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Photobiomodulation (PBM) therapy displays relevant properties for tissue healing and regeneration, which may be of interest for the tissue engineering field. Here, we show that PBM is able to improve cell survival and to interact with recombinant human Bone Morphogenetic Protein 4 (rhBMP4) to direct and accelerate odonto/osteogenic differentiation of dental derived mesenchymal stem cells (MSCs). MSCs were encapsulated in an injectable and thermo-responsive cell carrier (Pluronic® F-127) loaded with rhBMP4 and then photoactivated. PBM improved MSCs self-renewal and survival upon encapsulation in the Pluronic® F-127. In the presence of rhBMP4, cell odonto/osteogenic differentiation was premature and markedly improved in the photoactivated MSCs. An in vivo calvarial critical sized defect model demonstrated significant increase in bone formation after PBM treatment. Finally, a balance in the reactive oxygen species levels may be related to the favorable results of PBM and rhBMP4 association. PBM may act in synergism with rhBMP4 and is a promise candidate to direct and accelerate hard tissue bioengineering.
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Proteína Morfogenética Ósea 4/administración & dosificación , Portadores de Fármacos , Terapia por Luz de Baja Intensidad/métodos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de la radiación , Poloxámero/química , Ingeniería de Tejidos/métodos , Andamios del Tejido , Adolescente , Adulto , Animales , Proteína Morfogenética Ósea 4/química , Regeneración Ósea , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Células Cultivadas , Humanos , Hidrogeles , Inyecciones , Láseres de Semiconductores , Terapia por Luz de Baja Intensidad/instrumentación , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Ratones Desnudos , FN-kappa B/metabolismo , Osteogénesis/efectos de los fármacos , Osteogénesis/efectos de la radiación , Hueso Parietal/lesiones , Hueso Parietal/patología , Hueso Parietal/cirugía , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo , Adulto JovenRESUMEN
The development of specific tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia (CML). However, chemoresistance of tumor cells to TKIs has already been described, and several mechanisms account for the multidrug resistance (MDR) phenotypes, including the overexpression of P-glycoprotein (P-gp). This decreases the rate of healing and complete tumor remission. Nanotechnological tools have been studied to allow advances in this field. Poloxamers (Pluronics(®)) have been proposed as drug carriers to improve therapeutic efficacy and decrease side effects, even in cancer therapy, due to their ability to inhibit P-gp. Antipsychotic phenothiazines have been described as potent cytotoxic drugs against several types of tumor cells in vitro. Here, we show that nanostructured micellar systems containing the phenothiazine derivative chlorpromazine (CPZ) potentiated the cytotoxicity of free CPZ and increased the selectivity against CML tumor cells, demonstrating the pharmacological potential of these poloxamer-based nanostructured systems containing CPZ in cancer therapy.
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Antineoplásicos/farmacología , Clorpromazina/farmacología , Portadores de Fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nanomedicina/métodos , Nanopartículas , Poloxámero/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Clorpromazina/química , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Liberación de Fármacos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Micelas , Poloxámero/química , Solubilidad , Factores de TiempoRESUMEN
We investigated the structure of the binary mixture of Pluronic F-127 (PL F-127) and Pluronic L-81 (PL L-81), as hydrogels for sumatriptan delivery and investigated the mixture possible use via subcutaneous route for future applications as a long-acting antimigraine formulation. We studied the drug-micelle interaction by dynamic light scattering and differential scanning calorimetry, sol-gel process by rheology, and small-angle X-ray scattering (SAXS). We also employed pharmaceutical formulation aspects by dissolution rate, release profile, and cytotoxicity studies for apoptosis and/or necrosis in fibroblasts (3T3) and neural cells (Neuro 2a). Micellar hydrodynamic diameter studies revealed the formation of binary PL-micelles by association of PL F-127/PL L-81. The mixed micelle and binary hydrogels formation was also verified by only one phase transition temperature for all formulations, even in the presence of sumatriptan. The characterization of the hydrogel supramolecular organization by SAXS, rheology studies, and in vitro dissolution/release results showed a probable relationship between the transition of the lamellar to the hexagonal phase and the lower release constant values observed, indicating that PL L-81 participates in micelle-hydrogel formation and aggregation processes. Furthermore, the reduced cytotoxicity (annexin V-fluorescein isothiocyanate positive staining), with minor PL L-81 concentration, points to its potential use for the development of binary PL-systems containing sumatriptan capable of modulating the gelation process. This use may employ the minimum PL concentration and be interesting for pharmaceutical applications, particularly for migraine treatment.
