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. Particular attention has been paid to the use of phytochemicals in combination with other drugs (co-administrations) or administration of phytochemicals as prodrugs or conjugates, particularly when these approaches are supported by nanotechnologies exploiting conjugation strategies with appropriate targeting molecules. These aspects are described for polyphenols and essential oil components, which can improve their loading as prodrugs in nanocarriers, or be part of nanocarriers designed for targeted co-delivery to achieve synergistic anti-glioma or anti-neurodegenerative effects. The use of in vitro models, able to simulate the blood-brain barrier, neurodegeneration or glioma, and useful for optimizing innovative formulations before their in vivo administration via intravenous, oral, or nasal routes, is also summarised. Among the described compounds, quercetin, curcumin, resveratrol, ferulic acid, geraniol, and cinnamaldehyde can be efficaciously formulated to attain brain-targeting characteristics, and may therefore be therapeutically useful against glioma or neurodegenerative diseases.

Improving Dermal Delivery of Rose Bengal by Deformable Lipid Nanovesicles for Topical Treatment of Melanoma.

Cutaneous melanoma is one of the most aggressive and metastatic forms of skin cancer. However, current therapeutic options present several limitations, and the annual death rate due to melanoma increases every year. Dermal delivery of nanomedicines can effectively eradicate primary melanoma lesions, avoid the metastatic process, and improve survival. Rose Bengal (RB) is a sono-photosensitizer drug with intrinsic cytotoxicity toward melanoma without external stimuli but the biopharmaceutical profile limits its clinical use. Here, we propose deformable lipid nanovesicles, also known as transfersomes (TF), for the targeted dermal delivery of RB to melanoma lesions to eradicate them in the absence of external stimuli. Considering RB's poor ability to cross the stratum corneum and its photosensitizer nature, transfersomal carriers were selected simultaneously to enhance RB penetration to the deepest skin layers and protect RB from undesired photodegradation. RB-loaded TF dispersion (RB-TF), prepared by a modified reverse-phase evaporation method, were nanosized with a ζ-potential value below -30 mV. The spectrophotometric and fluorimetric analysis revealed that RB efficiently interacted with the lipid phase. The morphological investigations (transmission electron microscopy and small-angle X-ray scattering) proved that RB intercalated within the phospholipid bilayer of TF originating unilamellar and deformable vesicles, in contrast to the rigid multilamellar unloaded ones. Such outcomes agree with the results of the in vitro permeation study, where the lack of a burst RB permeation peak for RB-TF, observed instead for the free drug, suggests that a significant amount of RB interacted with lipid nanovesicles. Also, RB-TF proved to protect RB from undesired photodegradation over 24 h of direct light exposure. The ex vivo epidermis permeation study proved that RB-TF significantly increased RB's amount permeating the epidermis compared to the free drug (78.31 vs 38.31%). Finally, the antiproliferative assays on melanoma cells suggested that RB-TF effectively reduced cell growth compared to free RB at the concentrations tested (25 and 50 µM). RB-TF could potentially increase selectivity toward cancer cells. Considering the outcomes of the characterization and cytotoxicity studies performed on RB-TF, we conclude that RB-TF represents a valid potential alternative tool to fight against primary melanoma lesions via dermal delivery in the absence of light.

Increasing protective activity of genistein by loading into transfersomes: A new potential adjuvant in the oxidative stress-related neurodegenerative diseases?

BACKGROUND: Genistein is a soy-derived isoflavone and phytoestrogen with antioxidant and neuroprotective activity. Genistein has intrinsically low oral bioavailability that affects its dose-response activities. PURPOSE: Nanotechnologies were used to obtain the delivery of genistein to the brain: lipid-based nanovesicles, transfersomes, loaded with the phytoestrogen were developed as potential therapeutic or preventive strategy against neurodegenerative diseases by intranasal administration. METHODS: Phosphatidylcholine from soybean and different edge activators were used to prepare transfersomes. The effect of selected nanovesicles on the oxidative damage was studied in PC12 cell line. RESULTS: Suitable nanovesicles as carrier of genistein were obtained; their composition affects deformability, drug permeation behavior and cytotoxicity. In particular, the formulation containing Span 80, GEN-TF2, showed efficiency of internalization into the cell and it was able to attenuate ROS formation and to reduce the amount of apoptotic cells generated by H2O2 treatment compared to genistein. CONCLUSION: GEN-TF2 was able to reduce the oxidative damage suggesting a possible antioxidant role of this drug delivery system. These obtained data confer to GEN-TF2 a potential antioxidant activity and then it could be used as adjuvant therapy in oxidative stress-related neurodegenerative diseases.

Engineered polymeric microspheres obtained by multi-step method as potential systems for transarterial embolization and intraoperative imaging of HCC: Preliminary evaluation.

The aim of this study was the development of novel fluorescent microspheres as embolic agent for transarterial embolization (TAE) of advanced stages of hepatocellular carcinoma (HCC). TAE is a minimally invasive procedure that induces tumour regression blocking the blood flow by injection of microparticles. The microspheres currently used in clinical application cannot be visualized in vivo. Surgeon could exploit the intraoperative detection of embolic agents during resection of the malignant mass. Biocompatible indocyanine green (ICG)-loaded microspheres (CAB-CS-ICG) were prepared using a multi-step method. Chitosan (CS)-ICG particles were prepared via spray-dryer and then loaded into cellulose acetate butyrate (CAB) microspheres, fabricated by emulsion solvent extraction method. Technological parameters such as yield, size, encapsulation efficiency and morphology were studied. CAB-CS-ICG microspheres showed spherical shape and smooth surface, as well as good injectability through a 21 G×1½ needle. ICG release from CAB-CS-ICG was very low due to the strong interaction between CS and ICG. This result was also confirmed by in vitro fluorescence imaging studies, conducted using Photodynamic Eye (PDE) for the detection of particles incubated in human plasma. CAB-CS-ICG were capable to maintain the fluorescence selectivity for 4weeks. Our data suggested the potential usefulness of CAB-CS-ICG in TAE application as embolic agents and following imaging of tumour during surgical procedure.

Transarterial chemoembolization of hepatocellular carcinoma. Agents and drugs: an overview. Part 1.

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common lethal malignancies. The prognosis is poor despite progress in early diagnosis. The initial treatment of choice is hepatic resection; unfortunately, not all patients are eligible for liver resection. Moreover, there are significant recurrences. Different liver-directed therapies have been developed to increase the number of patients eligible for liver resection. Among them, transarterial chemoembolization (TACE) is a technique of improving importance that involves the intra-arterial administration of anticancer drugs and embolization agents into the liver tumor. In the first part of this review, an overview of the present situation in the field of TACE has been made, referring in particular to the use of Lipiodol. AREAS COVERED: Clinical overview of TACE with attention to the present limits and problems of this technique. EXPERT OPINION: The use of TACE techniques is important in the treatment of HCCs. However, this technique needs to be improved in particular taking into account the use of new materials for the preparation of embolizing agents able to control the drug release.

Evaluation of the effect of hydroxypropyl-ß-cyclodextrin on topical administration of milk thistle extract.

Two water in oil emulsions composed by eudermic ingredients as glycerin, cocoa butter, almond oil and a variety of lipids, were enriched respectively with milk thistle dry extract (MT) or with a binary complex composed by MT and hydroxypropyl-ß-cyclodextrin (HP) (1:4 w/w) correspondent to 1% (w/w) in sylimarine in order to obtain two different emulsions designed for the skin delivery and determine influence of hydroxypropyl-ß-cyclodextrin on the extract delivery and permeation. Uv-vis spectrophotometric analyses demonstrated that phytocomplex formation influences the finding of MT after the complexation process and the in vitro antioxidant activity. Further in vitro and ex vivo experiments demonstrated that the penetration capability of MT from formulations is strictly influenced by the phytocomplex able to control MT permeation; moreover phytocomplex increases flavonoids stability during the in vitro tests. Additionally, in vivo studies showed that the penetration into the stratum corneum of the active ingredients is effectively achieved by the phytocomplex formation, in fact about 80% of MT is absorbed by the skin along 1h despite the 30% of MT not complexed absorbed during the same period.

Preparation, in vitro characterization and preliminary in vivo evaluation of buccal polymeric films containing chlorhexidine.

The aim of this work was to investigate the suitability of some polymeric films as buccal systems for the delivery of the antiseptic drug chlorhexidine diacetate, considered as a valid adjunct in the treatment of oral candidiasis. Six different film formulations, mono- or double-layered, containing 5 or 10 mg of chlorhexidine diacetate, respectively, and alginate and/or hydroxypropylmethylcellulose and/or chitosan as excipients, were prepared by a casting-solvent evaporation technique and characterized in terms of drug content, morphology (scanning electron microscopy), drug release behavior, and swelling properties. Moreover, the in vivo concentrations of chlorhexidine diacetate in saliva were evaluated after application of a selected formulation on the oral mucosa of healthy volunteers. The casting-solvent evaporation proved to be a suitable technique for preparing soft, flexible, and easily handy mono- or double-layered chlorhexidine-loaded films. Some prepared formulations showed favorable in vitro drug release rates and swelling properties. The behavior of a selected formulation, chosen on the basis of its in vitro release results, was preliminarily investigated in vivo after application in the oral cavity of healthy volunteers. The films were well tolerated and the salivary chlorhexidine concentrations were maintained above the minimum inhibitory concentration for Candida albicans for almost 3 h. These preliminary results indicate that polymeric films can represent a valid vehicle for buccal delivery of antifungal/antimicrobial drugs.

Solid lipid microparticles (SLM) containing juniper oil as anti-acne topical carriers: preliminary studies.

Solid lipid microparticles (SLM) were used as carriers of juniper oil and proposed for the topical treatment of acne vulgare. The formulations were obtained by the o/w emulsification method. Compritol and Precirol were employed as lipidic materials. Emulsions containing 1.5% (w/w) of lipophilic phase (lipid and oil) and two different lipid to oil ratios (1:1 and 2:1) were prepared. Blank particles were also prepared, as a comparison. The SLM were characterized in terms of encapsulation efficiency, size, and morphology. The particle size stability in aqueous dispersions was monitored over one month. Evaporation of volatile compounds of oil from microparticles by weight loss was investigated. The qualitative composition of Juniper oil before and after the encapsulation process was determined by gas chromatography (GC) and gas chromatography/mass spectrum (GC/MS) analyses. The antimicrobial activity of the oil encapsulated into the lipid microparticles against P. acnes was studied as contact time assay and compared to the activity of the oil not encapsulated. The emulsification method here described was a good technique for the encapsulation of essential oils. Percentage yields of production and encapsulation efficiencies were higher for Compritol preparations than for these prepared using Precirol. All preparations were characterized by similar particle size distributions (dvs about 3-4 microm) regardless of lipid type and lipid to oil ratios. Microscopy observations showed that the microparticles in aqueous dispersions had almost spherical shape, independently from their composition. The scanning electron microscopy (SEM) analyses showed that when the particles were dried, they had an irregular shape and a rough surface. The SLM dispersions based on Compritol revealed particle size stability over the investigated period of 30 days. In contrast, an increase of the mean dimensions in the preparations containing Precirol was observed. A low loss of volatile oil compounds owing to evaporation from dry particles was found in all preparations. This indicated that the microparticles were able to substantially maintain the oil loaded inside their lipidic structure, reducing its volatility. Some modifications of composition were found in the oil encapsulated in SLM with respect to the juniper oil raw material, but these modifications did not decrease the antibacterial activity of the oil. The SLM here described are promising carriers for the development of anti-acne topical formulations containing Juniper oil.

Polyvinylalcohol substituted with triethyleneglycolmonoethylether as a new material for preparation of solid dispersions of hydrophobic drugs.

Among the different methods used to increase the aqueous drug solubility, the preparation of a solid dispersion with a soluble carrier represents an interesting formulative approach. We substituted polyvinylalcohol with triethyleneglycolmonoethylether and obtained a suitable material for the formulation of a solid dispersion of progesterone, by spray-drying. In particular, we evaluated the influence of the polyvinylalcohol substitution degree and the polymer-drug weight ratios in the preparative mixture on the progesterone dissolution rate in the aqueous environment.

Formulation and in vivo evaluation of chlorhexidine buccal tablets prepared using drug-loaded chitosan microspheres.

This investigation deals with the development of buccal formulations (tablets) based on chitosan microspheres containing chlorhexidine diacetate. The microparticles were prepared by a spray-drying technique, their morphological characteristics were studied by scanning electron microscopy and the in vitro release behaviour was investigated in pH 7.0 USP buffer. Chlorhexidine in the chitosan microspheres dissolves more quickly in vitro than does chlorhexidine powder. The anti-microbial activity of the microparticles was investigated as minimum inhibitory concentration, minimum bacterial concentration and killing time. The loading of chlorhexidine into chitosan is able to maintain or improve the anti-microbial activity of the drug. The improvement is particularly high against Candida albicans. This is important for a formulation whose potential use is against buccal infections. Drug-empty microparticles have an anti-microbial activity due to the polymer itself. Buccal tablets were prepared by direct compression of the microparticles with mannitol alone or with sodium alginate. After their in vivo administration the determination of chlorhexidine in saliva showed the capacity of these formulations to give a prolonged release of the drug in the buccal cavity.