In Vitro Antioxidant Activity and In Vivo Topical Efficacy of Lipid Nanoparticles Co-Loading Idebenone and Tocopheryl Acetate

Idebenone (IDE) is a strong antioxidant that has been proposed for the treatment of skin disorders, including skin ageing. Unfavorable physico-chemical properties make IDE a poor skin permeant where effectiveness could be improved by its loading into suitable delivery systems such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC). In this work, we designed novel IDE-loaded NLC containing tocopheryl acetate (VitE) as a liquid component to obtain a synergic effect between IDE and VitE. The resulting NLC showed small particle sizes (24-42 nm), low polydispersity indices (<0.300), good stability, and were assessed for their in vitro antioxidant activity and in vivo topical effects. IDE-loaded SLN and NLC showed a high antioxidant activity in in vitro assays (DPPH and reducing power method) and provided a similar and significant protection from oxidative stress of fibroblast cells, HS-68, exposed to UV light. After a two-week topical treatment of human volunteers with gels containing IDE-loaded SLN or NLC, a similar increase in skin hydration was observed, while IDE NLC reduced skin pigmentation to a greater extent than IDE SLN. These results suggest that co-loading IDE and VitE into NLC could be a promising strategy to obtain topical formulations with improved photo-protection

Dual sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: design, synthesis and pharmacological evaluation

The development of σ1 receptor antagonists hybridized with a H2S-donor is here reported. We aimed to obtain improved analgesic effects when compared to σ1 receptor antagonists or H2S-donors alone. In an in vivo model of sensory hypersensitivity, thioamide 1a induced analgesia which was synergistically enhanced when associated with the σ1 receptor antagonist BD-1063. The selective σ1 receptor agonist PRE-084 completely reversed this effect. Four thioamide H2S-σ1 receptor hybrids (5a8a) and their amide derivatives (5b8b) were synthesized. Compound 7a (AD164) robustly released H2S and showed selectivity for σ1 receptor over σ2 and opioid receptors. This compound induced marked analgesia that was reversed by PRE-084. The amide analogue 7b (AD163) showed only minimal analgesia. Further studies showed that 7a exhibited negligible acute toxicity, together with a favorable pharmacokinetic profile. To the best of our knowledge, compound 7a is the first dual-acting ligand with simultaneous H2S-release and σ1 antagonistic activities.This work was financially supported by University of Catania, PIA.CE.RI. 20202022 Linea di intervento 3 Starting Grant project CARETO (grant 57722172136). This study was partially supported by the Spanish State Research Agency (10.13039/501100011033) under the auspices of MINECO (grant number PID2019-108691RB-I00), the Andalusian Regional Government (grant CTS109), the University of Catania PIA.CE.RI. 20202022 Linea di intervento 2 project DETTAGLI (grant 57722172125), and by Italian MUR, PRIN 2017, Code: 201744BN5T

Resveratrol-Loaded Lipid Nanocarriers: Correlation between In Vitro Occlusion Factor and In Vivo Skin Hydrating Effect

Lipid nanocarriers show occlusive properties that may be related to their ability to improve skin hydration. The aim of this work was to evaluate the relationship between in vitro occlusion factor and in vivo skin hydration for three types of lipid nanocarriers: nanoemulsions (NEs), solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers were loaded with trans-resveratrol (RSV) and incorporated in gel vehicles. In vitro occlusion factor was in the order SLNs > NLCs > NEs. Gels containing unloaded or RSV loaded lipid nanocarriers were applied on the back of a hand of 12 healthy volunteers twice a day for one week, recording skin hydration changes using the instrument Soft Plus. An increase of skin hydration was observed for all lipid nanocarriers (SLNs > NLCs > NEs). RSV loading into these nanocarriers did not affect in vitro and in vivo lipid nanocarriers effects. A linear relationship (r2 = 0.969) was observed between occlusion factor and in vivo increase of skin hydration. Therefore, the results of this study showed the feasibility of using the occlusion factor to predict in vivo skin hydration resulting from topical application of different lipid nanocarriers loading an active ingredient with no inherent hydrating activity

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy

The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE’s unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro-emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification. The results of these studies will be illustrated with emphasis on the most innovative strategies and their future perspectives

In Vitro Evaluation of Sunscreen Safety: Effects of the Vehicle and Repeated Applications on Skin Permeation from Topical Formulations

The evaluation of UV-filter in vitro percutaneous absorption allows the estimation of the systemic exposure dose (SED) and the margin of safety (MoS) of sunscreen products. As both the vehicle and pattern of application may affect sunscreen safety and efficacy, we evaluated in vitro release and skin permeation of two widely used UV-filters, octylmethoxycinnamate (OMC) and butylmethoxydibenzoylmethane (BMBM) from topical formulations with different features (oil in water (O/W) emulsions with different viscosity, water in oil (W/O) emulsion, oils with different lipophilicity). To mimic in-use conditions, we carried out experiments repeating sunscreen application on the skin surface for three consecutive days. BMBM release from all these vehicles was very low, thus leading to poor skin permeation. The vehicle composition significantly affected OMC release and skin permeation, and slight increases of OMC permeation were observed after repeated applications. From skin permeation data, SED and MoS values of BMBM and OMC were calculated for all the investigated formulations after a single application and repeated applications. While MoS values of BMBM were always well beyond the accepted safety limit, the safety of sunscreen formulations containing OMC may depend on the vehicle composition and the application pattern

LP1 and LP2: Dual-Target MOPr/DOPr Ligands as Drug Candidates for Persistent Pain Relief

Although persistent pain is estimated to affect about 20% of the adult population, current treatments have poor results. Polypharmacology, which is the administration of more than one drug targeting on two or more different sites of action, represents a prominent therapeutic approach for the clinical management of persistent pain. Thus, in the drug discovery process the “one-molecule-multiple targets” strategy nowadays is highly recognized. Indeed, multitarget ligands displaying a better antinociceptive activity with fewer side effects, combined with favorable pharmacokinetic and pharmacodynamic characteristics, have already been shown. Multitarget ligands possessing non-opioid/opioid and opioid/opioid mechanisms of action are considered as potential drug candidates for the management of various pain conditions. In particular, dual-target MOPr (mu opioid peptide receptor)/DOPr (delta opioid peptide receptor) ligands exhibit an improved antinociceptive profile associated with a reduced tolerance-inducing capability. The benzomorphan-based compounds LP1 and LP2 belong to this class of dual-target MOPr/DOPr ligands. In the present manuscript, the structure–activity relationships and the pharmacological fingerprint of LP1 and LP2 compounds as suitable drug candidates for persistent pain relief is described

Rosemary Essential Oil-Loaded Lipid Nanoparticles: In Vivo Topical Activity from Gel Vehicles

Although rosemary essential oil (EO) shows many biological activities, its topical benefits have not been clearly demonstrated. In this work, we assessed the effects on skin hydration and elasticity of rosemary EO after topical application via gel vehicles in human volunteers. To improve its topical efficacy, rosemary EO was loaded into lipid nanoparticles (NLCs) consisting of cetyl palmitate as a solid lipid, and non-ionic surfactants. Such NLCs were prepared using different ratios of EO/solid lipid and those containing EO 3% w/w and cetyl pamitate 7% w/w were selected for in vivo studies, showing the best technological properties (small particle size, low polydispersity index and good stability). Gels containing free EO or EO-loaded NLCs were applied on the hand skin surface of ten healthy volunteers twice a day for one week. Skin hydration and elasticity changes were recorded using the instrument Soft Plus. Gels containing EO-loaded NLCs showed a significant increase in skin hydration in comparison with gels containing free EO. Skin elasticity increased, as well, although to a lesser extent. The results of this study point out the usefulness of rosemary EO-loaded NLCs for the treatment of cutaneous alterations involving loss of skin hydration and elasticity

From Plant to Chemistry: Sources of Antinociceptive Non-Opioid Active Principles for Medicinal Chemistry and Drug Design

Pain is associated with many health problems and a reduced quality of life and has been a common reason for seeking medical attention. Several therapeutics are available on the market, although side effects, physical dependence, and abuse limit their use. As the process of pain transmission and modulation is regulated by different peripheral and central mechanisms and neurotransmitters, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery due to their chemical structural variety and different analgesic mechanisms. Numerous studies suggested that some chemicals from medicinal plants could be alternative options for pain relief and management. Previously, we conducted a literature search aimed at identifying natural products interacting either directly or indirectly with opioid receptors. In this review, instead, we have made an excursus including active ingredients derived from plants whose mechanism of action appears from the literature to be other than the modulation of the opioid system. These substances could, either by themselves or through synthetic and/or semi-synthetic derivatives, be investigated in order to improve their pharmacokinetic characteristics and could represent a valid alternative to the opioid approach to pain therapy. They could also be the basis for the study of new mechanisms of action in the approach to this complex and disabling pathology

A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

Sigma receptors are a fascinating receptor protein class whose ligands are actually under clinical evaluation for the modulation of opioid analgesia and their use as positron emission tomography radiotracers. In particular, peculiar biological and therapeutic functions are associated with the sigma-2 (σ2) receptor. The σ2 receptor ligands determine tumor cell death through apoptotic and non-apoptotic pathways, and the overexpression of σ2 receptors in several tumor cell lines has been well documented, with significantly higher levels in proliferating tumor cells compared to quiescent ones. This acknowledged feature has found practical application in the development of cancer cell tracers and for ligand-targeting therapy. In this context, the development of new ligands that target the σ2 receptors is beneficial for those diseases in which this protein is involved. In this paper, we conducted a search of new potential σ2 receptor ligands among a database of 1517 “small” marine natural products constructed by the union of the Seaweed Metabolite and the Chemical Entities of Biological Interest (ChEBI) Databases. The structures were passed through two filters that were constituted by our developed two-dimensional (2D) and three-dimensional Quantitative Structure-Activity Relationship (3D-QSAR) statistical models, and successively docked upon a σ2 receptor homology model that we built according to the FASTA sequence of the σ2/TMEM97 (SGMR2_HUMAN) receptor