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Sistemas de Liberación de Medicamentos , Hidrogeles/química , Poloxámero/química , Sumatriptán/farmacología , Sumatriptán/farmacocinética , Células 3T3 , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Química Física , Relación Dosis-Respuesta a Droga , Liberación de Fármacos/efectos de los fármacos , Hidrogeles/farmacología , Cinética , Ratones , Poloxámero/farmacología , Relación Estructura-Actividad , Sumatriptán/administración & dosificación , TermodinámicaRESUMEN
The challenges for developing new pharmaceutical formulations based on natural and synthetic polymers has led to innovation into the design of systems responsive environmental stimuli such as temperature. However, the presence of hydrophilic or hydrophobic molecules, charged groups, or metallic elements can affect their structural behavior and their biopharmaceutical performance This work aims to study and characterize the morphology and structure of polymeric formulations based on Poloxamer (PL) 407 (15 % and 30 % m/v) and its binary with PL 338 (15 % PL 407 + 15 % PL 338) and hyaluronic acid (0.5 % m/v), as drug delivery systems of local anesthetic bupivacaine (0.5 % m/v) and ropivacaine (0.5 % m/v) hydrochloride. For this, it was performed SANS analysis for determination of supramolecular organization and lattice parameters; calorimetry was done to characterize their thermodynamic parameters; rheological analysis flow curve, consistency and adhesion calculation, Maxwell model study. Also, it was performed drug release profiles and calculation of diffusion coefficients. It was identified lamellar structures in PL 407 15 % formulations, and coexistence of cubic and hexagonal phases in PL 407 30 % and binary formulations, however hyaluronic acid, bupivacaine or ropivacaine seem do not affect the type of supramolecular structure. In addition, these additives can modulate viscosity among poloxamers chains, increasing micelle-micelle interactions as it happens in presence of bupivacaine. On the other hand, addition of hyaluronic acid can promote increased structural stabilization by hydrophilic interactions between hyaluronic and micellar corona. It reflects the ability how to control the drug release, as in case of binary system that retained bupivacaine for longer time than other systems, as well it happens when hyaluronic acid is added in PL 407 15 % and PL 407 30 %.
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Ácido Hialurónico , Hidrogeles , Hidrogeles/química , Ácido Hialurónico/química , Micelas , Ropivacaína , Sistemas de Liberación de Medicamentos , Poloxámero/química , Temperatura , Polímeros , Bupivacaína/farmacologíaRESUMEN
Bisphosphonates are a class of drugs that induce bone cancer cell death and favor bone regeneration, making them suitable for bone cancer treatment. However, when combined with bioactive glasses to enhance bone regeneration, a chemical bond between biphosphonates and the glass surface inactivates their mechanism of action. A new colloidal hydrogel-based drug delivery system could overcome that limitation once bisphosphonates, such as zoledronic acid (ZA), are incorporated into hydrogel micelles, avoiding their interaction with the glass surface. In this work, we proposed formulations based on a poloxamer 407 thermo-responsive hydrogel matrix containing holmium-doped bioactive glass nanoparticles and different concentrations (0.05 and 5 mg/mL) of ZA. We characterized the influence of the glass and the ZA on the hydrogel properties. In addition, a drug concentration screening was performed, and biological characterizations evaluated the best result. The biological characterization consisted of evaluating cytotoxicity and in vitro bone regeneration ability through cell migration and quantification of genes related to osteogeneses through RT-PCR. The results suggest that the addition of glasses and ZA to the poloxamer did not significantly influence the sol-gel transition of the hydrogels (around 13 °C) regardless of the ZA content. However, the ZA at high concentration (PL-ZA100) decreased the enthalpy of gel formation from 68 to 43 kJ.mol-1 when compared with the pure hydrogel formulation (PL), suggesting a water structurer role of ZA, which is withdrawn when glass particles are added to the system (PL-BG5Ho-ZA100). Solid-state 31P nuclear resonance spectroscopy results showed that part of the ZA is chemically bonded to the glass surface, which explains the withdrawal in the water structurer role of ZA when the glasses were incorporated into the hydrogel. Besides, based on the drug release results, we proposed a model where part of the ZA is "free," encapsulated in the hydrogel matrix, while another part of the ZA is bonded to the glass surface. Finally, considering the in vitro results and our proposed model, the ratio between "free" and "bonded" ZA in our drug delivery systems showed in vitro evidence of a cancer treatment that selectively kills osteosarcoma cells while still favoring an osteogenic microenvironment. By overcoming the limitation of combining bisphosphonates with bioactive glasses, hydrogel-based drug delivery systems can be a solution for the development of new formulations proposed for bone cancer treatment in conjunction with bone regeneration.
