Nasal Administration of a Nanoemulsion Based on Methyl Ferulate and Eugenol Encapsulated in Chitosan Oleate: Uptake Studies in the Central Nervous System.

: The phytochemicals ferulic acid (Fer) and eugenol display neuroprotective effects for their anti-oxidative properties; moreover, eugenol can induce dopamine (DA) release from dopaminergic neuronal cells. However, poor bioavailability and/or fast elimination rate limit their clinical benefits. We therefore propose a new nasal formulation based on a nanoemulsion (NE) for the jointed brain-targeting of eugenol and methyl ferulate (Fer-Me, i.

In Vitro Studies to Evaluate the Intestinal Permeation of an Ursodeoxycholic Acid-Conjugated Oligonucleotide for Duchenne Muscular Dystrophy Treatment.

Delivery represents a major hurdle to the clinical advancement of oligonucleotide therapeutics for the treatment of disorders such as Duchenne muscular dystrophy (DMD). In this preliminary study, we explored the ability of 2'--methyl-phosphorothioate antisense oligonucleotides (ASOs) conjugated with lipophilic ursodeoxycholic acid (UDCA) to permeate across intestinal barriers in vitro by a co-culture system of non-contacting IEC-6 cells and DMD myotubes, either alone or encapsulated in exosomes. UDCA was used to enhance the lipophilicity and membrane permeability of ASOs, potentially improving oral bioavailability.

Characterization and Hydrolysis Studies of a Prodrug Obtained as Ester Conjugate of Geraniol and Ferulic Acid by Enzymatic Way.

Ferulic acid (Fer) and geraniol (Ger) are natural compounds whose antioxidant and anti-inflammatory activity confer beneficial properties, such as antibacterial, anticancer, and neuroprotective effects. However, the short half-lives of these compounds impair their therapeutic activities after conventional administration. We propose, therefore, a new prodrug (Fer-Ger) obtained by a bio-catalyzed ester conjugation of Fer and Ger to enhance the loading of solid lipid microparticles (SLMs) designed as Fer-Ger delivery and targeting systems.

Dimeric ferulic acid conjugate as a prodrug for brain targeting after nasal administration of loaded solid lipid microparticles.

Objective: Ferulic acid (Fer) displays antioxidant/anti-inflammatory properties useful against neurodegenerative diseases. To increase Fer uptake and its central nervous system residence time, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed.

Methods: The prodrug was synthesized as Fer dimeric conjugate methylated on the carboxylic moiety.

Conjugation, Prodrug, and Co-Administration Strategies in Support of Nanotechnologies to Improve the Therapeutic Efficacy of Phytochemicals in the Central Nervous System.

Phytochemicals, produced as secondary plant metabolites, have shown interesting potential therapeutic activities against neurodegenerative diseases and cancer. Unfortunately, poor bioavailability and rapid metabolic processes compromise their therapeutic use, and several strategies are currently proposed for overcoming these issues. The present review summarises strategies for enhancing the central nervous system's phytochemical efficacy.

Pharmacokinetic and Permeation Studies in Rat Brain of Natural Compounds Led to Investigate Eugenol as Direct Activator of Dopamine Release in PC12 Cells.

Eugenol, cinnamaldehyde and D-limonene, the main components of natural essential oils, are endowed with antioxidant and anti-inflammatory properties which allow them to induce beneficial effects on intestinal, cardiac and neuronal levels. In order to characterize their pharmacokinetic profiles and aptitude to permeate in the central nervous system after intravenous and oral administration to rats, new analytical procedures, easily achievable with HPLC-UV techniques, were developed. The terminal half-lives of these compounds range from 12.

cell models merging circadian rhythms and brain waves for personalized neuromedicine.

New evidence is emerging about the dynamics of interaction between circadian rhythms and brain waves, whose coordination occurs through the entrainment process. The so-called "oscillopathies" or dysfunctions in synchronization of neuronal oscillation in key brain networks lead to the onset of neurodegenerative diseases. A typical example of alteration is insomnia, a risk factor for the oscillopathies, increasingly widespread worldwide.

Effects of Microencapsulated Ferulic Acid or Its Prodrug Methyl Ferulate on Neuroinflammation Induced by Muramyl Dipeptide.

Ferulic acid (Fer) is known for its antioxidant and anti-inflammatory activities, which are possibly useful against neurodegenerative diseases. Despite the ability of Fer to permeate the brain, its fast elimination from the body does not allow its therapeutic use to be optimized. The present study proposes the preparation and characterization of tristearin- or stearic acid-based solid lipid microparticles (SLMs) as sustained delivery and targeting systems for Fer.

β-Estradiol 17-acetate enhances the vitality of endothelial cells isolated from the brain of patients subjected to neurosurgery.

In the current landscape of endothelial cell isolation for building in vitro models of the blood-brain barrier, our work moves towards reproducing the features of the neurovascular unit to achieve glial compliance through an innovative biomimetic coating technology for brain chronic implants. We hypothesized that the autologous origin of human brain microvascular endothelial cells (hBMECs) is the first requirement for the suitable coating to prevent the glial inflammatory response triggered by foreign neuroprosthetics. Therefore, this study established a new procedure to preserve the in vitro viability of hBMECs isolated from gray and white matter specimens taken from neurosurgery patients.

Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?

Cyclodextrins (CDs) are oligosaccharides widely used in the pharmaceutical field. In this review, a detailed examination of the literature of the last two decades has been made to understand the role of CDs in nasal drug delivery systems. In nasal formulations, CDs are used as pharmaceutical excipients, as solubilizers and absorption promoters, and as active ingredients due to their several biological activities (antiviral, antiparasitic, anti-atherosclerotic, and neuroprotective).

Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration.

About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization.

Evaluation of the In Vitro Biocompatibility of PEDOT:Nafion Coatings.

Poly(3,4-ethylenedioxythiophene)-Nafion (PEDOT:Nafion) is emerging as a promising alternative to PEDOT-polystyrene sulfonate (PEDOT:PSS) in organic bioelectronics. However, the biocompatibility of PEDOT:Nafion has not been investigated to date, limiting its deployment toward in vivo applications such as neural recording and stimulation. In the present study, the in vitro cytotoxicity of PEDOT:Nafion coatings, obtained by a water-based PEDOT:Nafion formulation, was evaluated using a primary cell culture of rat fibroblasts.

Cancer stem cells and nanomedicine: new opportunities to combat multidrug resistance?

'Multidrug resistance' (MDR) is a difficult challenge for cancer treatment. The combined role of cytochrome P450 enzymes (CYPs) and active efflux transporters (AETs) in cancer cells appears relevant in inducing MDR. Chemotherapeutic drugs can be substrates of both CYPs and AETs and CYP inducers or inhibitors can produce the same effects on AETs.

Vibrational spectral fingerprinting for chemical recognition of biominerals.

Pathologies associated with calcified tissue, such as osteoporosis, demand in vivo and/or in situ spectroscopic analysis to assess the role of chemical substitutions in the inorganic component. High energy X-ray or NMR spectroscopies are impractical or damaging in biomedical conditions. Low energy spectroscopies, such as IR and Raman techniques, are often the best alternative.

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.

Bile salt-coating modulates the macrophage uptake of nanocores constituted by a zidovudine prodrug and enhances its nose-to-brain delivery.

We have previously demonstrated that the ester conjugation of zidovudine (AZT) with ursodeoxycholic acid (UDCA) allows to obtain a prodrug (U-AZT) which eludes the active efflux transporters (AET). This allows the prodrug to more efficiently permeates and remains in murine macrophages than the parent compound. Here we demonstrate that U-AZT can be formulated, by a nanoprecipitation method, as nanoparticle cores coated by bile acid salt (taurocholate or ursodeoxycholate) corona, without any other excipients.

Uptake in the Central Nervous System of Geraniol Oil Encapsulated in Chitosan Oleate Following Nasal and Oral Administration.

The pharmacological activities of geraniol include anticancer and neuroprotective properties. However, its insolubility in water easily induces separation from aqueous formulations, causing administration difficulties. Here we propose new emulsified formulations of geraniol by using the amphiphilic polymer chitosan-oleate (CS-OA) as surfactant to combine mucoadhesive and absorption enhancer properties with stabilization effects on the oil dispersion.

The Role of Combined Penetration Enhancers in Nasal Microspheres on In Vivo Drug Bioavailability.

Microspheres based on both methyl-β-cyclodextrins and chitosan were prepared by spray-drying as nasal formulations of a model polar drug to analyze, firstly, how the composition of the carrier affects drug permeation across synthetic membranes and, secondly, how it induces systemic or brain delivery of the drug. Microparticles with different weight ratios of the two penetration enhancers (10⁻90, 50⁻50, 90⁻10) were characterized with respect to morphology, size, structural composition, water uptake, and the in vitro drug permeation profile. The leader formulation (weight ratio of 50⁻50) was then nasally administered to rats; systemic and cerebrospinal fluid (CSF) drug concentrations were analyzed by high performance liquid chromatography (HPLC) over time.

Retinal pigment epithelial cells as a therapeutic tool and target against retinopathies.

Retinal pigment epithelium (RPE) is a cell monolayer essential for photoreceptor function and forming the blood-retinal barrier. RPE and retinal neurons share the same origin and a polarized cytoarchitecture. Several factors determine the phagocytosis and permeability of RPE, influencing photoreceptor renewal and drug delivery, efficacy and toxicity.

Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?

Although several viruses can easily infect the central nervous system (CNS), antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs). These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1), multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5), and breast cancer resistance protein (ABCG2 or BCRP).

Brain targeting of resveratrol by nasal administration of chitosan-coated lipid microparticles.

Lipid microparticles (LMs) uncoated or coated with chitosan and containing the neuroprotective polyphenol resveratrol were developed for its targeting to the brain via nasal administration. The lipid microparticles loaded with resveratrol (LMs-Res) were produced by melt emulsification, using stearic acid as lipid material and phosphatidylcholine as the surfactant. The chitosan coated particles LMs-Res-Ch (1.

Carbonate substitution in the mineral component of bone: Discriminating the structural changes, simultaneously imposed by carbonate in A and B sites of apatite.

The mineral component of bone and other biological calcifications is primarily a carbonate substituted calcium apatite. Integration of carbonate into two sites, substitution for phosphate (B-type carbonate) and substitution for hydroxide (A-type carbonate), influences the crystal properties which relate to the functional properties of bone. In the present work, a series of AB-type carbonated apatites (AB-CAp) having varying A-type and B-type carbonate weight fractions were prepared and analyzed by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD), and carbonate analysis.

Geraniol Pharmacokinetics, Bioavailability and Its Multiple Effects on the Liver Antioxidant and Xenobiotic-Metabolizing Enzymes.

Geraniol is a natural monoterpene showing anti-inflammatory, antioxidant, neuroprotective and anticancer effects. No pharmacokinetic and bioavailability data on geraniol are currently available. We therefore performed a systematic study to identify the permeation properties of geraniol across intestinal cells, and its pharmacokinetics and bioavailability after intravenous and oral administration to rats.