Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers: evaluation of antioxidant potential for dermal applications

Evren H Gokce1, Emrah Korkmaz1, Eleonora Dellera2, Giuseppina Sandri2, M Cristina Bonferoni2, Ozgen Ozer11Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Ege, Izmir, Turkey; 2Department of Drug Sciences, University of Pavia, Pavia, ItalyBackground: Excessive generation of radical oxygen species (ROS) is a contributor to skin pathologies. Resveratrol (RSV) is a potent antioxidant. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can ensure close contact and increase the amount of drug absorbed into the skin. In this study, RSV was loaded into SLN and NLC for dermal applications.Methods: Nanoparticles were prepared by high shear homogenization using Compritol 888ATO, Myglyol, Poloxamer188, and Tween80. Particle size (PS), polydispersity index (PI), zeta potential (ZP), drug entrapment efficiency (EE), and production yield were determined. Differential scanning calorimetry (DSC) analysis and morphological transmission electron microscopy (TEM) examination were conducted. RSV concentration was optimized with cytotoxicity studies, and net intracellular accumulation of ROS was monitored with cytofluorimetry. The amount of RSV was determined from different layers of rat abdominal skin.Results: PS of uniform RSV-SLN and RSV-NLC were determined as 287.2 nm ± 5.1 and 110.5 nm ± 1.3, respectively. ZP was –15.3 mV ± 0.4 and –13.8 mV ± 0.1 in the same order. The drug EE was 18% higher in NLC systems. TEM studies showed that the drug in the shell model was relevant for SLN, and that the melting point of the lipid in NLC was slightly lower. Concentrations below 50 µM were determined as suitable RSV concentrations for both SLN and NLC in cell culture studies. RSV-NLC showed less fluorescence, indicating less ROS production in cytofluorometric studies. Ex vivo skin studies revealed that NLC are more efficient in carrying RSV to the epidermis.Conclusion: This study suggests that both of the lipid nanoparticles had antioxidant properties at a concentration of 50 µM. When the two systems were compared, NLC penetrated deeper into the skin. RSV-loaded NLC with smaller PS and higher drug loading appears to be superior to SLN for dermal applications.Keywords: solid lipid nanoparticles, nanostructured lipid carriers, resveratro

Bentonite- and Palygorskite-Based Gels for Topical Drug Delivery Applications

Bentonite or palygorskite-based hydrogels have recently been suggested as a strategy to increase bioavailability and control the retention and release of therapeutic candidates. In this work, clay-based hydrogels loaded with diclofenac acid nanocrystals have been successfully designed and developed. The aim was to improve diclofenac solubility, its dissolution rate and to enhance its local bioavailability after topical application. For this purpose, diclofenac acid nanocrystals were prepared by wet media milling technology and then loaded into inorganic hydrogels based on bentonite and/or palygorskite. Diclofenac acid nanocrystals were characterized by morphology, size, and zeta potential. Moreover, rheological behavior, morphology, solid state, release studies, and in vitro skin penetration/permeation of diclofenac acid nanocrystals-loaded hydrogels were performed. The hydrogels were characterized by a crystalline structure, and demonstrated that the inclusion of diclofenac in clay-based hydrogels resulted in an increased thermal stability. The presence of both palygorskite and bentonite reduced nanocrystal mobility, and consequently its release and penetration into the skin. On the other hand, bentonite- or palygorskite-based hydrogels revealed great potential as an alternative strategy to enhance topical bioavailability of DCF nanocrystals, enhancing their penetration to the deeper skin layers

Epigenetic targeting of bromodomain protein BRD4 counteracts cancer cachexia and prolongs survival

Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting. Remarkably, in C26-tumor-bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq and ChIP analyses, we unveil that BET proteins directly promote the muscle atrophy program during cachexia. In addition, BET proteins are required to coordinate an IL6-dependent AMPK nuclear signaling pathway converging on FoxO3 transcription factor. Overall, these findings indicate that BET proteins may represent a promising therapeutic target in the management of cancer cachexia

Wound Healing Activity of Nanoclay/Spring Water Hydrogels

Background: hydrogels prepared with natural inorganic excipients and spring waters are commonly used in medical hydrology. Design of these clay-based formulations continues to be a field scarcely addressed. Safety and wound healing properties of different fibrous nanoclay/spring water hydrogels were addressed. Methods: in vitro biocompatibility, by means of MTT assay, and wound healing properties were studied. Confocal Laser Scanning Microscopy was used to study the morphology of fibroblasts during the wound healing process. Results: all the ingredients demonstrated to be biocompatible towards fibroblasts. Particularly, the formulation of nanoclays as hydrogels improved biocompatibility with respect to powder samples at the same concentration. Spring waters and hydrogels were even able to promote in vitro fibroblasts motility and, therefore, accelerate wound healing with respect to the control. Conclusion: fibrous nanoclay/spring water hydrogels proved to be skin-biocompatible and to possess a high potential as wound healing formulations. Moreover, these results open new prospects for these ingredients to be used in new therapeutic or cosmetic formulations.This research was funded by Ministerio de Ciencia e Innovación, CGL2016–80833-R; Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, P18-RT-3786 and Ministerio de Educación, Cultura y Deporte, FPU15/01577.Peer reviewe

Topographical and compositional gradient tubular scaffold for bone to tendon interface regeneration

The enthesis is an extremely specific region, localized at the tendon–bone interface (TBI) and made of a hybrid connection of fibrocartilage with minerals. The direct type of enthesis tissue is commonly subjected to full laceration, due to the stiffness gradient between the soft tissues and hard bone, and this often reoccurs after surgical reconstruction. For this purpose, the present work aimed to design and develop a tubular scaffold based on pullulan (PU) and chitosan (CH) and intended to enhance enthesis repair. The scaffold was designed with a topographical gradient of nanofibers, from random to aligned, and hydroxyapatite (HAP) nanoparticles along the tubular length. In particular, one part of the tubular scaffold was characterized by a structure similar to bone hard tissue, with a random mineralized fiber arrangement; while the other part was characterized by aligned fibers, without HAP doping. The tubular shape of the scaffold was also designed to be extemporarily loaded with chondroitin sulfate (CS), a glycosaminoglycan effective in wound healing, before the surgery. Micro CT analysis revealed that the scaffold was characterized by a continuous gradient, without interruptions from one end to the other. The gradient of the fiber arrangement was observed using SEM analysis, and it was still possible to observe the gradient when the scaffold had been hydrated for 6 days. In vitro studies demonstrated that human adipose stem cells (hASC) were able to grow and differentiate onto the scaffold, expressing the typical ECM production for tendon in the aligned zone, or bone tissue in the random mineralized part. CS resulted in a synergistic effect, favoring cell adhesion/proliferation on the scaffold surface. These results suggest that this tubular scaffold loaded with CS could be a powerful tool to support enthesis repair upon surgery.Horizon 2020 Research and Innovation Programme under Grant Agreement No. 81460

Ciprofloxacin carrier systems based on hectorite/halloysite hybrid hydrogels for potential wound healing applications

The design of multifunctional nanomaterials which can help the healing processes of skin, preventing the bacterial infections, is crucial for the development of suitable therapy for the treatment of chronic lesions. The use of clay minerals in wound healing applications is well documented since the prehistoric period and offers several advantages due to their intrinsic properties. Herein, we report the development of ciprofloxacin carrier systems based on hectorite/halloysite (Ht/Hal) hybrid hydrogels for potential wound healing applications. To achieve this objective firstly the ciprofloxacin molecules were loaded onto Hal by a supramolecular and covalent approach. The so obtained fillers were thoroughly investigated by several techniques and at molecular level by means of quantum mechanics calculations along with empirical interatomic potentials. Afterwards the modified Hal were used as filler for Ht hydrogels. The introduction of modified Hal, in hectorite hydrogel, helps the gel formation with an improvement of the rheological properties. The in vitro kinetic release from both the fillers and from the hybrid hydrogels was studied both at skin's pH (5.4) and under neutral conditions (pH 7.4); in addition, the factors controlling the ciprofloxacin release process were determined and discussed. Finally, the in vitro biocompatibility of the Hal fillers was evaluated by means of cytotoxic assays and laser scanning confocal microscopy on normal human dermal fibroblasts.The work was carried out in the frame of the PON “AIM: Attrazione e Mobilità Internazionale” No. 1808223-1 project. Authors are thankful to H.A. Duarte for providing atomic coordinates of halloysite, to the CSIC Computational Center and the University of Granada Computation Center for computation facilities, and the Andalusian project grants RNM-1897 and P18-RT-3786 , and the Spanish MINECO projects , PCIN-2017-098 , FIS2016-77692-C2-2-P and CGL2016-80833-R , for the financial support of this research

Mycelium-based biomaterials as smart devices for skin wound healing

Introduction: Recently, mycelia of Ganoderma lucidum and Pleurotus ostreatus, edible fungi, have been characterized in vitro as self-growing biomaterials for tissue engineering since they are constituted of interconnected fibrous networks resembling the dermal collagen structure.Aim: This work aims to investigate the biopharmaceutical properties of G. lucidum and P. ostreatus mycelia to prove their safety and effectiveness in tissue engineering as dermal substitutes.Methods: The mycelial materials were characterized using a multidisciplinary approach, including physicochemical properties (morphology, thermal behavior, surface charge, and isoelectric point). Moreover, preclinical properties such as gene expression and in vitro wound healing assay have been evaluated using fibroblasts. Finally, these naturally-grown substrates were applied in vivo using a murine burn/excisional wound model.Conclusions: Both G. lucidum and P. ostreatus mycelia are biocompatible and able to safely and effectively enhance tissue repair in vivo in our preclinical model

Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection. \ua9 2018 The Author(s). Published by Baishideng Publishing Group Inc. All rights reserved