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Neoplasias Óseas , Osteosarcoma , Humanos , Difosfonatos/farmacología , Hidrogeles , Regeneración Ósea , Sistemas de Liberación de Medicamentos , Ácido Zoledrónico , Neoplasias Óseas/tratamiento farmacológico , Microambiente TumoralRESUMEN
Topical delivery of local anesthetics (LAs) is commonly used to decrease painful sensations, block pain throughout procedures, and alleviate pain after surgery. Dermal and/or transdermal delivery of LAs has other advantages, such as sustained drug delivery and decreased systemic adverse effects. This study reports the development of poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles coated with chitosan for the sustained release and topicality of benzocaine (BZC) and topical delivery. BZC PLGA nanoparticles or nonencapsulated drugs were further incorporated into Poloxamer hydrogels (Pluronic™ F-127). The nanoparticles showed a mean diameter of 380 ± 4 nm, positive zeta potential after coating with chitosan (23.3 ± 1.7 mV), and high encapsulation efficiency (96.7 ± 0.02%). Cellular viability greater than 70% for both fibroblasts and keratinocytes was observed after treatment with nanoparticles, which is in accordance with the preconized guidelines for biomedical devices and delivery systems. Both the nanoparticles and hydrogels were able to modulate BZC delivery and increase drug permeation when compared to the nonencapsulated drug. Furthermore, the incorporation of limonene into hydrogels containing BZC-loaded nanoparticles increased the BZC permeation rates. Non-Newtonian and pseudoplastic behaviors were observed for all hydrogel nanoformulations with or without nanoparticles. These results demonstrate that the hydrogel-nanoparticle hybrids could be a promising delivery system for prolonged local anesthetic therapy.
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Quitosano , Nanopartículas , Anestésicos Locales , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Hidrogeles , Limoneno , Tamaño de la Partícula , PolímerosRESUMEN
Coumaric acid (CouH), an antioxidant molecule assimilated by food consumption, was intercalated into layered double hydroxide (LDH) nanocarrier, having zinc and aluminium ions in the layers (LDH-Cou), to evaluate its pharmacological activity through in vitro and in vivo assays in mice. Therefore, the following tests were performed: coumarate delivery in saline solution, fibroblasts' cell viability using neutral red, peritonitis induced by carrageenan, formalin test, acetic-acid-induced writhing, and tail-flick assay, for the non-intercalated CouH and the intercalated LDH-Cou system. Furthermore, different pharmacological pathways were also investigated to evaluate their possible anti-inflammatory and antinociceptive mechanisms of action, in comparison to traditionally used agents (morphine, naloxone, caffeine, and indomethacin). The LDH-Cou drug delivery system showed more pronounced anti-inflammatory effect than CouH but not more than that evoked by the classic non-steroidal anti-inflammatory drug (NSAID) indomethacin. For the analgesic effect, according to the tail-flick test, the treatment with LDH-Cou expressively increased the analgesia duration (p < 0.001) by approximately 1.7−1.8 times compared to CouH or indomethacin. Thus, the results pointed out that the LDH-Cou system induced in vivo analgesic and anti-inflammatory activities and possibly uses similar mechanisms to that observed for classic NSAIDs, such as indomethacin.
