RESUMEN
Hepatocellular carcinoma (HCC) is a malignant tumor that affects many patients diagnosed with hepatic cell inflammation and liver cirrhosis. Targeted polymeric nanocapsules could facilitate the internalization and accumulation of anticancer drugs. Dual-targeted folic acid/lactobionic acid-poly lactic co-glycolic acid nanocapsules (NCs) were prepared and loaded with pterostilbene (PTN) and characterized for their physicochemical properties, as well as in vitro and in vivo anticancer activity. NCs displayed a size of 222 nm, zeta potential of - 16.5 mV, and sustained release for 48 h. The IC50 of PTN NCs (5.87 ± 0.8 µg/mL) was 20 times lower than unencapsulated PTN (121.26 ± 9.42 µg/mL) on HepG2 liver cancer cells owing to the enhanced cellular uptake of the former, as delineated by flow cytometry. In vivo study on HCC-induced animals delineated the superiority of the dual-targeted NCs over the unencapsulated PTN, which significantly reduced the liver markers ALT, AST, and ALP, as well as the tumor-related markers AFP and Bcl2, and elevated the anti-apoptotic marker caspase 3. Furthermore, the NCs significantly reduced the oxidative stress and exhibited almost comparable histological features to the normal group. Therefore, it can be concluded that the dual-ligated folic acid/lactobionic acid nanocapsules can be considered a promising potential treatment option for hepatocellular carcinoma.
Asunto(s)
Carcinoma Hepatocelular , Disacáridos , Neoplasias Hepáticas , Nanocápsulas , Animales , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Polímeros/uso terapéutico , Ácido Fólico , Línea Celular TumoralRESUMEN
Abnormal expression of acetylcholinesterase (AChE) causes Alzheimer's disease (AD). Inhibiting AChE is a common strategy for reducing the degradation of neurotransmitter acetylcholine, in order to treat early-stage AD. Therefore, it is crucial to screen and explore AChE inhibitors which are safer and cause fewer side effects. Our research is focused on establishing a platform of ruptured organosilica nanocapsules (RONs) immobilized AChE coupled with an MnO2-OPD colorimetric assay, which could monitor AChE activity and screen AChE inhibitors. The fabricated RONs immobilized AChE possessed excellent pH and thermal stability. Huperzine A was introduced into the established platform to evaluate the inhibition kinetics of the immobilized AChE, which promoted its application in the screening of AChE inhibitors. The satisfactory results of enzyme inhibition kinetics proved the feasibility and applicability of the established method. Thus, the proposed platform was applied to screen AChE inhibitors from 14 compounds isolated from Inula macrophylla, and ß-cyclocostunolide (compound 4) demonstrated the best AChE inhibitory activity among these compounds. This work confirms the existence of chemical components that inhibit AChE activity in Inula macrophylla, and provides a new idea for the application of immobilized enzyme-nanozyme in the field of enzyme inhibitor screening.
Asunto(s)
Enfermedad de Alzheimer , Inula , Nanocápsulas , Acetilcolinesterasa/química , Inula/metabolismo , Nanocápsulas/uso terapéutico , Compuestos de Manganeso , Óxidos , Inhibidores de la Colinesterasa/farmacología , Enfermedad de Alzheimer/tratamiento farmacológicoRESUMEN
The objective of this work was to develop an implantable therapeutic hydrogel that will ensure continuity in treatment between surgery and radiochemotherapy for patients with glioblastoma (GBM). A hydrogel of self-associated gemcitabine-loaded lipid nanocapsules (LNC) has shown therapeutic efficacy in vivo in murine GBM resection models. To improve the targeting of GBM cells, the NFL-TBS.40-63 peptide (NFL), was associated with LNC. The LNC-based hydrogels were formulated with the NFL. The peptide was totally and instantaneously adsorbed at the LNC surface, without modifying the hydrogel mechanical properties, and remained adsorbed to the LNC surface after the hydrogel dissolution. In vitro studies on GBM cell lines showed a faster internalization of the LNC and enhanced cytotoxicity, in the presence of NFL. Finally, in vivo studies in the murine GBM resection model proved that the gemcitabine-loaded LNC with adsorbed NFL could target the non-resected GBM cells and significantly delay or even inhibit the apparition of recurrences.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanocápsulas , Ratones , Humanos , Animales , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Hidrogeles/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Gemcitabina , Sistemas de Liberación de Medicamentos , Lípidos/química , Lípidos/uso terapéuticoRESUMEN
Inflammation and immune system activation are key pathologic events in the onset and escalation of diabetic retinopathy (DR). Both are driven by cytokines and complement originating from the retinal pigment epithelium (RPE). Despite the RPE's pivotal role, there is no therapeutic tool to specifically interfere with the RPE-related pathomechanism. A therapy that addresses RPE cells and counteracts inflammation and immune response would be of paramount value for the early treatment of DR, where currently are no specific therapies available. Here, we utilized lipoprotein-mimetic lipid nanocapsules to deliver the anti-inflammatory and immunosuppressive drug cyclosporin A (CsA) to RPE cells. Using a mouse model of DR that mirrors all pathologic aspects of human DR, we demonstrate that intravenously applied CsA-loaded lipid nanocapsules comprehensively counteract inflammation and immune system activation. One single injection suppressed the expression of pro-inflammatory cytokines, dampened macrophage infiltration, and prevented macrophage and microglia activation in eyes with DR. This work shows that CsA-loaded lipid nanocapsules can offer new avenues for the treatment of DR.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Nanocápsulas , Animales , Humanos , Retinopatía Diabética/tratamiento farmacológico , Ciclosporina/uso terapéutico , Nanocápsulas/uso terapéutico , Inyecciones Intravenosas , Inflamación/tratamiento farmacológico , Modelos Animales de Enfermedad , Citocinas , Sistema Inmunológico/metabolismo , Sistema Inmunológico/patología , Lípidos , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
OBJECTIVES: Curcumin has antioxidant and antiproliferative properties, and its therapeutic effect must be considered. Nanocurcumin capsules showed a potential increase against in vitro biological cancer. This study sought to determine how curcumin nanoparticles and nanocapsules affected the expression of p53, Bcl-2, Bax, and Bax in a liver cancer cell line (Hep-G2). Mechanisms of apoptosis were also examined in this cell line. METHODS: This study used quantitative real-time polymerase chain reaction (qRT-PCR) to analyze the p53, Bcl-2, Bax, and Caspase-3 gene pathways and to evaluate the molecular mechanisms responsible for the efficacy of curcumin nanoparticles (CNPs) and curcumin nanocapsules (CNCs) against liver cell lines. Flow cytometry was used to check for signs of apoptosis and the cell cycle. RESULTS: Curcumin nanocapsules produced by the ball milling process at 90 min significantly boosted the populations of apoptotic cells in a dose- and time-dependent manner. The mRNA expression analysis revealed that the proapoptotic Bax, Caspase-3, and the tumor suppressor gene p53 were upregulated throughout the process started by curcumin nanocapsules and decreased in the Bcl-2/Bax ratio. CONCLUSION: This research provides a fresh understanding of the molecular mechanisms behind the liver cancer-fighting abilities of curcumin nanoparticles. Curcumin nanocapsules produced through a unique mechanical technique can be used as an anticancer agent.
Asunto(s)
Curcumina , Neoplasias Hepáticas , Nanocápsulas , Humanos , Curcumina/farmacología , Nanocápsulas/uso terapéutico , Caspasa 3/genética , Caspasa 3/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ciclo Celular , Apoptosis/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Línea Celular , Expresión Génica , Línea Celular TumoralRESUMEN
Background: Gastric ulcer develops from imbalance of gastro-aggressive and protective factors. As existing drugs have adverse effects, use of natural products is in continuous expansion. In this study, we prepared nanoformulation with catechin and polylactide-co-glycolide to provide a sustained, controlled and targeted delivery. Materials & methods: Detailed characterization and toxicity study of nanoparticles were done on cells and Wistar rats. The comparative actions of free compound and nanocapsule were investigated in vitro and in vivo during treatment of gastric injury. Results: Nanocatechin improved bioavailability, reduced gastric damage at a significantly lower dose (2.5 mg/kg) by safeguarding from reactive oxygen species, restored mitochondrial integrity and downregulated MMP-9 and other inflammatory mediators. Conclusion: Nanocatechin is a better alternative for preventing and healing gastric ulcers.
Gastric ulcer, a chronic disease, has a widespread effect on the global populace. Side effects become an issue with available drugs, so natural products are getting acceptance. A promising nanodrug has been designed with catechin, the primary component of green tea, to offer enhanced potency at a lower dose. Toxicity and efficacy studies on laboratory rats have shown its suitability for biological use. In our experimental model of gastric ulcer in rats, nanocatechin was given as drug. It showed improved absorption and relatively fast healing without any adverse impacts. Molecular-level research demonstrated its role in restoring mitochondrial integrity. Thus, it may be an alternative choice for treating stomach ulcers in the clinical setting.
Asunto(s)
Catequina , Nanocápsulas , Úlcera Gástrica , Ratas , Animales , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/prevención & control , Nanocápsulas/uso terapéutico , Catequina/uso terapéutico , Ratas Wistar , Glicoles/uso terapéutico , Ácido LácticoRESUMEN
Demyelinating disorders, with a particular focus on multiple sclerosis (MS), have a multitude of detrimental cognitive and physical effects on the patients. Current treatment options that involve substances promoting remyelination fail in the clinics due to difficulties in reaching the central nervous system (CNS). Here, the dual encapsulation of retinoic acid (RA) into lipid nanocapsules with a nominal size of 70 nm, and a low PdI of 0.1, coupled with super paramagnetic iron oxide nanoparticles (SPIONs) was accomplished, and joined by an external functionalization process with a transferrin-receptor binding peptide. This nanosystem showed a 3-fold improved internalization by endothelial cells compared to the free drug, ability to interact with oligodendrocyte progenitor cells and microglia, and improvements in the permeability through the blood-brain barrier by 5-fold. The lipid nanocapsules also induced the differentiation of oligodendrocyte progenitor cells into more mature, myelin producing oligodendrocytes, as evaluated by high-throughput image screening, by 3-5-fold. Furthermore, the ability to tame the inflammatory response was verified in lipopolysaccharide-stimulated microglia, suppressing the production of pro-inflammatory cytokines by 50-70%. Overall, the results show that this nanosystem can act in both the inflammatory microenvironment present at the CNS of affected patients, but also stimulate the differentiation of new oligodendrocytes, paving the way for a promising platform in the therapy of MS.
Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple , Nanocápsulas , Enfermedades Neurodegenerativas , Animales , Ratones , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/metabolismo , Nanocápsulas/uso terapéutico , Tretinoina/farmacología , Células Endoteliales/metabolismo , Esclerosis Múltiple/tratamiento farmacológico , Vaina de Mielina , Inflamación/tratamiento farmacológico , Oligodendroglía , Diferenciación Celular , Enfermedades Neurodegenerativas/tratamiento farmacológico , Lípidos/farmacología , Ratones Endogámicos C57BLRESUMEN
Non-alcoholic fatty liver disease (NAFLD) affects approximately 25% of the global adult population and can progress to end-stage liver disease with life-threatening complications; however, no pharmacologic therapy has been approved. Drug delivery systems such as lipid nanocapsules (LNCs) are a very versatile platform, easy to produce, and can induce the secretion of the native glucagon-like peptide 1 (GLP-1) when orally administered. GLP-1 analogs are currently being extensively studied in clinical trials in the context of NAFLD. Our nanosystem provides with increased levels of GLP-1, triggered by the nanocarrier itself, and by the plasmatic absorption of the encapsulated synthetic analog (exenatide). Our goal in this study was to demonstrate a better outcome and a greater impact on the metabolic syndrome and liver disease progression associated with NAFLD with our nanosystem than with the subcutaneous injection of the GLP-1 analog alone. To that end, we studied the effect of chronic administration (one month) of our nanocarriers in two mouse models of early NASH: a genetic model (foz/foz mice fed a high fat diet (HFD)) and a dietary model (C57BL/6J mice fed with a western diet plus fructose (WDF)). Our strategy had a positive impact in promoting the normalization of glucose homeostasis and insulin resistance in both models, mitigating the progression of the disease. In the liver, diverging results were observed between the models, with the foz/foz mice presenting a better outcome. Although a complete resolution of NASH was not achieved in either model, the oral administration of the nanosystem was more efficient at preventing the progression of the disease into more severe states than the subcutaneous injection. We thus confirmed our hypothesis that the oral administration of our formulation has a stronger effect on alleviating the metabolic syndrome associated with NAFLD than the subcutaneous injection of the peptide.
Asunto(s)
Síndrome Metabólico , Nanocápsulas , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Nanocápsulas/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Ratones Endogámicos C57BL , Hígado/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Modelos Animales de Enfermedad , Dieta Alta en Grasa , Lípidos/farmacologíaRESUMEN
Aerobic glycolysis is the primary energy supply mode for glioblastoma (GBM) cells to maintain growth and proliferation. However, due to the metabolic reprogramming of tumor cells, GBM can still produce energy through fatty acid oxidation (FAO) and amino acid metabolism after blocking this metabolic pathway. In addition, GBM can provide a steady stream of nutrients through high-density neovascularization, which puts the block energy metabolism therapy for glioma in the situation of "internal and external problems". Herein, based on the abundant reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment and cytoplasm, we successfully designed and developed a cascade-responsive 2-DG nanocapsule delivery system. This nanocapsule contains a conjugate of anti-VEGFR2 monoclonal antibody (aV) and CPT1C siRNA (siCPT1C) linked by a disulfide cross-linker (aV-siCPT1C). The surface of this nanocapsule (2-DG/aV-siCPT1C NC) is loaded with the glycolysis inhibitor 2-DG, and it utilizes GLUT1, which is highly expressed on the blood-brain barrier (BBB) and GBM cells, to effectively penetrate the BBB and target GBM. The nanocapsule realizes multidrug codelivery, jointly blocks glycolysis and FAO of GBM, and reduces angiogenesis. Meanwhile, it also solves the problems of low delivery efficiency of mAb in the central nervous system (CNS) and easy degradation of siRNA. In general, this drug joint delivery strategy could open up a new avenue for the treatment of GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanocápsulas , Humanos , Glioblastoma/tratamiento farmacológico , Nanocápsulas/uso terapéutico , Línea Celular Tumoral , Metabolismo Energético , ARN Interferente Pequeño/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Microambiente TumoralRESUMEN
OBJECTIVES: Baicalin is a promising anticancer nutraceutical compound, but its application is hindered by its low water solubility and bioavailability, which can be remedied by its encapsulation in nanoparticles. METHODS: Lipid nanocapsules (LNCs) were developed to enhance baicalin delivery via intravenous and intranasal routes, and potentiate its therapeutic activity in treatment of glioma. RESULTS: LNCs displayed a particle size of 17.76 nm and sustained release of 74.36% after 24 h. The IC50 of baicalin LNCs (13 ± 5 µg/ml) was 60 times lower than free baicalin (780 ± 107 µg/ml) on human glioblastoma multiform cell line U87, with adequate cellular uptake as delineated by confocal laser microscopy. Both baicalin and LNCs induced cell cycle arrest at S and G2/M phases, with significant up-regulation in P21 gene, and decline in Nrf-2, HO-1 and VEGF gene expression. LNCs increased baicalin's bioavailability, either after intravenous (AUC0-24 h 10.94 ± 0.28 vs 3.53 ± 0.09 µg/ml*h), or intranasal administration (AUC0-24 h 6.26 ± 0.11 vs 3.17 ± 0.04 µg/ml*h). They also bypassed the blood brain barrier and achieved significantly higher brain delivery compared to free baicalin (drug targeting efficiency 160.73% vs 52.9%). CONCLUSION: Baicalin LNCs is a promising treatment modality for glioma, when administered through intravenous or intranasal routes.
Asunto(s)
Glioma , Nanocápsulas , Humanos , Nanocápsulas/uso terapéutico , Flavonoides/uso terapéutico , Flavonoides/farmacocinética , Glioma/tratamiento farmacológico , LípidosRESUMEN
Retinopathy of prematurity (ROP) is a retinal disease that threatens the vision of prematurely born infants. Severe visual impairment up to complete blindness is caused by neovascularization and inflammation, progressively destroying the immature retina. ROP primarily affects newborns in middle- and low-income countries with limited access to current standard treatments such as intraocular drug injections and laser- or cryotherapy. To overcome these limitations, we developed a nanotherapeutic that effectively prevents ROP development with one simple intravenous injection. Its lipid nanocapsules transport the antiangiogenic and anti-inflammatory cyclosporin A efficiently into disease-driving retinal pigment epithelium cells. In a mouse model of ROP, a single intravenous injection of the nanotherapeutic prevented ROP and led to normal retinal development by counteracting neovascularization and inflammation. This nanotherapeutic approach has the potential to bring about a change of paradigm in ROP therapy and prevent millions of preterm born infants from developing ROP.
Asunto(s)
Nanocápsulas , Retinopatía de la Prematuridad , Animales , Ciclosporina/farmacología , Ciclosporina/uso terapéutico , Humanos , Recién Nacido , Inflamación/tratamiento farmacológico , Inyecciones Intravenosas , Lípidos , Ratones , Nanocápsulas/uso terapéutico , Retinopatía de la Prematuridad/tratamiento farmacológico , Retinopatía de la Prematuridad/prevención & control , Factor A de Crecimiento Endotelial VascularRESUMEN
Colorectal cancer (CRC) is the third most common worldwide. Its treatment includes adjuvant chemotherapy with 5-fluorouracil (5FU) administered intravenously. 5FU is an antineoplastic drug of the fluoropyrimidines group, widely used in the treatment of solid tumors, mainly CRC. Nevertheless, it causes several adverse effects and poor effectiveness due to its short half-life. This work aimed to employ bacterial nanocellulose (BNC) as an encapsulation material for the oral administration of 5FU. First, the adsorption phenomena were analyzed by isotherms, thermodynamic parameters, and kinetic models. Then, encapsulation was carried out using spray-drying, and encapsulated 5FU desorption profiles were assessed in simulated fluids. The biological behavior was evaluated on colon cancer SW480 and SW620 cell lines. As result, it was found that at 25 °C a monolayer of 5FU was formed and the process showed to be the most spontaneous one. In the characterization of the nanocapsules, important changes were detected by the presence of 5FU. The delivery in the colon corresponded to a controlled release behavior. The in vitro assay indicated an improvement in the toxicity effect of the drug and its mechanism of action. Accordingly, BNC is a promising biomaterial for the development of a colon drug delivery platform of 5FU.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Nanocápsulas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Materiales Biocompatibles/uso terapéutico , Neoplasias Colorrectales/patología , Preparaciones de Acción Retardada/uso terapéutico , Sistemas de Liberación de Medicamentos , Fluorouracilo , Humanos , Nanocápsulas/uso terapéuticoRESUMEN
Myocardial infarction (MI) is a common disease that seriously threatens human health. It is noteworthy that oxygen is one of the key factors in the regulation of MI pathology procession: the controllable hypoxic microenvironment can enhance the tolerance of cardiac myocytes (CMs) and oxygen therapy regulates the immune microenvironment to repair the myocardial injury. Thus, the development of an oxygen-controllable treatment is critically important to unify MI prevention and timely treatment. Here, a hydrogel encapsulated upconversion cyanobacterium nanocapsule for both MI prevention and treatment is successfully synthesized. The engineered cyanobacteria can consume oxygen via respiration to generate a hypoxic microenvironment, resulting in the upregulation of heat shock protein70 (HSP70), which can enhance the tolerance of CMs for MI. When necessary, under 980 nm near-infrared (NIR) irradiation, the system releases photosynthetic oxygen through upconversion luminescence (UCL) to inhibit macrophage M1 polarization, and downregulates pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α), thereby repairing myocardial injury. To sum up, a photoresponsive upconversion cyanobacterium nanocapsule is developed, which can achieve MI prevention and treatment for only one injection via NIR-defined respiration and photosynthesis.
Asunto(s)
Cianobacterias , Infarto del Miocardio , Nanocápsulas , Humanos , Nanocápsulas/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéutico , Macrófagos/patología , Hidrogeles , Interleucina-6/uso terapéutico , Infarto del Miocardio/prevención & control , Infarto del Miocardio/tratamiento farmacológico , Citocinas/uso terapéutico , OxígenoRESUMEN
In this work, a series of mesoporous carbon nanocapsules (mCNS) of size below 10 nm have been prepared from Azadirachta indica seeds with a very easy and cost-effective approach. These nanocapsules can emit red and green light and are effective for cell imaging. Further, these carbon nanocapsules are biocompatible toward the normal healthy cells, however, they possess modest cytotoxicity against the MCF-7 (human breast cancer) and triple-negative breast cancer (TNBC) (MDA- MB-231 breast cancer cells), and the rate of killing cancer cells strongly depends on the dose of mCNCs. Further, the mitochondrial membrane potential and apoptosis assay were performed to analyze the therapeutic significance of these nanocapsules to kill breast cancer. Results showed that these carbon nanocapsules can depolarize the mitochondrial membrane potential alone (without using conventional drugs) and can change the physiological parameters and cellular metabolic energy of the cancer cells and kill them. The apoptosis results confirmed the death of breast cancer cells in the form of apoptosis and necrosis. Moreover, the results suggested that the porous carbon nanocapsules (mCNCs) reported herein can be used as a potential candidate and useful for the theranostic applications such as for cancer cell detection and therapy without using any conventional drugs.
Asunto(s)
Azadirachta , Nanocápsulas , Neoplasias de la Mama Triple Negativas , Carbono/farmacología , Carbono/uso terapéutico , Línea Celular Tumoral , Humanos , Potencial de la Membrana Mitocondrial , Nanocápsulas/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Lung cancer is the most common cause of cancer death worldwide. Thereby, new treatment strategies as targeting nano-therapy present promising possibilities to control the aggressiveness of lung cancer. Dual CD44 and folate receptors targetable nanocapsule based on folic-polyethylene glycol-hyaluronic (FA-PEG-HA) were fabricated to improve the therapeutic activity of 4-Methylumbelliferone (4-MU) toward lung cancer. In this study, we fabricate 4-MU Nps as a hybrid polymeric (protamine) protein (albumin) nanocapsule, then functionalized by targeting layer to form 4-MU@FA-PEG-HA Nps with encapsulation efficacy 96.15%. The in vitro study of free 4-MU, 4-MU Nps and 4-MU@FA-PEG-HA Nps on A549 lung cancer cells reveal that the 4-MU Nps and 4-MU@FA-PEG-HA Nps were more cytotoxic than free 4-MU on A549 cells. The observed therapeutic activity of 4-MU@FA-PEG-HA Nps on urethane-induced lung cancer model, potentiality revealed a tumor growth inhibition via apoptotic mechanisms and angiogenesis inhibition. The results were supported by Enzyme-linked immunosorbent assay (ELIZA) of transforming growth factors (TGFß1) and serum HA, histopathological analysis as well as immunohistochemical Ki67, CD44, Bcl-2 and caspace-3 staining. Moreover, 4-MU@FA-PEG-HA Nps exhibited a promising safety profile. Hence, it is expected that our developed novel nano-system can be used for potential application on tumor therapy for lung cancer.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Nanocápsulas , Nanopartículas , Antineoplásicos/farmacología , Línea Celular Tumoral , Ácido Fólico , Humanos , Ácido Hialurónico , Himecromona/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Nanocápsulas/uso terapéutico , Polietilenglicoles/uso terapéuticoRESUMEN
Recent studies in our laboratories have shown promising effects of bile acids in â drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D® and â viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D® capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic ß-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D® capsules, and capsules' images, viability, inflammation, and bioenergetics of encapsulated cells assessed. The capsules' thermal and chemical stability assays were also assessed to ascertain an association between capsules' stability and cellular biological activities. Bile acid-Eudragit NM30D® capsules showed improved cell viability (e.g., F1 < F2 & F8; p < 0.05), insulin, inflammatory profile, and bioenergetics as well as thermal and chemical stability, compared with control. These effects were formulation-dependent and suggest, overall, that changes in ratios of bile acids to Eudragit NM30D® can change the microenvironment of the capsules and subsequent cellular biological activities.
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Antiinflamatorios , Ácidos y Sales Biliares , Células Inmovilizadas/metabolismo , Colesterol , Células Secretoras de Insulina/metabolismo , Nanocápsulas , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Ácidos y Sales Biliares/química , Ácidos y Sales Biliares/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Colesterol/química , Colesterol/farmacología , Ratones , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacologíaRESUMEN
Short time treatment with reduced dosages of selol-loaded PLGA nanocapsules (NcSel) combined with magnetic hyperthermia (MHT) is evaluated in aged Erhlich tumor-bearing mice. Clinical, hematological, biochemical, genotoxic and histopathological parameters are assessed during 7 d treatment with NcSel and MHT, separately or combined. The time evolution of the tumor volume is successfully modeled using the logistic mathematical model. The combined therapy comprising NcSel and MHT is able to hinder primary tumor growth and a case of complete tumor remission is recorded. Moreover, no metastasis was diagnosed and the adverse effects are negligible. NcSel plus MHT may represent an effective and safe alternative to cancer control in aged patients. Future clinical trials are encouraged.
Asunto(s)
Neoplasias de la Mama/terapia , Hipertermia Inducida , Nanopartículas de Magnetita/uso terapéutico , Nanocápsulas/uso terapéutico , Compuestos de Selenio/uso terapéutico , Animales , Neoplasias de la Mama/patología , Carcinoma de Ehrlich/patología , Carcinoma de Ehrlich/terapia , Ciclo Celular/efectos de los fármacos , Terapia Combinada , Fragmentación del ADN/efectos de los fármacos , Femenino , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/ultraestructura , Ratones , Nanocápsulas/química , Nanocápsulas/ultraestructura , Compuestos de Selenio/química , Factores de Tiempo , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
Glioblastoma remains a cancer for which the effectiveness of treatments has shown little improvement over the last decades. For this pathology, multiple therapies combining resection, chemotherapy and radiotherapy remain the norm. In this context, the use of high-Z nanoparticles such as gold or hafnium to potentiate radiotherapy is attracting more and more attention. Here, we evaluate the potentiating effect of hollow shells made of gold and iron oxide nanoparticles (hybridosomes®) on the radiotherapy of glioblastoma, using murine GL261-Luc+ brain tumor model. While iron oxide seems to have no beneficial effect for radiotherapy, we observe a real effect of gold nanoparticles-despite their low amount-with a median survival increase of almost 20% compared to radiotherapy only and even 33% compared to the control group. Cellular and in vivo studies show that a molecule of interest nano-precipitated in the core of the hybridosomes® is released and internalized by the surrounding brain cells. Finally, in vivo studies show that hybridosomes® injected intra-tumorally are still present in the vicinity of the brain tumor more than 5â¯days after injection (duration of the Stupp protocol's radiation treatment). Interestingly, one mouse treated with radiotherapy in the presence of gold-containing hybridosomes® survived 78â¯days. Monitoring of the tumoral growth of this long-term survivor using both MRI and bioluminescence revealed a decrease of the tumor size after treatment. These very encouraging results are a proof-of-concept that hybridosomes® are really effective tools for the development of combined therapies (chemo-radiotherapy).
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanopartículas del Metal , Nanocápsulas , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Oro/uso terapéutico , Nanopartículas del Metal/uso terapéutico , Ratones , Nanocápsulas/uso terapéuticoRESUMEN
The increasing use of mechanical thrombectomy in stroke management has opened the window to local intraarterial brain delivery of therapeutic agents. In this context, the use of nanomedicine could further improve the delivery of new treatments for specific brain targeting, tracking and guidance. In this study we take advantage of this new endovascular approach to deliver biocompatible poly(D-L-lactic-co-glycolic acid) (PLGA) nanocapsules functionalized with superparamagnetic iron oxide nanoparticles and Cy7.5 for magnetic targeting, magnetic resonance and fluorescent molecular imaging. A complete biodistribution study in naïve (n = 59) and ischemic (n = 51) mice receiving intravenous or intraarterial nanocapsules, with two different magnet devices and imaged from 30 min to 48 h, showed an extraordinary advantage of the intraarterial route for brain delivery with a specific improvement in cortical targeting when using a magnetic device in both control and ischemic conditions. Safety was evaluated in ischemic mice (n = 69) showing no signs of systemic toxicity nor increasing mortality, infarct lesions or hemorrhages. In conclusion, the challenging brain delivery of therapeutic nanomaterials could be efficiently and safely overcome with a controlled endovascular administration and magnetic targeting, which could be considered in the context of endovascular interventions for the delivery of multiple treatments for stroke.
Asunto(s)
Carbocianinas , Medios de Contraste , Campos Magnéticos , Nanopartículas Magnéticas de Óxido de Hierro/química , Imagen por Resonancia Magnética , Nanocápsulas , Imagen Óptica , Accidente Cerebrovascular , Animales , Carbocianinas/química , Carbocianinas/farmacología , Medios de Contraste/química , Medios de Contraste/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with ß-cyclodextrin and iron NPs (Fe3O4) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained (p < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the Wnt/ß-catenin signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the Wnt/ß-catenin signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism.