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.

Prolonged skin retention of clobetasol propionate by bio-based microemulsions: a potential tool for scalp psoriasis treatment.

Novel effective and cosmetically acceptable formulations are needed for the treatment of scalp psoriasis, due to the poor efficacy of the current products. The challenge in developing safe, efficient, and convenient delivery systems for this drug was addressed in the present work by formulating clobetasol propionate-loaded W/O microemulsions (MEs). Pseudo-ternary phase diagrams were constructed by using a combination of biocompatible and biodegradable excipients. Characterization studies demonstrated that selected MEs had suitable technological features such as being Newtonian fluids, possessing low viscosity, and high thermodynamic stability. Photomicrographs showed a significant alteration of the skin structure after treatment with MEs, and a preferential concentration of these in the stratum corneum and epidermis. These data, together with ex vivo permeation results, suggested an enhanced topical targeted effect due to an increased drug retention efficacy in the upper skin layers, as desired. Moreover, the bio-based excipients selected could contribute to the healing of the psoriatic scalp. In this way, the improvement of clobetasol efficacy is combined with the useful properties of the microemulsion components and with environmental safety.

Engineered microparticles based on drug-polymer coprecipitates for ocular-controlled delivery of Ciprofloxacin: influence of technological parameters.

Ciprofloxacin is a drug active against a broad spectrum of aerobic Gram-positive and Gram-negative bacteria, for the therapy of ocular infections. It requires frequent administrations owing to rapid ocular clearance and it is a good candidate for ocular controlled release formulations. The preparation of such drug release systems is still a challenge. Ionic interactions between ciprofloxacin and the polyelectrolytes chondroitin sulfate or lambda carrageenan result in coprecipitates that can act as microparticulate controlled release systems from which the drug is released after being displaced by the medium's ions. In some formulations, Carbopol was added to improve the mucoadhesive properties. The aim of this research was the study of the influence of the technological parameters of the preparation method of coprecipitates on their particle size, with the goal of achieving particles engineered with a size suitable for the ocular administration. Technological parameters taken into account were: concentration of drug and polymer solutions utilized for the preparation of interaction products, possible use of surfactants (kind and concentration), temperature of the solutions and stirring during the process of preparation of the coprecipitates. Preliminary stability study tests were carried out to further characterize the leader formulation. Particle size in suspensions for ocular drug delivery is a critical parameter influencing the quality of the formulation. The results obtained from this study show that chondroitin sulfate coprecipitates present the best characteristics in terms of particle size suitable for ocular administration. A further improvement of the particle size characteristics has been obtained with the addition of surfactants.

The effect of formulative parameters on the size and physical stability of SLN based on "green" components.

Cocoa butter (CB) is a largely used excipient in pharmaceutical field. Aim of this work was to set formulative parameters for the preparation of SLN based on "green" lipid matrix for drug delivery as natural, both human and environmental safe systems. Double emulsion technique (w1/o/w2) was selected for SLN preparation. The effect on the dimensional properties of different surfactants (Tween 80 and PEG 40 monostearate) and co-surfactants (PEG400 monostearate, Emulium® Kappa2 and Plurol®Stearique) at different concentrations was evaluated. Stability tests were performed. SLN dispersions were exsiccated and the effect of the dried process on SLN size was evaluated. The influence of temperature on SLN dimensions was investigated at 37 °C. MTT test was performed on raw materials and formulations. The w1/o/w2 is suitable, rapid and economic technique for the preparation of CB SLN. Tween 80-Plurol Stearique combination gives the best results: particles size less than 400 nm and PI of about 0.4 are obtained when PS 2% is used. Both raw materials and formulations are safe. The importance to evaluate the effect of different surfactant and/or co-surfactant on the dimensional properties of SLN is evident by selecting substances with preferable safety profiles, and favorable environmental properties to develop stable "green" SLN.

Design and development of a chitosan-based nasal powder of dimethyl fumarate-cyclodextrin binary systems aimed at nose-to-brain administration. A stability study.

The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between the nasal cavity and the brain. Dimethyl fumarate is used to treat relapsing-remitting multiple sclerosis, with a role as an immunomodulator towards T- T-cells and a cytoprotector towards neurons and glial cells. Its use in therapy is hindered by its low aqueous solubility, and low stability, due to hydrolysis and sublimation at room temperature. To overcome this limitation, in this study we evaluated the feasibility of using two amorphous ß-cyclodextrin derivatives, namely hydroxypropyl ß-cyclodextrin and methyl ß-cyclodextrin, to obtain a nasally administrable powder with a view to nose-to-brain administration. Initially, the interaction product was studied using different analytical methods (differential scanning calorimetry, Fourier transform infrared spectroscopy and powder X-ray diffraction) to detect the occurrence of binary product formation, while phase solubility analysis was used to probe the complexation in solution. The dimethyl fumarate-cyclodextrin binary product showing best solubility and stability properties was subsequently used in the development of a chitosan-based mucoadhesive nasally administrable powder comparing different preparative methods. The best performance in terms of both hydrolytic stability and DMF recovery was achieved by the powder obtained via freeze-drying.

A water-soluble preparation for intravenous administration of isorhamnetin and its pharmacokinetics in rats.

Flavonoids are considered as health-protecting food constituents. The testing of their biological effects is however hampered by their low oral absorption and complex metabolism. In order to investigate the direct effect(s) of unmetabolized flavonoid, a preparation in a biologically friendly solvent for intravenous administration is needed. Isorhamnetin, a natural flavonoid and a human metabolite of the most frequently tested flavonoid quercetin, has very low water solubility (<3.5 µg/mL). The aim of this study was to improve its solubility to enable intravenous administration and to test its pharmacokinetics in an animal model. By using polyvinylpyrrolidone (PVP10) and benzalkonium chloride, we were able to improve the solubility approximately 600 times to 2.1 mg/mL. This solution was then administered intravenously at a dose of 0.5 mg/kg of isorhamnetin to rats and its pharmacokinetics was analyzed. The pharmacokinetics of isorhamnetin corresponded to two compartmental model with a rapid initial distribution phase (t1/2α: 5.7 ± 4.3 min) and a slower elimination phase (t1/2ß: 61 ± 47.5 min). Two sulfate metabolites were also identified. PVP10 and benzalkonium did not modify the properties of isorhamnetin (iron chelation and reduction, and cell penetration) substantially. In conclusion, the novel preparation reported in this study is suitable for future testing of isorhamnetin effects under in vivo conditions.

Improved pharmacokinetic and lymphatic uptake of Rose Bengal after transfersome intradermal deposition using hollow microneedles.

The lymphatic system is active in several processes that regulate human diseases, among which cancer progression stands out. Thus, various drug delivery systems have been investigated to promote lymphatic drug targeting for cancer therapy; mainly, nanosized particles in the 10-150 nm range quickly achieve lymphatic vessels after an interstitial administration. Herein, a strategy to boost the lymphotropic delivery of Rose Bengal (RB), a hydrosoluble chemotherapeutic, is proposed, and it is based on the loading into Transfersomes (RBTF) and their intradermal deposition in vivo by microneedles. RBTF of 96.27 ± 13.96 nm (PDI = 0.29 ± 0.02) were prepared by a green reverse-phase evaporation technique, and they showed an RB encapsulation efficiency of 98.54 ± 0.09%. In vitro, RBTF remained physically stable under physiological conditions and avoided the release of RB. In vivo, intravenous injection of RBTF prolonged RB half-life of 50 min in healthy rats compared to RB intravenous injection; the RB half-life in rat body was further increased after intradermal injection reaching 24 h, regardless of the formulation used. Regarding lymphatic targeting, RBTF administered intravenously provided an RB accumulation in the lymph nodes of 12.3 ± 0.14 ng/mL after 2 h, whereas no RB accumulation was observed after RB intravenous injection. Intradermally administered RBTF resulted in the highest RB amount detected in lymph nodes after 2 h from the injection (84.2 ± 25.10 ng/mL), which was even visible to the naked eye based on the pink colouration of the drug. In the case of intradermally administered RB, RB in lymph node was detected only at 24 h (13.3 ± 1.41 ng/mL). In conclusion, RBTF proved an efficient carrier for RB delivery, enhancing its pharmacokinetics and promoting lymph-targeted delivery. Thus, RBTF represents a promising nanomedicine product for potentially facing the medical need for novel strategies for cancer therapy.

Green Routes for Bio-Fabrication in Biomedical and Pharmaceutical Applications.

In the last decade, significant advances in nanotechnologies, rising from increasing knowledge and refining of technical practices in green chemistry and bioengineering, enabled the design of innovative devices suitable for different biomedical applications. In particular, novel bio-sustainable methodologies are developing to fabricate drug delivery systems able to sagely mix properties of materials (i.e., biocompatibility, biodegradability) and bioactive molecules (i.e., bioavailability, selectivity, chemical stability), as a function of the current demands for the health market. The present work aims to provide an overview of recent developments in the bio-fabrication methods for designing innovative green platforms, emphasizing the relevant impact on current and future biomedical and pharmaceutical applications.

Improving in vivo oral bioavailability of a poorly soluble drug: a case study on polymeric versus lipid nanoparticles.

Poorly soluble drugs must be appropriately formulated for clinical use to increase the solubility, dissolution rate, and permeation across the intestinal epithelium. Polymeric and lipid nanocarriers have been successfully investigated for this aim, and their physicochemical properties, and in particular, the surface chemistry, significantly affect the pharmacokinetics of the drugs after oral administration. In the present study, PLGA nanoparticles (SS13NP) and solid lipid nanoparticles (SS13SLN) loaded with SS13, a BCS IV model drug, were prepared. SS13 bioavailability following the oral administration of SS13 (free drug), SS13NP, or SS13SLN was compared. SS13NP had a suitable size for oral administration (less than 300 nm), a spherical shape and negative zeta potential, similarly to SS13SLN. On the contrary, SS13NP showed higher physical stability but lower encapsulation efficiency (54.31 ± 6.66%) than SS13SLN (100.00 ± 3.11%). When orally administered (0.6 mg of drug), SS13NP showed higher drug AUC values with respect to SS13SLN (227 ± 14 versus 147 ± 8 µg/mL min), with higher Cmax (2.47 ± 0.14 µg/mL versus 1.30 ± 0.15 µg/mL) reached in a shorter time (20 min versus 60 min). Both formulations induced, therefore, the oral bioavailability of SS13 (12.67 ± 1.43% and 4.38 ± 0.39% for SS13NP and SS12SLN, respectively) differently from the free drug. These in vivo results confirm that the chemical composition of nanoparticles significantly affects the in vivo fate of a BCS IV drug. Moreover, PLGA nanoparticles appear more efficient and rapid than SLN in allowing drug absorption and transport to systemic circulation.

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.

Sericin/crocetin micro/nanoparticles for nucleus pulposus cells regeneration: An "active" drug delivery system.

Introduction: Initiation and progression of intervertebral disk degeneration are linked to oxidative stress, with reactive oxygen species being a key factor. Therefore, as a potentially novel approach able to regenerate the damaged intervertebral disk, this work aimed to prepare an "active per sé" drug delivery system by combining sericin and crocetin: both are bioactive compounds with antioxidant, anti-inflammatory, immunomodulant and regenerative properties. Methods: In detail, sericin nanoparticles were prepared using crocetin as a cross-linker; then, the nanoparticle dispersions were dried by spray drying as it is (NP), with an excess of sericin (NPS) or crocin/crocetin (NPMix), obtaining three microparticle formulations. Results and Discussion: Before drying, the nanoparticles were nanometric (about 250 nm), with a negative surface charge, and appeared spherical and smooth. Following the drying process, spherical and smooth microparticles were obtained, with a mean diameter of about 1.7-2.30 µm. NPMix was the most active in antioxidant and anti-tyrosinase activities, likely due to the excess of crocin/crocetin, while NPS had the best anti-elastase activity, likely due to sericin in excess. Furthermore, all the formulations could prevent oxidative stress damage on nucleus pulposus cells, with NPMix being the best. Overall, the intrinsic anti-tyrosinase and anti-elastase activities and the ability to protect from oxidative stress-induced damages justify future investigations of these "active per sé" formulations in treating or preventing intervertebral disk degeneration.

Solid lipid nanoparticles with and without hydroxypropyl-ß-cyclodextrin: a comparative study of nanoparticles designed for colonic drug delivery.

New solid lipid nanoparticles (SLN), composed of Compritol ATO888 (C) and hydroxypropyl-ß-cyclodextrin (HP), were developed in order to study a new colon-specific formulation for diclofenac sodium (D) delivery. The prepared batches differ from each other by the molecular ratio between HP and D and by the composition of the matrix. Nanoparticles composed of an exclusively lipid matrix and nanoparticles with an oligomeric and lipid matrix were compared in order to establish the effect of both components on the drug delivery tests performed. The SLN preparation method was based on the oil/water hot homogenization process. Emulsions produced were cooled at room temperature and lyophilized in order to obtain dried nanoparticles; possible damage to nanoparticle shape and size was avoided by the addition of cryoprotectants to the aqueous dispersion of nanoparticles before exsiccation. An in vitro toxicity study was performed using CaCo(2) cells to establish the safety of the prepared SLN. Data obtained showed that production method studied guarantees emulsions composed of nanosized drops which can be dried by lyophilization into SLN with a size range of 300-600 nm. In vitro and ex vivo tests demonstrated that dried SLN can be considered as colon delivery systems; however, the matrix composition as well as the presence of cryoprotectant on their surface influences the release and permeation rate of D. The in vitro toxicity studies indicated that the SLN are well tolerated.

Surfactant-Free Chitosan/Cellulose Acetate Phthalate Nanoparticles: An Attempt to Solve the Needs of Captopril Administration in Paediatrics.

The Paediatric Committee of the European Medicines Agency encourages research into medicinal products for children, in particular, the development of an age-appropriate formulation of captopril is required in the cardiovascular therapeutic area. The aim of this study was the development of a liquid formulation using nanoparticles based only on chitosan and cellulose acetate phthalate containing captopril for the treatment of hypertension, heart failure and diabetic nephropathy in paediatric patients. Nanoparticles were prepared by a nanoprecipitation method/dropping technique without using surfactants, whose use can be associated with toxicity. A range of different cellulose to chitosan weight ratios were tested. A good encapsulation efficiency (61.0 ± 6.5%) was obtained when a high chitosan concentration was used (1:3 ratio); these nanoparticles (named NP-C) were spherical with a mean diameter of 427.1 ± 32.7 nm, 0.17 ± 0.09 PDI and +53.30 ± 0.95 mV zeta potential. NP-C dispersion remained stable for 28 days in terms of size and drug content and no captopril degradation was observed. NP-C dispersion released 70% of captopril after 2 h in pH 7.4 phosphate buffer and NP-C dispersion did not have a cytotoxicity effect on neonatal human fibroblasts except at the highest dose tested after 48 h. As a result, chitosan/cellulose nanoparticles could be considered a suitable platform for captopril delivery in paediatrics for preparing solid/liquid dosage forms.

Novel Utilization of Therapeutic Coatings Based on Infiltrated Encapsulated Rose Bengal Microspheres in Porous Titanium for Implant Applications.

Despite the increasing progress achieved in the last 20 years in both the fabrication of porous dental implants and the development of new biopolymers for targeting drug therapy, there are important issues such as bone resorption, poor osseointegration, and bacterial infections that remain as critical challenges to avoid clinical failure problems. In this work, we present a novel microtechnology based on polycaprolactone microspheres that can adhere to porous titanium implant models obtained by the spacer holder technique to allow a custom biomechanical and biofunctional balance. For this purpose, a double emulsion solvent evaporation technique was successfully employed for the fabrication of the microparticles properly loaded with the antibacterial therapeutic agent, rose bengal. The resulting microspheres were infiltrated into porous titanium substrate and sintered at 60 °C for 1 h, obtaining a convenient prophylactic network. In fact, the sintered polymeric microparticles were demonstrated to be key to controlling the drug dissolution rate and favoring the early healing process as consequence of a better wettability of the porous titanium substrate to promote calcium phosphate nucleation. Thus, this joint technology proposes a suitable prophylactic tool to prevent both early-stage infection and late-stage osseointegration problems.

Surface thermodynamics of mucoadhesive dry powder formulation of zolmitriptan.

Microparticle powders for nasal delivery were formulated to contain the model drug, zolmitriptan, and varying proportions of different polymers. The objective of the study was to investigate the effects of these formulative parameters on the surface chemistry of the spray-dried microparticles and their potential for adhesion to the tested substrates, porcine mucin, and nasal tissue. The polymers used were chitosans of varying ionization states and molecular weights and hydroxypropyl methyl cellulose. The surface energies of the surfaces of the microparticles were determined using contact angle measurements and the van Oss model. The theory of surface thermodynamics was applied to determine the theoretical potential for the different materials to adhere to the substrates. It was found that the drug or polymers alone, as well as the various formulations, were more likely to adhere to mucin than to nasal tissue. Further, there was a trend for higher molecular weight chitosans to adhere better to the substrates than lower molecular weight chitosans. Similarly, adhesion was improved for formulations with a higher content of polymers. These theoretical predictions may be compared with further experimental results and be of use in making informed decisions on the choice of formulations for future expensive bio-studies.

Polymeric and Lipid Nanoparticles: Which Applications in Pediatrics?

This review aims to provide the state of the art on polymeric and lipid nanoparticles, used or suggested to approach pediatric diseases' problems and needs, and to inspire new researches in this field. Several drugs are currently not available in formulations suitable for pediatric patients. The United States Pediatric Formulation Initiative suggested applying new technologies to pediatric drug formulations, for instance, nanotechnology. The literature analysis showed that polymeric and lipid nanoparticles have been widely studied to treat pediatric diseases, and albumin nanoparticles and liposomes are already used in clinical practice. Nevertheless, these studies are focused almost exclusively on pediatric cancer treatment. Although nanomedicine may solve many needs of pediatric diseases and medicines, the unavailability of data on pharmacokinetics, safety and efficacy of both drugs and nanoparticles in pediatric patients limits the development of new pediatric medicines based on nanoparticles. Therefore, nanomedicine applied in pediatrics remains a significant challenge in the near future.

Identifying a Role of Red and White Wine Extracts in Counteracting Skin Aging: Effects of Antioxidants on Fibroblast Behavior.

Dermal fibroblasts are the main actor in many proteins' secretion, including collagen, preserving skin function. Free radicals are involved in skin aging and damages involving different cellular components. The imbalance between reactive oxygen species (ROS) amount and natural antioxidant enzymes negatively affects skin homeostasis. Natural compounds have recently emerged as a potential anti-aging tool in tissue regeneration. In the present paper we evaluated the antioxidant activity of white and red wines, considering their probable use, as raw materials, for the formulation of cosmetic products with anti-aging properties. We studied a method that would allow the removal of the alcoholic fraction of wines and determined their composition by LC-MS analysis. We then tested the possible cytotoxic effects of red and white wines on fibroblasts by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, and their antioxidant activity by the catalase activity test in stressing conditions. Finally, we evaluated their anti-aging potential through the ß-galactosidase colorimetric assay. Our results showed that wine extracts exhibit a remarkable antioxidant and anti-aging activity, especially on cells exposed to a marked stressful event. These properties could suggest their possible application as cosmetical products for skin regeneration.

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). The use of CDs in nasal formulations allowed obtaining versatile drug delivery systems intended for local and systemic effects, as well as for nose-to-brain transport of drugs. In vitro and in vivo models currently employed are suitable to analyze the effects of CDs in nasal formulations. Therefore, CDs are versatile pharmaceutical materials, and due to the continual synthesis of new CDs derivatives, the research on the new nasal applications is an interesting field evolving in the coming years, to which Italian research will still contribute.

Crocetin as New Cross-Linker for Bioactive Sericin Nanoparticles.

The nose-to-brain delivery route is used to bypass the blood-brain barrier and deliver drugs directly into the brain. Over the years, significant signs of progress have been made in developing nano-drug delivery systems to address the very low drug transfer levels seen with conventional formulations (e.g., nasal solutions). In this paper, sericin nanoparticles were prepared using crocetin as a new bioactive natural cross-linker (NPc) and compared to sericin nanoparticles prepared with glutaraldehyde (NPg). The mean diameter of NPc and NPg was about 248 and 225 nm, respectively, and suitable for nose-to-brain delivery. The morphological investigation revealed that NPc are spherical-like particles with a smooth surface, whereas NPg seem small and rough. NPc remained stable at 4 °C for 28 days, and when freeze-dried with 0.1% w/v of trehalose, the aggregation was prevented. The use of crocetin as a natural cross-linker significantly improved the in vitro ROS-scavenging ability of NPc with respect to NPg. Both formulations were cytocompatible at all the concentrations tested on human fibroblasts and Caco-2 cells and protected them against oxidative stress damage. In detail, for NPc, the concentration of 400 µg/mL resulted in the most promising to maintain the cell metabolic activity of fibroblasts higher than 90%. Overall, the results reported in this paper support the employment of NPc as a nose-to-brain drug delivery system, as the brain targeting of antioxidants is a potential tool for the therapy of neurological diseases.

Electrochemotherapy of Deep-Seated Tumors: State of Art and Perspectives as Possible "EPR Effect Enhancer" to Improve Cancer Nanomedicine Efficacy.

Surgical resection is the gold standard for the treatment of many kinds of tumor, but its success depends on the early diagnosis and the absence of metastases. However, many deep-seated tumors (liver, pancreas, for example) are often unresectable at the time of diagnosis. Chemotherapies and radiotherapies are a second line for cancer treatment. The "enhanced permeability and retention" (EPR) effect is believed to play a fundamental role in the passive uptake of drug-loaded nanocarriers, for example polymeric nanoparticles, in deep-seated tumors. However, criticisms of the EPR effect were recently raised, particularly in advanced human cancers: obstructed blood vessels and suppressed blood flow determine a heterogeneity of the EPR effect, with negative consequences on nanocarrier accumulation, retention, and intratumoral distribution. Therefore, to improve the nanomedicine uptake, there is a strong need for "EPR enhancers". Electrochemotherapy represents an important tool for the treatment of deep-seated tumors, usually combined with the systemic (intravenous) administration of anticancer drugs, such as bleomycin or cisplatin. A possible new strategy, worthy of investigation, could be the use of this technique as an "EPR enhancer" of a target tumor, combined with the intratumoral administration of drug-loaded nanoparticles. This is a general overview of the rational basis for which EP could be envisaged as an "EPR enhancer" in nanomedicine.