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Organogels (ORGs) are remarkable matrices due to their versatile chemical composition and straightforward preparation. This study proposes the development of ORGs as dual drug-carrier systems, considering the application of synthetic monoketonic curcuminoid (m-CUR) and lidocaine (LDC) to treat topical inflammatory lesions. The monoketone curcuminoid (m-CUR) was synthesized by using an innovative method via a NbCl5-acid catalysis. ORGs were prepared by associating an aqueous phase composed of Pluronic F127 and LDC hydrochloride with an organic phase comprising isopropyl myristate (IPM), soy lecithin (LEC), and the synthesized m-CUR. Physicochemical characterization was performed to evaluate the influence of the organic phase on the ORGs supramolecular organization, permeation profiles, cytotoxicity, and epidermis structural characteristics. The physico-chemical properties of the ORGs were shown to be strongly dependent on the oil phase constitution. Results revealed that the incorporation of LEC and m-CUR shifted the sol-gel transition temperature, and that the addition of LDC enhanced the rheological G'/Gâ³ ratio to higher values compared to original ORGs. Consequently, highly structured gels lead to gradual and controlled LDC permeation profiles from the ORG formulations. Porcine ear skin epidermis was treated with ORGs and evaluated by infrared spectroscopy (FTIR), where the stratum corneum lipids were shown to transition from a hexagonal to a liquid crystal phase. Quantitative optical coherence tomography (OCT) analysis revealed that LEC and m-CUR additives modify skin structuring. Data from this study pointed ORGs as promising formulations for skin-delivery.
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In the last year, the advent of the COVID-19 pandemic brought a new consideration for the multidisciplinary sciences. The unknown mechanisms of infection used by SARS-CoV-2 and the absence of effective antiviral pharmacological therapy, diagnosis methods, and vaccines evoked scientific efforts on the COVID-19 outcome. In general, COVID-19 clinical features are a result of local and systemic inflammatory processes that are enhanced by some preexistent comorbidities, such as diabetes, obesity, cardiovascular, and pulmonary diseases, and biological factors, like gender and age. However, the discrepancies in COVID-19 clinical signs observed among those patients lead to investigations about the critical factors that deeply influence disease severity and death. Herein, we present the viral infection mechanisms and its consequences after blocking the angiotensin-converting enzyme 2 (ACE2) axis in different tissues and the progression of inflammatory and immunological reactions, especially the influence of genetic features on those differential clinical responses. Furthermore, we discuss the role of genotype as an essential indicator of COVID-19 susceptibility, considering the expression profiles, polymorphisms, gene identification, and epigenetic modifications of viral entry factors and their recognition, as well as the infection effects on cell signaling molecule expression, which amplifies disease severity.
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Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/patología , Sistema Renina-Angiotensina/fisiología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Antivirales/farmacología , Citocinas/sangre , Citocinas/inmunología , Humanos , Factores de Riesgo , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Since patients suffer pain in the post-surgery of bone repair interventions, bioactive glass/hydrogel drug delivery systems containing local anesthetics, such as ropivacaine, could improve patient life quality by combining bone regeneration with anesthetics. However, poloxamer-based hydrogel properties are sensitive to ions, temperature, and water contents and could be structurally influenced by the ionic dissolution products from bioactive glasses of different compositions. Therefore, this study evaluated the interplay between bioactive glass dissolution kinetics and poloxamer 407 properties, establishing a correlation between changes in the hydrogel and drug release kinetics. Three glass compositions were produced, yielding Ca-rich, Na-rich, and an intermediate glass composition. The influence of Ca/Na ratios on the glass structure and dissolution was investigated. Further, the glasses and ropivacaine were incorporated in the poloxamer hydrogel, and the self-assembly ability of poloxamer, the degradation rate, and the drug release kinetics of the composites were evaluated. The results suggested that glass connectivity affected the early-stage of glass dissolution, while sodium mobility influenced the long-term. The dissolution products from the glasses interact with the supramolecular structure of the poloxamer, causing structural changes responsible for hydrogel degradation. Consequently, by changing the Ca/Na ratio in the glasses, it is possible to modulate glass dissolution that, in turn, influences the ropivacaine release. Thus, we propose that the Ca/Na ratio in quaternary bioactive glasses can be used to modulate drug-delivery properties from systems based on bioactive glasses and poloxamer 407.
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Hidrogeles , Poloxámero , Materiales Biocompatibles , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Vidrio , Humanos , Cinética , SolubilidadRESUMEN
Holmium-containing bioactive glasses can be applied in bone cancer treatment because the holmium content can be neutron activated, having suitable properties for brachytherapy applications, while the bioactive glass matrix can regenerate the bone alterations induced by the tumor. To facilitate the application of these glasses in clinical practice, we proposed a composite based on Poloxamer 407 thermoresponsive hydrogel, with suitable properties for applications as injectable systems. Therefore, in this work, we evaluated the influence of holmium-containing glass particles on the properties of Poloxamer 407 hydrogel (20 w/w.%), including self-assembly ability and biological properties. 58S bioactive glasses (58SiO2-33CaO-9P2O5) containing different Ho2O3 amounts (1.25, 2.5, 3.75, and 5 wt.%) were incorporated into the hydrogel. The formulations were characterized by scanning electron microscopy, differential scanning calorimetry, rheological tests, and [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] MTT cell viability against pre-osteoblastic and osteosarcoma cells. The results evidenced that neither the glass particles dispersed in the hydrogel nor the holmium content in the glasses significantly influenced the hydrogel self-assembly ability (Tmic ~13.8 °C and Tgel ~20 °C). Although, the glass particles considerably diminished the hydrogel viscosity in one order of magnitude at body temperature (37 °C). The cytotoxicity results evidenced that the formulations selectively favored pre-osteoblastic cell proliferation and osteosarcoma cell death. In conclusion, the formulation containing glass with the highest fraction of holmium content (5 wt.%) had the best biological results outcomes aiming its application as theragenerative materials for bone cancer treatment.
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It is known that guanosine derivatives (G) self-assemble in water forming long, flexible, and interacting aggregates (the so-called G-quadruplexes): by modulating the quadruplex charges, e.g. simply using a mixture of guanosine 5'-monophosphate (GMP) and guanosine (Gua), multi-responsive, self-healing hydrogels can be obtained. In this paper, the potential application of G-hydrogels as drug delivery systems has been assessed. Hydrogels were prepared at different Gua:GMP molar ratios. The photosensitizer Methylene Blue and the pro-apoptotic protein cytochrome C were used as cargo molecules. Small angle x-ray scattering and atomic force microscopy experiments confirmed the presence of G-quadruplexes disposed in swollen matrices with different mesh-sizes. Rheology measurements showed that the Gua:GMP molar ratio leads to specific drug release mechanisms, as the gel strength is finely tuned by electrostatic repulsion and van der Waals attraction between G-quadruplexes. Noteworthy, the gel cohesion and the drug release were pH responsive. Swelling, self-healing and cell viability features were also investigated: the results qualify the Gua:GMP hydrogel as an excellent biomaterial that can entrap and deliver key biomolecules in a sustained and responsive release manner.
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Hidrogeles , Azul de Metileno , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Guanosina , Concentración de Iones de HidrógenoRESUMEN
Tetracaine (TTC) is a local anesthetic broadly used for topical and spinal blockade, despite its systemic toxicity. Encapsulation in nanostructured lipid carriers (NLC) may prolong TTC delivery at the site of injection, reducing such toxicity. This work reports the development of NLC loading 4% TTC. Structural properties and encapsulation efficiency (%EE > 63%) guided the selection of three pre-formulations of different lipid composition, through a 23 factorial design of experiments (DOE). DLS and TEM analyses revealed average sizes (193-220 nm), polydispersity (< 0.2), zeta potential |- 21.8 to - 30.1 mV| and spherical shape of the nanoparticles, while FTIR-ATR, NTA, DSC, XRD and SANS provided details on their structure and physicochemical stability over time. Interestingly, one optimized pre-formulation (CP-TRANS/TTC) showed phase-separation after 4 months, as predicted by Raman imaging that detected lack of miscibility between its solid (cetyl palmitate) and liquid (Transcutol) lipids. SANS analyses identified lamellar arrangements inside such nanoparticles, the thickness of the lamellae been decreased by TTC. As a result of this combined approach (DOE and biophysical techniques) two optimized pre-formulations were rationally selected, both with great potential as drug delivery systems, extending the release of the anesthetic (> 48 h) and reducing TTC cytotoxicity against Balb/c 3T3 cells.
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Anestésicos Locales/farmacología , Proliferación Celular , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Liberación de Fármacos , Nanoestructuras/administración & dosificación , Tetracaína/farmacología , Anestésicos Locales/química , Animales , Células 3T3 BALB , Ratones , Nanoestructuras/química , Tetracaína/químicaRESUMEN
Melanoma is the most aggressive skin carcinoma and nanotechnology can bring new options for its pharmacological treatment. Nanostructured lipid carriers (NLC) are ideal drug-delivery carriers for hydrophobic drugs, such as the antineoplastic docetaxel (DTX), and hybrid (NLC-in-hydrogel) systems are suitable for topical application. This work describes a formulation of NLCDTX in xanthan-chitosan hydrogel containing lidocaine (LDC) with anticancer and analgesia effects. The optimized nanoparticles encapsulated 96% DTX and rheological analysis revealed inherent viscoelastic properties of the hydrogel. In vitro assays over murine fibroblasts (NIH/3T3) and melanoma cells (B16-F10), human keratinocytes (HaCaT) and melanoma cells (SK-MEL-103) showed reduction of docetaxel cytotoxicity after encapsulation in NLCDTX and HGel-NLCDTX. Addition of LDC to the hybrid system (HGel-NLCDTX-LDC) increased cell death in tumor and normal cells. In vivo tests on C57BL/6J mice with B16-F10-induced melanoma indicated that LDC, NLCDTX, HGel-NLCDTX-LDC and NLCDTX + HGel-LDC significantly inhibited tumor growth while microPET/SPECT/CT data suggest better prognosis with the hybrid treatment. No adverse effects were observed in cell survival, weight/feed-consumption or serum biochemical markers (ALT, AST, creatinine, urea) of animals treated with NLCDTX or the hybrid system. These results confirm the adjuvant antitumor effect of lidocaine and endorse HGel-NLCDTX-LDC as a promising formulation for the topical treatment of melanoma.
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Painful conditions of the temporomandibular joint (TMJ) are challenging to manage and most attempts often result in unsatisfactory outcomes. In such context, nanocarrier systems, such as polymeric micelles, have been showing encouraging results in solving therapeutic limitations. Poloxamers are widely used, especially PL 407, because of their high biocompatibility and approval by the Food and Drug Administration (FDA) for clinical use. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has shown important antinociceptive and anti-inflammatory activity. The present study evaluated the efficacy and viability of the micellar system of PL-15dPGJ2 in a formalin-induced acute pain model in the temporomandibular joint of rats. The PL-15dPGJ2 was prepared and characterized. The animals were pretreated with an intra-articular injection of PL-15dPGJ2 followed by the formalin challenge. The nociceptive response was evaluated at different time-periods and the periarticular tissue and articular wash were collected for analysis. We found that intra-articular injection of PL-15d-PGJ2 produced pain relief at lower concentrations and in a sustained manner compared with free 15d-PGJ2. Moreover, a strong anti-inflammatory effect was observed with decreased levels of key pro-inflammatory cytokines and modulation of the leukocyte migration process. Our findings suggest that 15d-PGJ2 combined with a poloxamer micellar system provided clinical relevance in terms of bioavailability, long-lasting effect, and safe dosage. The formulation investigated herein is a promising micellar carrier system for managing pain conditions of the TMJ.
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Antiinflamatorios/administración & dosificación , Artralgia/prevención & control , Portadores de Fármacos , Poloxámero/química , Prostaglandina D2/análogos & derivados , Trastornos de la Articulación Temporomandibular/prevención & control , Articulación Temporomandibular/efectos de los fármacos , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Artralgia/inducido químicamente , Artralgia/metabolismo , Artralgia/fisiopatología , Disponibilidad Biológica , Quimiotaxis de Leucocito/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Composición de Medicamentos , Formaldehído , Mediadores de Inflamación/metabolismo , Inyecciones Intraarticulares , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Micelas , Prostaglandina D2/administración & dosificación , Prostaglandina D2/química , Prostaglandina D2/farmacocinética , Ratas Wistar , Articulación Temporomandibular/metabolismo , Articulación Temporomandibular/fisiopatología , Trastornos de la Articulación Temporomandibular/inducido químicamente , Trastornos de la Articulación Temporomandibular/metabolismo , Trastornos de la Articulación Temporomandibular/fisiopatología , Distribución TisularRESUMEN
In recent years, the development of hybrid drug delivery systems, such as hydrogels and nanoparticles, has gained considerable attention as new formulations for skin-delivery. Meanwhile, transdermal diffusion synthetic membranes have been used to assess skin permeability to these systems, providing key insights into the relationships between drug and nanoformulations. In this study, benzocaine-loaded poly-ε-caprolactone nanoparticles (BZC:NPs) were synthesized, characterized and incorporated into Poloxamer 407-based hydrogel (PL407). Benzocaine (BZC) was used as a drug model since has been commonly applied as a topical pain reliever in the last years. Hence, we developed a hybrid polymeric nanoparticle/thermosensitive hydrogels system and evaluated the in vitro permeation of the BZC, as well as nanoformulation tracking in an artificial membrane. In vitro permeation study was conducted in a vertical diffusion cell system using a Strat-M® membrane model. BZC:NPs were prepared by coprecipitation method and their physicochemical stability measured before incorporating into the thermosensitive hydrogel. Also, viscosity measurements and sol-gel transition temperature were performed by rheological analysis. Different techniques, including microscopy, were used to tracking the nanoparticles on both receptor medium and synthetic membranes. Results showed high BZC encapsulation efficiency into NPs (93%) and good physicochemical stability before and after hydrogel incorporation. BZC in vitro permeation kinetics from NPs-loaded Poloxamer 407-based hydrogel presented slower permeation profile compared with the BZC: Poloxamer 407-based hydrogel. Also, NPs were observed into the diffusion cells receptor compartment after the in vitro permeation study. These results contribute to a better understanding the interaction between hydrogels, nanoparticles and synthetic membrane, as well as open perspectives for the development of new drug delivery systems for skin.
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Benzocaína/administración & dosificación , Caproatos/administración & dosificación , Sistemas de Liberación de Medicamentos , Hidrogeles/administración & dosificación , Lactonas/administración & dosificación , Membranas Artificiales , Nanopartículas/administración & dosificación , Polímeros/administración & dosificación , Piel/metabolismo , Animales , Benzocaína/química , Caproatos/química , Permeabilidad de la Membrana Celular , Composición de Medicamentos , Humanos , Hidrogeles/química , Lactonas/química , Nanopartículas/química , Polímeros/química , TemperaturaRESUMEN
Functional polymeric nanoparticles have attracted attention for different biomedical applications, including drug delivery. Poloxamers (PL), a synthetic copolymers of poly(ethyleneoxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), that exhibit thermoreversible behavior in aqueous solutions. Physicochemical properties of Oleic Acid-Poloxamer (OA-PL) organogel for intravaginal controlled Voriconazole (VRC) delivery were assessed using three different oils (isopropyl myristate - IPM, isopropyl palmitate - IPP, and oleic acid - OA, in order to select the most suitable oil phase for increasing the solubility of the drug and its dispersion in the final aqueous phase. Organogel structural organization was assessed by VRC partition coefficient, differential scanning calorimetry (DSC), rheological analysis, and drug release assay. These data are complementary to the research article entitled "Sodium alginate in oil-poloxamer organogels for intravaginal drug delivery: influence on structural parameters, drug release mechanisms, cytotoxicity and in vitro antifungal activity" - Materials Science and Engineering: C, 2019. 99: p. 1350-1361.
RESUMEN
Local administration of antimicrobial agents is the first therapeutic approach for the treatment of Candida albicans infections. The duration of contact of formulations with the vaginal mucosa is critical for therapeutic efficacy. This study describes the development of organogels employing an oil phase composed of oleic acid (OA) and an aqueous phase consisting of the poloxamer PL407, alone or in association with PL188, together with 0.25-1% sodium alginate (SA), in order to obtain an intravaginal drug delivery system capable of modulating the release of voriconazole (VRC). VRC was solubilized in oleic acid homogenized with the PL-SA aqueous phase, at a final concentration of 5â¯mg/mL. Physicochemical characterization was performed for evaluation of the influence of SA on organogel structural organization, biopharmaceutical properties, pharmacological efficacy, and cytotoxicity, envisaging use of the formulation for the treatment of vaginal candidiasis. The enthalpy variation values showed greater changes in the presence of PL188 and after the incorporation of SA or VRC in the organogels. Rheological analysis showed Tsol-gel values in the ranges 11-39⯰C and 27-30⯰C for the OA-PL407 and OA-PL407-188 formulations, respectively. Oscillatory analysis of OA-PL407-188 showed that G' was ~20-fold higher than Gâ³, even after submitting the formulation to temperature variation. VRC-OA-PL407 showed fast drug release from 0.5 to 4â¯h, maintaining total release (~100%) up to 24â¯h. The incorporation of SA in the organogels enabled modulation of VRC release, with different release percentages for 0.25% SA (~75%), 0.5% SA (~55%), and 1% SA (~35%). The formulation was non-cytotoxic towards HeLa and Vero cell lines. In diffusion tests, it was able to prevent the growth of Candida albicans and Candida krusei. In conclusion, the results suggested that OA-PL407-188-SA organogels could be possible new systems for VRC delivery, with potential for use in future vaginal applications.
Asunto(s)
Alginatos/química , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Geles/química , Aceites/química , Poloxámero/química , Administración Intravaginal , Animales , Antifúngicos/química , Rastreo Diferencial de Calorimetría , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Células HeLa , Humanos , Cinética , Pruebas de Sensibilidad Microbiana , Transición de Fase , Reología , Temperatura , Células Vero , Voriconazol/administración & dosificación , Voriconazol/química , Voriconazol/farmacología , Difracción de Rayos XRESUMEN
The present study examined the efficacy of the topical 15dPGJ2poloxamer 407 hydrogel in an atopic dermatitis (AD) animal model. The 15dPGJ2 hydrogel was prepared and characterized. The examined rats possessed ADLike cutaneous lesions, which were induced using 2,4dinitrochlorobenzene, the rats were then treated with a hydrogel vehicle, 15dPGJ2 hydrogel or tacrolimus for 14 days. The rats were sacrificed and blood samples were collected to quantify the IgE levels. Subsequently, skin biopsies were stained with toluidine blue to identify mast cells and immunohistochemistry was performed for RORγt and TNFα. Histological analyses demonstrated that 15dPGJ2 hydrogel significantly decreased mast cell infiltration (P<0.05) when compared with the ADgroup. Tacrolimus at 0.1% exhibited decreased mast cell infiltration; however, this difference was not statistically significant from the ADgroup. Topical 15dPGJ2 hydrogel and Tacrolimus 0.1% significantly reduced the serum levels of IgE (P<0.05) compared with the ADgroup. Immunohistochemistry revealed a significant decrease in RORγt and TNFα positive cell expression (P<0.05) in the 15dPGJ2 hydrogel group compared with the ADgroup. In summary, topical administration of 15dPGJ2 hydrogel had a beneficial effect on AD symptoms, suggesting that this formulation may be a useful strategy for the treatment of AD.
Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Dinitroclorobenceno/farmacología , Hidrogeles/farmacología , Inmunosupresores/farmacología , Prostaglandina D2/análogos & derivados , Administración Tópica , Animales , Dermatitis Atópica/patología , Inmunoglobulina E/sangre , Inmunohistoquímica , Masculino , Mastocitos/efectos de los fármacos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Prostaglandina D2/farmacología , Ratas , Ratas Wistar , Piel , Tacrolimus/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Ropivacaine (RVC) is an enantiomerically pure local anesthetic (LA) largely used in surgical procedures, which presents physico-chemical and therapeutic properties similar to those of bupivacaine (BPV), but associated to less systemic toxicity. This study focuses on the development and pharmacological evaluation of a RVC in 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-beta-CD (9.46 M(-1)) and showed an increase on RVC solubility upon complexation. Release kinetics revealed a decrease on RVC release rate and reduced hemolytic effects after complexation (onset at 3.7 mM and 11.2mM for RVC and RVC HP-beta-CD, respectively) were observed. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray analysis (X-ray) showed the formation and the morphology of the complex. Nuclear magnetic resonance (NMR) and job-plot experiments afforded data regarding inclusion complex stoichiometry (1:1) and topology. Sciatic nerve blockade studies showed that RVC HP-beta-CD was able to reduce the latency without increasing the duration of motor blockade, but prolonging the duration and intensity of the sensory blockade (p<0.001) induced by the LA in mice. These results identify the RVC HP-beta-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation.