hitchhiking strategy was used for the targeted delivery of IVM-loaded nanoparticles (NPs) to the lung. IVM-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (IVM-PNPs) and chitosan-coating IVM-PNPs (IVM-CSPNPs) were prepared and adsorbed onto RBCs. Both RBC-hitchhiked IVM-PNPs and IVM-CSPNPs could significantly enhance IVM delivery to lungs, improve IVM accumulation in lung tissue, inhibit the inflammatory responses and finally significantly alleviate the progression of acute lung injury. Specifically, the redistribution and circulation effects were related to the properties of NPs. RBC-hitchhiked cationic IVM-CSPNPs showed a longer circulation time, slower accumulation and elimination rates, and higher anti-inflammatory activities than RBC-hitchhiked anionic IVM-PNPs. Therefore, RBC-hitchhiking provides an alternative strategy to improve IVM pharmacokinetics and bioavailability for repurposing of IVM to treat COVID-19. Furthermore, according to different redistribution effects of different NPs, RBC-hitchhiked NPs may achieve various accumulation rates and circulation times for different requirements of drug delivery.
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Tratamiento Farmacológico de COVID-19 , Nanopartículas , Eritrocitos , Humanos , Ivermectina , Pulmón , SARS-CoV-2RESUMEN
Chromium poisoning has become one of the most common heavy metal poisoning occupational diseases with high morbidity and mortality. However, most antidotes detoxify the whole body and are highly toxic. To achieve hepato-targeted chromium poisoning detoxification, a novel hepato-targeted strategy was developed using aging erythrocyte membranes (AEMs) as biomimetic material coated with a dimercaptosuccinic acid (DMSA) nanostructured lipid carrier to construct a biomimetic nano-drug delivery system. The particle size, potential, drug loading, encapsulation rate, in vitro release, and stability of the nanoparticles (NPs) were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be phagocytized by RAW264.7 macrophage cells. The efficacy of AEM-DMSA-NPs for targeted liver detoxification was evaluated by in vitro MTT analysis and an in vivo model of chromium poisoning. The results showed that the NPs could safely and efficiently achieve targeted liver chromium poisoning detoxification. All the results indicated that the biomimetic nano-drug delivery system mediated by aging erythrocyte membranes and containing DMSA nanoparticles could be used as a novel therapeutic drug delivery system potentially targeting liver detoxification.
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Antídotos/farmacología , Materiales Biomiméticos/metabolismo , Cromo/envenenamiento , Membrana Eritrocítica/metabolismo , Nanopartículas/química , Succímero/farmacología , Animales , Antídotos/administración & dosificación , Antídotos/farmacocinética , Química Farmacéutica , Portadores de Fármacos , Liberación de Fármacos , Hígado/efectos de los fármacos , Masculino , Ratones , Tamaño de la Partícula , Células RAW 264.7 , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Succímero/administración & dosificación , Succímero/farmacocinéticaRESUMEN
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. It has been reported that microRNAs (miRs) play important roles in the progression and development of HCC. The expression of miR-490-3p has been shown to be downregulated in HCC tissues. Therefore, the present study aimed to investigate the effects of miR-490-3p on HCC cells and the underlying mechanism. Cell Counting Kit-8, flow cytometry, and Transwell migration and invasion assays were performed to determine the viability, apoptosis, migration and invasion of HCC cells, respectively. Furthermore, a luciferase activity assay was used to verify the association between miR-490-3p and its predicted target tropomodulin 3 (TMOD3). In addition, the protein levels of Bax, Bcl-2, cleaved caspase-3, TMOD3, phosphorylated (p)-p38 and p-ERK in HCC cells were detected using western blot analysis. The results demonstrated that the overexpression of miR-490-3p via transfection with miR-490-3p mimics significantly inhibited the proliferation of Huh-7 and HEP 3B2.1-7 cells. In addition, overexpression of miR-490-3p markedly suppressed the migration and invasion abilities of Huh-7 cells. miR-490-3p mimics significantly induced liver cancer cell apoptosis via upregulating Bax and cleaved caspase-3 and downregulating anti-apoptotic protein Bcl-2. Additionally, a luciferase activity assay indicated that TMOD3 is a downstream target gene of miR-490-3p. The protein levels of TMOD3, p-p38 and p-ERK were significantly downregulated in Huh-7 cells following transfection with miR-490-3p mimics, and the overexpression of TMOD3 attenuated these effects. In conclusion, the aforementioned results suggest that the overexpression of miR-490-3p inhibited the proliferation and invasion of HCC cells by targeting TMOD3. Therefore, the miR-490-3p/TMOD3 axis may be a potent target for the treatment of HCC.
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BACKGROUND: The aim of this paper was to observe the efficacy of combination therapy of laparoscopic left hepatectomy and choledochoscopy for calculus of left intrahepatic duct. METHODS: We retrospectively analyzed the clinical data of 76 patients with calculus of left intrahepatic duct who were admitted and diagnosed in this hospital between August 2014 and August 2015. Patients who received the laparotomy for treatment were enrolled into the control group (N.=32), and those who received the combination therapy of laparoscopic left hepatectomy and choledochoscopy were enrolled into the study group (N.=44). The surgical efficacy and the occurrence of surgery complications were compared between the two groups, and the recurrence of calculus was observed in follow-up after the operation. RESULTS: Comparison of the surgical duration showed no statistically significant difference between the two groups (P>0.05); bleeding amount, evacuation time and length of stay in the study group were less or shorter than those in the control group (P<0.05); the overall incidence rate of surgery complications in the study group was 9.10%, which was lower than the overall incidence rate of surgery complications, 43.75%, in the control group (P<0.05). No statistically significant differences were identified in the comparisons of the levels of albumin (ALB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at 1d before and 10d after operation, hospitalization expenses, and operation fee between the two groups (P>0.05). The average duration of follow-up after operation was 12 months, during which 2 patients in the control group were found with a calculus in a diameter of 0.4 cm in the left intrahepatic duct which was later removed using choledochoscopy followed by the extraction of T duct, and the conditions of patient were well-controlled; no recurrence of calculus was observed in the study group. CONCLUSIONS: Combination therapy of laparoscopic left hepatectomy and choledochoscopy is worth being promoted in clinical practice of treatment for calculus of intrahepatic duct with various advantages, such as significant effect, small trauma, high safety and reliability, rapid recovery after operation and few recurrences.
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Conductos Biliares Intrahepáticos/cirugía , Colelitiasis/cirugía , Endoscopía del Sistema Digestivo/métodos , Hepatectomía/métodos , Laparoscopía/métodos , Adulto , Anciano , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Estudios de Casos y Controles , Colelitiasis/sangre , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Endoscopía del Sistema Digestivo/efectos adversos , Estudios de Factibilidad , Femenino , Hepatectomía/efectos adversos , Humanos , Incidencia , Laparoscopía/efectos adversos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Tempo Operativo , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Seguridad , Albúmina Sérica/análisis , Resultado del Tratamiento , Adulto JovenRESUMEN
Phase-separated films of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) can be utilized to tailor drug release from coated pellets. In the present study, the effects of HPC levels and the pH, type, ionic strength and osmolarity of the media on the release profiles of soluble metoprolol succinates from the EC/HPC-coated pellets were investigated, and the differences in drug-release kinetics in multiple media were further elucidated through the HPC leaching and swelling kinetics of the pellets, morphology (SEM) and water uptake of the free films and the interaction between the coating polymers and the media compositions. Interestingly, the drug release rate from the pellets in different media was not in agreement with the drug solubility which have a positive correlation with the drug dissolution rate based on Noyesâ»Whitney equation law. In particular, the drug release rate in acetate buffer at pH 4.5 was faster than that in other media despite the solubility of drug was relatively lower, regardless of the HPC levels. It may be attributed to the mutual effect between the EC and acetate buffer, which improved the permeability of the film. In contrast, the release of drug in HCl solution was dependent on the HPC levels. Increasing the levels of HPC increased the effects of hydrogen ions on the polymer of HPC, which resulted in a lower viscosity and strength of the gel, forming the larger size of pores in polymer films, thus increasing the drug diffused from the coating film. Further findings in phosphate buffer showed a reduction in the drug release compared to that in other media, which was only sensitive to the osmolarity rather than the HPC level and pH of the buffer. Additionally, a mathematical theory was used to better explain and understand the experimentally measured different drug release patterns. In summary, the study revealed that the effects of the media overcompensated that of the drug solubility to some extent for controlled-release of the coating polymers, and the drug release mechanism in multiple media depend on EC and HPC rather than on HPC alone, which may have a potential to facilitate the optimization of ideally film-coated formulations.