Topical application of melatonin accelerates the maturation of skin wounds and increases collagen deposition in a rat model of diabetes.

AIMS: This study aimed to evaluate the cicatricial potential of melatonin when applied to wounds of diabetic rats. MATHERIALS AND METHODS: The formulation containing melatonin was developed and applied topically to cutaneous wounds of diabetic rats. 48 Wistar rats were used, divided into two groups of 24 diabetic animals each: (i) control group (CG), the animals received topical application of the no-melatonin formulation; (ii) treatment group (TG), the animals received topical application of the melatonin-containing formulation. All animals in each group were treated at four time points: 3, 7, 14, and 21 days. Each subgroup consisted of six animals. RESULTS: The treatment with melatonin improved wound healing by promoting wound closure earlier than the control group evaluated. Also improved a better resolution of the inflammatory phase observed mainly at 7 days, higher tissue maturation and expressive collagen deposition. CONCLUSION: The observed data reveal that the use of melatonin topically could be a promising strategy for the healing of wounds in diabetes. The results of this study elucidate the effects of previously described pathways in which it is proposed that melatonin acts promoting wound healing in diabetes.

Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system.

Mutations on the epidermal growth factor receptor (EGFR), induction of angiogenesis, and reprogramming cellular energetics are all biological features acquired by tumor cells during tumor development, and also known as the hallmarks of cancer. Targeted therapies that combine drugs that are capable of acting against such concepts are of great interest, since they can potentially improve the therapeutic efficacy of treatments of complex pathologies, such as glioblastoma (GBM). However, the anatomical location and biological behavior of this neoplasm imposes great challenges for targeted therapies. A novel strategy that combines alpha-cyano-4-hydroxycinnamic acid (CHC) with the monoclonal antibody cetuximab (CTX), both carried onto a nanotechnology-based delivery system, is herein proposed for GBM treatment via nose-to-brain delivery. The biological performance of Poly (D,L-lactic-co-glycolic acid)/chitosan nanoparticles (NP), loaded with CHC, and conjugated with CTX by covalent bonds (conjugated NP) were extensively investigated. The NP platforms were able to control CHC release, indicating that drug release was driven by the Weibull model. An ex vivo study with nasal porcine mucosa demonstrated the capability of these systems to promote CHC and CTX permeation. Blot analysis confirmed that CTX, covalently associated to NP, impairs EGRF activation. The chicken chorioallantoic membrane assay demonstrated a trend of tumor reduction when conjugated NP were employed. Finally, images acquired by fluorescence tomography evidenced that the developed nanoplatform was effective in enabling nose-to-brain transport upon nasal administration. In conclusion, the developed delivery system exhibited suitability as an effective novel co-delivery approaches for GBM treatment upon intranasal administration.

Nasal biocompatible powder of Geraniol oil complexed with cyclodextrins for neurodegenerative diseases: physicochemical characterization and in vivo evidences of nose to brain delivery.

Recently, many studies have shown that plant metabolites, such as geraniol (GER), may exert anti-inflammatory effects in neurodegenerative diseases and, in particular, Parkinson's disease (PD) models. Unfortunately, delivering GER to the CNS via nose-to-brain is not feasible due to its irritant effects on the mucosae. Therefore, in the present study ß-cyclodextrin (ßCD) and its hydrophilic derivative hydroxypropyl-beta-cyclodextrin (HPßCD) were selected as potential carriers for GER nose-to-brain delivery. Inclusion complexes were formulated and the biocompatibility with nasal mucosae and drug bioavailability into cerebrospinal fluid (CSF) were studied in rats. It has been demonstrated by DTA, FT-IR and NMR analyses that both the CDs were able to form 1:1 GER-CD complexes, arising long-term stable powders after the freeze-drying process. GER-HPßCD-5 and GER-ßCD-2 complexes exhibited comparable results, except for morphology and solubility, as demonstrated by SEM analysis and phase solubility study, respectively. Even though both complexes were able to directly and safely deliver GER to CNS, GER-ßCD-2 displayed higher ability in releasing GER in the CSF. In conclusion, ßCD complexes can be considered a very promising tool in delivering GER into the CNS via nose-to-brain route, preventing GER release into the bloodstream and ensuring the integrity of the nasal mucosa.

Frontal lifting using a tissue expander in pachydermoperiostosis: A case report.

Pachydermoperiostosis, a rare condition, is characterized by pachydermia, finger clubbing, and periostosis. We present an unusual treatment for frontal rhytids, for which we used a tissue expander that contributed to thinning of the skin and the depth of the rhytids prior to frontal lifting. The results were maintained after one year.

Nose-to-brain drug delivery mediated by polymeric nanoparticles: influence of PEG surface coating.

Intranasal administration of mucus-penetrating nanoparticles is an emerging trend to increase drug delivery to the brain. In order to overcome rapid nasal mucociliary clearance, low epithelial permeation, and local enzymatic degradation, we investigated the influence of PEGylation on nose-to-brain delivery of polycaprolactone (PCL) nanoparticles (PCL-NPs) encapsulating bexarotene, a potential neuroprotective compound. PEGylation with 1, 3, 5, and 10% PCL-PEG did not affect particle diameter or morphology. Upon incubation with artificial nasal mucus, only 5 and 10% of PCL-PEG coating were able to ensure NP stability and homogeneity in mucus. Rapid mucus-penetrating ability was observed for 98.8% of PCL-PEG5% NPs and for 99.5% of PCL-PEG10% NPs. Conversely, the motion of non-modified PCL-NPs was markedly slower. Fluorescence microscopy showed that the presence of PEG on NP surface did not reduce their uptake by RMPI 2650 cells. Fluorescence tomography images evidenced higher translocation into the brain for PCL-PEG5% NPs. Bexarotene loaded into PCL-PEG5% NPs resulted in area under the curve in the brain (AUCbrain) 3 and 2-fold higher than that for the drug dispersion and for non-PEGylated NPs (p < 0.05), indicating that approximately 4% of the dose was directly delivered to the brain. Combined, these results indicate that PEGylation of PCL-NPs with PCL-PEG5% is able to reduce NP interactions with the mucus, leading to a more efficient drug delivery to the brain following intranasal administration. Graphical abstract.

Nasal administration of nanoencapsulated geraniol/ursodeoxycholic acid conjugate: Towards a new approach for the management of Parkinson's disease.

The combined use of different therapeutic agents in the treatment of neurodegenerative disorders is a promising strategy to halt the disease progression. In this context, we aimed to combine the anti-inflammatory properties of geraniol (GER) with the mitochondrial rescue effects of ursodeoxycholic acid (UDCA) in a newly-synthesized prodrug, GER-UDCA, a potential candidate against Parkinson's disease (PD). GER-UDCA was successfully synthetized and characterized in vitro for its ability to release the active compounds in physiological environments. Because of its very poor solubility, GER-UDCA was entrapped into both lipid (SLNs) and polymeric (NPs) nanoparticles in order to explore nose-to-brain pathway towards brain targeting. Both GER-UDCA nanocarriers displayed size below 200 nm, negative zeta potential and the ability to increase the aqueous dissolution rate of the prodrug. As SLNs exhibited the higher GER-UDCA dissolution rate, this formulation was selected for the in vivo GER-UDCA brain targeting experiments. The nasal administration of GER-UDCA-SLNs (1 mg/kg of GER-UDCA) allowed to detect the prodrug in rat cerebrospinal fluid (concentration range = 1.1 to 4.65 µg/mL, 30-150 min after the administration), but not in the bloodstream, thus suggesting the direct nose to brain delivery of the prodrug. Finally, histopathological evaluation demonstrated that, in contrast to the pure GER, nasal administration of GER-UDCA-SLNs did not damage the structural integrity of the nasal mucosa. In conclusion, the present data suggest that GER-UDCA-SLNs could provide an effective and non-invasive approach to boost the access of GER and UDCA to the brain with low dosages.

Increased Nose-to-Brain Delivery of Melatonin Mediated by Polycaprolactone Nanoparticles for the Treatment of Glioblastoma.

PURPOSE: Intranasal administration has been extensively applied to deliver drugs to the brain. In spite of its unfavorable biopharmaceutic properties, melatonin (MLT) has demonstrated anticancer effects against glioblastoma. This study describes the nose-to-brain delivery of MLT-loaded polycaprolactone nanoparticles (MLT-NP) for the treatment of glioblastoma. METHODS: MLT-NP were prepared by nanoprecipitation. Following intranasal administration in rats, brain targeting of the formulation was demonstrated by fluorescence tomography. Brain and plasma pharmacokinetic profiles were analyzed. Cytotoxicity against U87MG glioblastoma cells and MRC-5 non-tumor cells was evaluated. RESULTS: MLT-NP increased the drug apparent water solubility ~35 fold. The formulation demonstrated strong activity against U87MG cells, resulting in IC50 ~2500 fold lower than that of the free drug. No cytotoxic effect was observed against non-tumor cells. Fluorescence tomography images evidenced the direct translocation of nanoparticles from nasal cavity to the brain. Intranasal administration of MLT-NP resulted in higher AUCbrain and drug targeting index compared to the free drug by either intranasal or oral route. CONCLUSIONS: Nanoencapsulation of MLT was crucial for the selective antitumoral activity against U87MG. In vivo evaluation confirmed nose-to-brain delivery of MLT mediated by nanoparticles, highlighting the formulation as a suitable approach to improve glioblastoma therapy.

Thermoreversible mucoadhesive polymer-drug dispersion for sustained local delivery of budesonide to treat inflammatory disorders of the GI tract.

Mucoadhesive drug formulations have been studied and used as alternatives to conventional formulations in order to achieve prolonged retention at the intended site. In addition to providing a controlled drug release, several drugs and disease conditions might benefit from mucoadhesive formulations, contributing to better therapeutic outcomes. Here, we describe the development and the in vitro/in vivo characterization of a mucoadhesive in situ gellifying formulation using PF127, a thermo reversible polymer, entrapping budesonide (BUD), a potent corticosteroid used for the treatment of a wide range of inflammatory diseases, including those affecting mucosas, such as in the GI tract. PF127 formulations (15-17%) were successfully prepared by a cold method as a thermo reversible in situ gelling dispersion for mucosal drug delivery, as confirmed by DSC. Sol-gel temperatures of PF127 formulations (25-39 °C) were observed by dynamic gelation and determined by microrheology and oscillatory rheometry. X-ray diffractograms and TEM images showed that BUD was completely solubilized within the polymeric micelles. In vitro, the gels showed 5-14 g force of mucoadhesion, and the ex vivo studies confirmed that the formulation efficiently adhered to the mucosa. Histopathological analysis combined with fluorescence images and ex vivo intestinal permeation confirmed that the formulation remained on the TGI mucosa for at least 4 h after administration. In vivo studies conducted in a murine model of intestinal mucositis demonstrated that the 16% PF127 BUD formulation was able to resolve the inflammatory injury in the intestinal mucosa. Results demonstrate that fine-tuning of PF127 formulations along with adequate selection of the drug agent, thorough characterization of the dispersions and their interactions with biological interfaces leads to the development of effective controlled drug delivery systems targeted to GI inflammatory diseases.

Functional and aesthetic evaluation after cranial reconstruction with polymethyl methacrylate prostheses using low-cost 3D printing templates in patients with cranial defects secondary to decompressive craniectomies: A prospective study.

BACKGROUND: Cranial reconstruction surgery is a procedure used as an attempt to reestablish the cranial bone anatomy. This study evaluates the symptomatic and aesthetic improvement of patients with cranial defects secondary to decompressive craniectomies after cranial reconstruction with customized polymethyl methacrylate (PMMA) prostheses. Secondly, we aim to divide our experience in the production of these prostheses with a low-cost method. METHODS: A prospective study was carried out with patients submitted to cranioplasty at the Hospital da Restauração between 2014 and 2017. A total of 63 cranioplasties were performed using customized PMMA prosthesis produced by 3D impression molds. All patients underwent a functional and aesthetic evaluation questionnaire in the preoperative period and in the sixth postoperative month. RESULTS: Sixty-three patients underwent cranioplasty with a mean age of 33 years, ranging from 13 to 58 years, 55 males and 8 females. The mean area of the defect was 147 cm2. The mean postoperative follow-up of the patients was 21 months, ranging from 6 to 33 months. Fifty-five patients attended the 6-month postoperative consultation. All patients presented symptomatic improvement after reconstruction of the skull. The infection rate was 3.2%, 4.8% of extrusion, 1.6% of prosthesis fracture, 7.9% of extradural hematoma, 17.4% of reoperation, 5% of wound dehiscence, and 4.8% of removal of the prosthesis. CONCLUSION: Cranioplasty, with a customized PMMA prosthesis, improved the symptoms and aesthetic appearance of all operated patients. The use of prototypes to customize cranial prostheses facilitated the operative technique and allowed the recovery of a cranial contour very close to normal.