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The E6 and E7 oncoproteins of high-risk types of human papillomavirus (HR-HPV) are crucial for the development of cervical cancer (CC). Small interfering RNAs (siRNAs) are explored as novel therapies that silence these oncogenes, but their clinical use is hampered by inefficient delivery systems. Modification (pegylation) with polyethylene glycol (PEG) of liposomal siRNA complexes (siRNA lipoplexes) may improve systemic stability. We studied the effect of siRNA targeting HPV16 E6, delivered via cationic liposomes (lipoplexes), on cellular processes in a cervical carcinoma cell line (CaSki) and its potential therapeutic use. Lipoplexes-PEG-HPV16 E6, composed of DOTAP, Chol, DOPE, and DSPE-PEG2000 were prepared. The results showed that pegylation (5% DSPE-PEG2000) provided stable siRNA protection, with a particle size of 86.42 ± 3.19 nm and a complexation efficiency of over 80%; the siRNA remained stable for 30 days. These lipoplexes significantly reduced HPV16 E6 protein levels and restored p53 protein expression, inhibiting carcinogenic processes such as proliferation by 25.74%, migration (95.7%), and cell invasion (97.8%) at concentrations of 20 nM, 200 nM, and 80 nM, respectively. In conclusion, cationic lipoplexes-PEG-HPV16 E6 show promise as siRNA carriers for silencing HPV16 E6 in CC.
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Epilepsy is a chronic neurological disease characterized by the presence of spontaneous seizures, with a higher incidence in the pediatric population. Anti-seizure medication (ASM) may produce adverse drug reactions (ADRs) with an elevated frequency and a high severity. Thus, the objective of the present study was to analyze, through intensive pharmacovigilance over 112 months, the ADRs produced by valproic acid (VPA), oxcarbazepine (OXC), phenytoin (PHT), and levetiracetam (LEV), among others, administered to monotherapy or polytherapy for Mexican hospitalized pediatric epilepsy patients. A total of 1034 patients were interviewed; 315 met the inclusion criteria, 211 patients presented ADRs, and 104 did not. A total of 548 ASM-ADRs were identified, and VPA, LEV, and PHT were the main culprit drugs. The most frequent ADRs were drowsiness, irritability, and thrombocytopenia, and the main systems affected were hematologic, nervous, and dermatologic. LEV and OXC caused more nonsevere ADRs, and PHT caused more severe ADRs. The risk analysis showed an association between belonging to the younger groups and polytherapy with ADR presence and between polytherapy and malnutrition with severe ADRs. In addition, most of the severe ADRs were preventable, and most of the nonsevere ADRs were nonpreventable.
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The synthesis of a new family of ethylenediaminetetraacetic acid (EDTA) core dimers and G0 dendrimers end-capped with two and four ß-cyclodextrin (ßCD) moieties was performed by click-chemistry conjugation, varying the spacers attached to the core. The structure analyses were achieved in DMSO-d6 and the self-inclusion process was studied in D2O by 1H-NMR spectroscopy for all platforms. It was demonstrated that the interaction with adamantane carboxylic acid (AdCOOH) results in a guest-induced shift of the self-inclusion effect, demonstrating the full host ability of the ßCD units in these new platforms without any influence of the spacer. The results of the quantitative size and water solubility measurements demonstrated the equivalence between the novel EDTA-ßCD platforms and the classical PAMAM-ßCD dendrimer. Finally, we determined the toxicity for all EDTA-ßCD platforms in four different cell lines: two human breast cancer cells (MCF-7 and MDA-MB-231), human cervical adenocarcinoma cancer cells (HeLa), and human lung adenocarcinoma cells (SK-LU-1). The new EDTA-ßCD carriers did not present any cytotoxicity in the tested cell lines, which showed that these new classes of platforms are promising candidates for drug delivery.
Assuntos
Dendrímeros , beta-Ciclodextrinas , Humanos , Ácido Edético/farmacologia , Dendrímeros/química , beta-Ciclodextrinas/farmacologia , beta-Ciclodextrinas/química , Sistemas de Liberação de Medicamentos , Fenômenos Químicos , SolubilidadeRESUMO
A healing material must have desirable characteristics such as maintaining a physiological environment, protective barrier-forming abilities, exudate absorption, easy handling, and non-toxicity. Laponite is a synthetic clay with properties such as swelling, physical crosslinking, rheological stability, and drug entrapment, making it an interesting alternative for developing new dressings. This study evaluated its performance in lecithin/gelatin composites (LGL) as well as with the addition of maltodextrin/sodium ascorbate mixture (LGL MAS). These materials were applied as nanoparticles, dispersed, and prepared by using the gelatin desolvation method-eventually being turned into films via the solvent-casting method. Both types of composites were also studied as dispersions and films. Dynamic Light Scattering (DLS) and rheological techniques were used to characterize the dispersions, while the films' mechanical properties and drug release were determined. Laponite in an amount of 8.8 mg developed the optimal composites, reducing the particulate size and avoiding the agglomeration by its physical crosslinker and amphoteric properties. On the films, it enhanced the swelling and provided stability below 50 °C. Moreover, the study of drug release in maltodextrin and sodium ascorbate from LGL MAS was fitted to first-order and Korsmeyer-Peppas models, respectively. The aforementioned systems represent an interesting, innovative, and promising alternative in the field of healing materials.
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In this work, two dendritic molecules containing an ethylenediaminetetraacetic acid (EDTA) core decorated with two and four ß-cyclodextrin (ßCD) units were synthesized and fully characterized. Copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click chemistry under microwave irradiation was used to obtain the target compounds with yields up to 99%. The classical ethylenediamine (EDA) core present in PAMAM dendrimers was replaced by an EDTA core, obtaining platforms that increase the water solubility at least 80 times compared with native ßCD. The synthetic methodology presented here represents a convenient alternative for the rapid and efficient construction of PAMAM analogs. These molecules are envisaged for future applications as drug carriers.
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This study aimed to detect intracellular trehalose in boar sperm that were cryopreserved with liposomes and conduct an analysis of its effects on some characteristics of thawed sperm, including rheological properties. First, soybean lecithin cholesterol-based liposomes were produced and characterized in the presence of 300 mM trehalose. Next, semen samples were frozen in two freezing media: a control medium with 300 mM trehalose and an experimental medium supplemented with 300 mM trehalose and 10% liposomes, both of which were thawed and then studied to ascertain their integrity, motility, rheological response, and trehalose quantities by testing two methods of spermatic lysis via high-performance liquid chromatography with an evaporative light-scattering detector (HPLC-ELSD). The results found spherical liposomes measuring 357 nm that were relatively stable in an aqueous medium and had an entrapment efficiency of 73%. An analysis of the cryopreserved ejaculates showed that their viability and motility did not significantly differ between groups (P > 0.05). The viscous response of the samples was influenced by the extracellular medium rather than by the freezing-thawing process, which resulted in a loss of interaction between the cells and cryoprotectants. Finally, intracellular trehalose levels were determined using HPLC-ELSD, with no differences observed (P > 0.05) when comparing both sperm lysis methods. The use of liposomes with trehalose appears to be a promising option for boar semen cryopreservation, with a marked effect on rheological properties. The proposed HPLC-ELSD method was effective for measuring trehalose in cryopreserved cell samples.
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Preservação do Sêmen , Sêmen , Masculino , Suínos , Animais , Sêmen/fisiologia , Trealose , Preservação do Sêmen/veterinária , Preservação do Sêmen/métodos , Lipossomos , Motilidade dos Espermatozoides/fisiologia , Dissacarídeos , Criopreservação/veterinária , Criopreservação/métodos , Crioprotetores/farmacologia , Espermatozoides/fisiologiaRESUMO
Hybrid materials based on Mesoporous Silica Nanoparticles (MSN) have attracted plentiful attention due to the versatility of their chemistry, and the field of Drug Delivery Systems (DDS) is not an exception. MSN present desirable biocompatibility, high surface area values, and a well-studied surface reactivity for tailoring a vast diversity of chemical moieties. Particularly important for DDS applications is the use of external stimuli for drug release. In this context, light is an exceptional alternative due to its high degree of spatiotemporal precision and non-invasive character, and a large number of promising DDS based on photoswitchable properties of azobenzenes have been recently reported. This review covers the recent advances in design of DDS using light as an external stimulus mostly based on literature published within last years with an emphasis on usually overlooked underlying chemistry, photophysical properties, and supramolecular complexation of azobenzenes.
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Compostos Azo/química , Sistemas de Liberação de Medicamentos , Luz , Nanopartículas/química , Dióxido de Silício/química , Liberação Controlada de Fármacos , Tamanho da Partícula , Porosidade , Propriedades de SuperfícieRESUMO
The study of pharmacological interactions between herbal remedies and conventional drugs is important because consuming traditional herbal remedies as supplements or alternative medicine is fairly common and their concomitant administration with prescribed drugs could either have a favorable or unfavorable effect. Therefore, this work aims to determine the pharmacological interactions of a turmeric acetone extract (TAE) and its main metabolite (curcumin) with common anti-ulcer drugs (ranitidine and bismuth subsalicylate), using an ethanol-induced ulcer model in Wistar rats. The analysis of the interactions was carried out via the Combination Index-Isobologram Equation method. The combination index (CI) calculated at 0.5 of the affected fraction (fa) indicated that the TAE or curcumin in combination with ranitidine had a subadditive interaction. The results suggest that this antagonistic mechanism is associated to the mucoadhesion of curcumin and the TAE, determined by rheological measurements. Contrastingly, both the TAE and curcumin combined with bismuth subsalicylate had an additive relationship, which means that there is no pharmacological interaction. This agrees with the normalized isobolograms obtained for each combination. The results of this study suggest that mucoadhesion of curcumin and the TAE could interfere in the effectiveness of ranitidine, and even other drugs.
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Antiulcerosos/uso terapêutico , Bismuto/uso terapêutico , Curcumina/farmacologia , Etanol/efeitos adversos , Compostos Organometálicos/uso terapêutico , Extratos Vegetais/farmacologia , Ranitidina/uso terapêutico , Salicilatos/uso terapêutico , Úlcera Gástrica/prevenção & controle , Animais , Antiulcerosos/antagonistas & inibidores , Curcuma , Modelos Animais de Doenças , Interações Medicamentosas , Mucosa Gástrica/efeitos dos fármacos , Interações Ervas-Drogas , Masculino , Compostos Organometálicos/antagonistas & inibidores , Ranitidina/antagonistas & inibidores , Ratos , Ratos Wistar , Salicilatos/antagonistas & inibidores , Úlcera Gástrica/induzido quimicamenteRESUMO
In this work, we prepared a novel composite based on hybrid gelatin carriers and montmorillonite clay (MMT) to analyze its viability as controlled drug delivery system. The objective of this research involves the characterization of composites formed by structured lipid-gelatin micro-particles (MP) and MMT clay. This analysis included the evaluation of the composite according to its rheological properties, morphology (SEM), particle size, XRD, FT-IR, and in vitro drug release. The effect of pH in the properties of the composite is evaluated. A novel raspberry-like or armor MP/MMT clay composite is reported, in which the pH has an important effect on the final structure of the composite for ad-hoc drug delivery systems. For pH values below the isoelectric point, we obtained defined morphologies with entrapment efficiencies up to 67%. The pH level controls the MP/MMT composite release mechanism, restringing drug release in the stomach-like environment. Intended for oral administration, these results evidence that the MP/MMT composite represents an attractive alternative for intestinal-colonic controlled drug delivery systems.
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Atorvastatina/química , Bentonita/química , Preparações de Ação Retardada/química , Nanocompostos/química , Atorvastatina/administração & dosagem , Atorvastatina/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Nanocompostos/ultraestrutura , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
PURPOSE: The aim of this study was to develop and characterize a liposomal product containing sirolimus to be administered subconjunctivally for the treatment of nonresponsive keratoconjunctivitis sicca (KCS) or dry eye. METHODS: Formulations were prepared using an ethanol injection method and an adaptation of the heating method in pursuance of the most suitable methodology for future industrial production. Liposomes were loaded with either a high dose of 1 mg/mL of sirolimus or a less toxic dose of 0.4 mg/mL. The effects of critical process and formulation parameters were investigated. Liposomes were characterized in terms of size, zeta potential, polydispersity, differential scanning calorimetry, morphology, entrapment efficiency, phospholipid content, thermal stability, and sterility. The formulation was evaluated clinically in dogs with spontaneous KCS. RESULTS: Sterile liposomal dispersions with sizes ranging from 140 to 211 nm, were successfully obtained. High entrapment efficiency of 93%-98% was achieved. The heating method allowed an easier production of liposomes with high entrapment efficiency, to significantly shorten production time and the elimination of the use of alcohol. The poor stability of the obtained liposomes in aqueous dispersion made the inclusion of a lyophilization step necessary to the manufacturing process. In vivo testing of the liposomal sirolimus formulations in the spontaneous KCS dog model have produced promising results, particularly with a sirolimus dose of 1 mg/mL, indicating the need for further development and study of proposed formulations in the treatment of canine KCS. Clinical improvement in tear production in dogs with spontaneous KCS treated with the 1 mg/mL dose product was observed. CONCLUSIONS: The heating method allowed easier production of high entrapment efficiency liposomes to significantly shorten production time and the elimination of the use of alcohol. Tear production was increased in dogs administered with the formulation.