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Osteomyelitis is an inflammation of bone tissue usually caused by pyogenic bacteria. The most recurrent clinical approach consists of bone debridement followed by parenteral administration of antibiotics. However, systemic antibiotic treatment has limitations regarding absorption rate and bioavailability over time. The main challenge of osteomyelitis treatment consists of coupling the persistent infection treatment with the regeneration of the bone debrided. In this work, we developed an injectable drug delivery system based on poloxamer 407 hydrogel containing undoped Mg, Zn-doped tricalcium phosphate (ß-TCP), and teicoplanin, a broad-spectrum antibiotic. We evaluated how the addition of teicoplanin and ß-TCP affected the micellization, gelation, particle size, and surface charge of the hydrogel. Later, we studied the hydrogel degradation and drug delivery kinetics. Finally, the bactericidal, biocompatibility, and osteogenic properties were evaluated through in vitro studies and confirmed by in vivo Wistar rat models. Teicoplanin was found to be encapsulated in the corona portions of the hydrogel micelles, yielding a bigger hydrodynamics radius. The encapsulated teicoplanin showed a sustained release over the evaluated period, enough to trigger antibacterial properties against Gram-positive bacteria. Besides, the formulations were biocompatible and showed bone healing ability and osteogenic properties. Finally, in vivo studies confirmed that the proposed locally injected formulations yielded osteomyelitis treatment with superior outcomes than parenteral administration while promoting bone regeneration. In conclusion, the presented formulations are promising drug delivery systems for osteomyelitis treatment and deserve further technological improvements.
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Antibacterianos , Fosfatos de Cálcio , Hidrogéis , Osteogênese , Osteomielite , Ratos Wistar , Teicoplanina , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Animais , Fosfatos de Cálcio/química , Teicoplanina/administração & dosagem , Teicoplanina/farmacologia , Teicoplanina/química , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Antibacterianos/química , Ratos , Hidrogéis/química , Hidrogéis/administração & dosagem , Osteogênese/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Staphylococcus aureus/efeitos dos fármacos , Poloxâmero/químicaRESUMO
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 Ósseas , Osteossarcoma , Humanos , Difosfonatos/farmacologia , Hidrogéis , Regeneração Óssea , Sistemas de Liberação de Medicamentos , Ácido Zoledrônico , Neoplasias Ósseas/tratamento farmacológico , Microambiente TumoralRESUMO
The treatment of bone cancer involves tumor resection followed by bone reconstruction of the defect caused by the tumor using biomaterials. Additionally, post-surgery protocols cover chemotherapy, radiotherapy, or drug administration, which are employed as adjuvant treatments to prevent tumor recurrence. In this work, we reviewed new strategies for bone cancer treatment based on bioactive glasses as carriers of cancer-targeted and other drugs that are intended for bone regeneration in conjunction with adjuvant treatments. Drugs used in combination with bioactive glasses can be classified into cancer-target, osteoclast-target, and new therapies (such as gene delivery and bioinorganic). Microparticulated, nanoparticulated, or mesoporous bioactive glasses have been used as drug-delivery systems. Additionally, surface modification through functionalization or the production of composites based on polymers and hydrogels has been employed to improve drug-release kinetics. Overall, although different drugs and drug delivery systems have been developed, there is still room for new studies involving kinase inhibitors or antibody-conjugated drugs, as these drugs have been poorly explored in combination with bioactive glasses.
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OBJECTIVES: To assess the effect of an experimental 58S bioactive glass on dentin permeability (dP) and erosive tooth wear (dentin surface loss - dSL). METHODS: 58S bioactive glass was synthetized using a sol-gel methodology, following by lyophilization and calcination, then mixed with phosphoric acid to obtain a paste (BGP). Forty-eight dentin disks (1 mm-thick) were used for dP, and 48 dentin slabs (3 mm × 3 mm) for dSL, which were assessed at three time intervals: post-EDTA (5 min in 17% EDTA solution); post-treatment (C: distilled water; BGP: experimental bioactive glass paste; NP: Nupro prophylaxis paste; CXT: Clinpro XT varnish); and post-erosive/abrasive cycling. Data were statistically analyzed (α=0.05). RESULTS: For dP and dSL, Groups did not differ significantly post-EDTA (p>0.05). Post-treatment, all groups showed lower dP than C (p<0.05), without differing significantly among them. For the dSL analysis, Groups C, BGP and NP did not differ significantly, showing lower values than CXT (p<0.05). Post-cycling, C continued to show the highest dP (p<0.05). Specimens from Group CXT had the lowest dP and did not differ from NP (p=0.86) which did not differ from BGP (p=0.193). For C and BGP, dP value was higher post-cycling than post-treatment (p<0.05). For NP and CXT, these experimental times did not differ (p>0.05). Post-cycling, dSL for C, BGP and NP did not differ significantly; values were higher than those for CXT (p<0.05). CONCLUSIONS: BGP reduced dP after application, with a reduced effect after cycling. Nonetheless, it was not able to protect dentin against erosive tooth wear. CLINICAL SIGNIFICANCE: Minimizing dentin hypersensitivity is a challenge in the field of dentistry. The development of alternative products with potential to obliterate dentinal tubules and provide resistance to chemical/mechanical stimuli is, thus, highly desirable. We have proposed a material able to reduce dentin permeability, which has emerged as a promising alternative for this purpose.
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Sensibilidade da Dentina , Atrito Dentário , Erosão Dentária , Desgaste dos Dentes , Humanos , Sensibilidade da Dentina/tratamento farmacológico , Ácido Edético/farmacologia , Ácido Edético/uso terapêutico , Dentina , Microscopia Eletrônica de Varredura , Erosão Dentária/prevenção & controleRESUMO
Magnetic bioactive glass-ceramics are biomaterials applied for magnetic hyperthermia in bone cancer treatment, thereby treating the bone tumor besides regenerating the damaged bone. However, combining high bioactivity and high saturation magnetization remains a challenge since the thermal treatment step employed to grow magnetic phases is also related to loss of bioactivity. Here, we propose a new nanocomposite made of superparamagnetic iron oxide nanoparticles (SPIONs) dispersed in a sol-gel-derived bioactive glass matrix, which does not need any thermal treatment for crystallization of magnetic phases. The scanning and transmission electron microscopies, X-ray diffraction, and dynamic light scattering results confirm that the SPIONs are actually embedded in a nanosized glass matrix, thus forming a nanocomposite. Magnetic and calorimetric characterizations evidence their proper behavior for hyperthermia applications, besides evidencing inter-magnetic nanoparticle interactions within the nanocomposite. Bioactivity and in vitro characterizations show that such nanocomposites exhibit apatite-forming properties similar to the highly bioactive parent glass, besides being osteoinductive. This methodology is a new alternative to produce magnetic bioactive materials to which the magnetic properties only rely on the quality of the SPIONs used in the synthesis. Thereby, these nanocomposites can be recognized as a new class of bioactive materials for applications in bone cancer treatment by hyperthermia.
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Hipertermia Induzida , Nanocompostos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Vidro/química , Nanopartículas Magnéticas de Óxido de Ferro , Fenômenos Magnéticos , Nanocompostos/químicaRESUMO
Epidemiological evidence indicates that plant antioxidants activity can treat or help to prevent the development of various diseases. One species with great potential as an antioxidant is Curcuma longa. However, different extraction techniquescan influence isolated chemical compounds. This study investigated chemical composition and antioxidant activity of two rhizome extracts of C. longa: hydroethanolic, obtained by exhaustion (HECLex); and dried by a spray dryer (HECLsd). The phytochemical composition was evaluated by GC/MS. Antioxidant activity was evaluated using DPPH and FRAP assays. Total phenolic compounds and soil analyses were performed. The main components of HECLex were ar-turmerone, γ-curcumene, α-turmerone, and ß-sesquiphellandrene. The main components of HECLsd were 9,12,15-octadecatrienoic acid, 2, 3-bis([trimethylsilyl]oxy) propyl ester, verrucarol, and 1-monolinoleoylglycerol trimethylsilyl ether. HECLsd had significantly higher levels of phenolic compounds and higher antioxidant capacity compared with HECLex. In conclusion, processes of the preparation of C. longarhizomes alter the chemical components and consequently their biological activity.
La evidencia epidemiológica indica que la actividad de los antioxidantes de las plantas pueden tratar o ayudar a prevenir el desarrollo de diversas enfermedades. Una especie con gran potencial como antioxidante es Curcuma longa. Sin embargo, diferentes técnicas de extracción pueden influir en los compuestos químicos aislados. Este estudio investigó la composición química y la actividad antioxidante de dos extractos de rizoma de C. longa: hidroetanólico, obtenido por agotamiento (HECLex); y se seca con un secador por pulverización (HECLsd). La composición fitoquímica se evaluó mediante GC/MS. La actividad antioxidante se evaluó mediante ensayos DPPH y FRAP. Se realizaron análisis de suelos y compuestos fenólicos totales. Los componentes principales de HECLex fueron ar-turmerona, γ-curcumene, α-turmerone y ß-sesquiphellandrene. Los componentes principales de HECLsd fueron ácido 9,12,15-octadecatrienoico, éster 2,3-bis ([trimetilsilil] oxi) propílico, verrucarol y éter 1-monolinoleoilglicerol trimetilsilil. HECLsd tenía niveles significativamente más altos de compuestos fenólicos y mayor capacidad antioxidante en comparación con HECLex. En conclusión, los procesos de preparación de los rizomas de C. longa alteran los componentes químicos y consecuentemente su actividad biológica.
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Extratos Vegetais/farmacologia , Curcuma/química , Antioxidantes/farmacologia , Extratos Vegetais/química , Suplementos Nutricionais , Diarileptanoides/química , Compostos Fenólicos/análise , Radicais Livres , Cromatografia Gasosa-Espectrometria de Massas , Fitoterapia , Antioxidantes/químicaRESUMO
OBJECTIVES: This study evaluated the influence of the cement composition and different polymerization protocols on the bonding chemical interaction of self-adhesive cements with synthetic hydroxyapatite. MATERIALS AND METHODS: Two commercial self-adhesive resin cements (RelyX U200 and Maxcem Elite) were selected, manipulated, mixed with hydroxyapatite dry powder (HAp), dispensed into molds, and distributed into three groups according to polymerization protocols: immediate photoactivation (IP); delayed photoactivation, 10 min self-curing and light-curing (DP); and chemical activation (CA, no light exposure). The detailed chemical information, at atomic scale, on the surface and deeper into the bulk of self-adhesive cement/hydroxyapatite mixtures was evaluated with X-ray photoelectron spectroscopy (XPS). RESULTS: Chemical elements were detected in both cements, such as Na, O, Ca, C, P, and Si. Other elements were detected in minor concentrations. RelyX U200 exhibited the most intense formation of calcium salts products when the cement/HAp mixtures were photoactivated (immediate or delayed). RelyX U200/HAp mixture under delayed photoactivation (DP) also exhibited higher binding energy between calcium moieties of the HAp and methacrylates in the cement. A higher energy difference in the interaction of HAp with the cement comparing the bulk and surface areas was observed when RelyX U200 underwent the delayed photoactivation protocol. Maxcem Elite exhibited an increased chemical reactivity when either chemically activated or immediately photoactivated and a higher binding energy of the carboxyl groups bonded to the calcium of HAp when chemically activated. CONCLUSIONS: The interaction of cements with hydroxyapatite is chemical in nature and leads to the formation of calcium salts, which may favor better integrity and longevity of adhesive restorations. The polymerization protocol affects the chemical interaction in mixtures of self-adhesive cements and hydroxyapatite, influencing the formation of these salts and the establishment of intermolecular interactions between the HAp and the cements.
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Cimentos Dentários/uso terapêutico , Hidroxiapatitas/uso terapêutico , Autocura de Resinas Dentárias , Cimentos Dentários/química , Cura Luminosa de Adesivos Dentários , Espectroscopia Fotoeletrônica , Polimerização , Cimentos de Resina/uso terapêuticoRESUMO
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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Traditional cancer treatments, such as surgery, radiotherapy, and chemotherapy, are still the most effective clinical practice options. However, these treatments may display moderate to severe side effects caused by their low temporal or spatial resolution. In this sense, photonic nanomedicine therapies have been arising as an alternative to traditional cancer treatments since they display more control of temporal and spatial resolution, thereby yielding fewer side effects. In this work, we reviewed the challenge of current cancer treatments, using the PubMed and Web of Science database, focusing on the advances of three prominent therapies approached by photonic nanomedicine: (i) photothermal therapy; (ii) photodynamic therapy; (iii) photoresponsive drug delivery systems. These photonic nanomedicines act on the cancer cells through different mechanisms, such as hyperthermic effect and delivery of chemotherapeutics and species that cause oxidative stress. Furthermore, we covered the recent advances in materials science applied in photonic nanomedicine, highlighting the main classes of materials used in each therapy, their applications in the context of cancer treatment, as well as their advantages, limitations, and future perspectives. Finally, although some photonic nanomedicines are undergoing clinical trials, their effectiveness in cancer treatment have already been highlighted by pre-clinical studies.
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Although the three main phases of iron oxide - hematite, maghemite, and magnetite - exhibit superparamagnetic properties at the nanoscale, only maghemite and magnetite phases have been explored in magnetic bioactive glass-ceramics aimed at applications in cancer treatment by hyperthermia. In this work, it is reported for the first time the superparamagnetic properties of hematite nanocrystals grown in a 58S bioactive glass matrix derived from sol-gel synthesis. The glass-ceramics are based on the (100-x)(58SiO2-33CaO-9P2O5)-xFe2O3 system (x = 10, 20 and 30 wt%). A thermal treatment leads to the growth of hematite (α-Fe2O3) nanocrystals, conferring superparamagnetic properties to the glass-ceramics, which is enough to produce heat under an external alternating magnetic field. Besides, the crystallization does not inhibit materials bioactivity, evidenced by the formation of calcium phosphate onto the glass-ceramic surface upon soaking in simulated body fluid. Moreover, their cytotoxicity is similar to other magnetic bioactive glass-ceramics reported in the literature. Finally, these results suggest that hematite nanocrystals' superparamagnetic properties may be explored in multifunctional glass-ceramics applied in bone cancer treatment by hyperthermia allied to bone regeneration.