Modelling acute myeloid leukemia (AML): What's new? A transition from the classical to the modern.

Acute myeloid leukemia (AML) is a heterogeneous malignancy affecting myeloid cells in the bone marrow (BM) but can spread giving rise to impaired hematopoiesis. AML incidence increases with age and is associated with poor prognostic outcomes. There has been a disconnect between the success of novel drug compounds observed in preclinical studies of hematological malignancy and less than exceptional therapeutic responses in clinical trials. This review aims to provide a state-of-the-art overview on the different preclinical models of AML available to expand insights into disease pathology and as preclinical screening tools. Deciphering the complex physiological and pathological processes and developing predictive preclinical models are key to understanding disease progression and fundamental in the development and testing of new effective drug treatments. Standard scaffold-free suspension models fail to recapitulate the complex environment where AML occurs. To this end, we review advances in scaffold/matrix-based 3D models and outline the most recent advances in on-chip technology. We also provide an overview of clinically relevant animal models and review the expanding use of patient-derived samples, which offer the prospect to create more "patient specific" screening tools either in the guise of 3D matrix models, microphysiological "organ-on-chip" tools or xenograft models and discuss representative examples.

Development and in vitro characterization of a novel pMDI diclofenac formulation as an inhalable anti-inflammatory therapy for cystic fibrosis.

Anti-inflammatory treatment options for cystic fibrosis (CF) patients are currently limited and as such, there is an imperative need to develop new anti-inflammatory agents to reduce the persistent inflammation present within CF lungs. This study explored the potential of Diclofenac (DICLO) as a novel inhaled anti-inflammatory drug for CF treatment. The anti-inflammatory activity of DICLO on an air-liquid interface (ALI) cell culture model of healthy (NuLi-1) and CF (CuFi-1) airways showed a significant reduction in the secretion of pro-inflammatory cytokines, IL-6 and IL-8. Therefore, pressurized metered dose inhaler (pMDI) DICLO formulations were developed to allow targeted DICLO delivery to CF airways. As such, two pMDI DICLO formulations with varying ethanol concentrations: 5% (w/w) equating to 150 µg of DICLO per dose (Low dose), and 15% (w/w) equating to 430 µg of DICLO per dose (High dose) were developed and characterized to determine the optimum formulation. The Low dose pMDI DICLO formulation showed a significantly smaller particle diameter with uniform distribution resulting in a greater aerosol performance when compared to High dose formulation. Consequently, the Low dose pMDI DICLO formulation was further evaluated in terms of in vitro transport characteristics and anti-inflammatory activity. Importantly, the DICLO pMDI displayed anti-inflammatory activity in both healthy and CF in vitro models, highlighting the potential of an aerosolized low-dose DICLO formulation as a promising inhaled anti-inflammatory therapy for CF treatment.

Incorporation in Lipid Microparticles of Acid Red 87, a Colorant Used in Tattoo Inks: Effect on Photodegradation Under Simulated Sunlight and Laser Radiation.

Tattoo colorants decompose under solar radiation and when exposed to laser light for their removal, leading to the accumulation in the dermis of toxic products. Aim of this study was to develop lipid microparticles (LMs) loaded with the colorant, Acid Red 87 (C.I. 45380) used in tattoo inks, and to investigate the effect of this system on the photostability of the colorant under simulated sunlight or laser irradiation. LMs loaded with C.I. 45380 were prepared by melt emulsification using tristearin and phosphatidylcholine as excipients. They were characterized by optical microscopy, laser diffraction, X-ray diffraction and release studies. Free C.I. 45380 and the colorant-loaded LMs were irradiated with a solar simulator or a Q-switched laser. Irradiation with a solar simulator demonstrated that photodecomposition of C.I. 45380 was markedly reduced by incorporation of the dye in the LMs, from 20.5 ± 4.6% to 1.3 ± 1.8%. Conversely, the laser-induced degradation of the colorant (30.1 ± 6.6%) was not significantly influenced by encapsulation in the LMs (the encapsulated C.I. 45380 loss was 27.4 ± 5.5%). Incorporation of C.I. 45380 in lipid microparticles enhances the photostability under sunlight of tattoo inks containing this colorant, without affecting its laser-induced degradation and hence laser removal efficiency.

Glyceryl Tristearate-Based Lipid Microparticles Loaded with the Tattoo Colorant, Acid Red 87: Colorant Retention Capacity in Excised Porcine Skin.

BACKGROUND: With the increasing diffusion of tattooing, the photolability of tattoo inks has become a critical issue, as available data indicated that several tattoo colorants are unstable under sunlight, generating potentially toxic photodegradation products. Therefore, it is desirable to enhance the photostability of coloring agents contained in tattoo inks. AIMS: Lipid microparticles (LMs) highly loaded with Acid Red 87 (C.I. 45380), a colorant used in tattoo inks, were evaluated for their effect on the colorant photoinstability. In addition, the capacity of the LMs to retain the incorporated C.I. 45380 colorant after their intradermal administration in excised porcine skin was investigated. METHODS: LMs loaded with C.I. 45380 were prepared using glyceryl tristearate as the lipidic material and phosphatidylcholine as the surfactant. Non-encapsulated C.I. 45380 or the colorant-loaded LMs were irradiated with a solar simulator for photodecomposition studies or introduced in the excised porcine skin mounted in Franz diffusion cells for stability evaluation in the dermal tissue. RESULTS AND CONCLUSION: The colorant content of the microparticles was 17.7%, and their size ranged from 25 to 170 µm. The light-induced degradation of C.I. 45380 was significantly decreased by its incorporation in the LMs from 20.2 ± 5.8% to 1.9 ± 2.1%. Moreover, after intradermal injection of free or microencapsulated C.I. 45380 in the excised pig skin, the LMs reduced by 93.7% (from 24.6 to 1.5%) the quantity of the colorant diffused and hence lost in the Franz cell receptor fluid. Hence, the LM carrier efficiently retained the entrapped C.I. 45380 following incubation in the dermal region of the isolated porcine skin, which is in favor of a long-lasting tattoo. Based on these data, the incorporation of C.I. 45380 in the LMs could represent a potentially useful strategy to reduce the photodecomposition of the tattoo colorant and its harmful interactions with the skin tissue.

Simvastatin Nanoparticles Reduce Inflammation in LPS-Stimulated Alveolar Macrophages.

Simvastatin (SV) is widely used as a lipid-lowering medication that has also been found to have beneficial immunomodulatory effects for treatment of chronic lung diseases. Although its anti-inflammatory activity has been investigated, its underlying mechanisms have not yet been clearly elucidated. In this study, the anti-inflammatory and antioxidant effects and mechanism of simvastatin nanoparticles (SV-NPs) on lipopolysaccharide-stimulated alveolar macrophages (AMs) NR8383 cells were investigated. Quantitative cellular uptake of SV-NPs, the production of inflammatory mediators (interleukin-6, tumor necrosis factor, and monocyte chemoattractant protein-1), and oxidative stress (nitric oxide) were tested. Furthermore, the involvement of the nuclear factor κB (NF-κB) signaling pathway in activation of inflammation in AMs and the efficacy of SV were visualized using immunofluorescence. Results indicated that SV-NPs exhibit a potent inhibitory effect on nitric oxide production and secretion of inflammatory cytokine in inflamed AM, without affecting cell viability. The enhanced anti-inflammatory activity of SV-NPs is likely due to SV-improved chemical-physical stability and higher cellular uptake into AM. The study also indicates that SV targets the inflammatory and oxidative response of AM, through inactivation of the NF-κB signaling pathway, supporting the pharmacological basis of SV for treatment of chronic inflammatory lung diseases.

In vivo Human Skin Penetration of the UV Filter Ethylhexyl Triazone: Effect of Lipid Microparticle Encapsulation.

BACKGROUND/AIMS: The data available on the skin permeability of ethylhexyl triazone (EHT), a widely used high-molecular-weight (823.1-Da) UV filter, are scarce and obtained only via in vitro studies. Therefore, we evaluated in vivo the penetration of EHT in human stratum corneum by the tape stripping technique. Moreover, the effect of EHT encapsulation in lipid microparticles (LMs) on its diffusion through the stratum corneum was examined. METHODS: LMs loaded with EHT were prepared using glyceryl behenate and phosphatidylcholine. Creams containing EHT free or encapsulated in LMs in conjunction with the two most commonly used UV filters, octyl methoxycinnamate (OMC) and butyl methoxydibenzoylmethane (BMDBM), were applied to human volunteers and the fraction of the applied sunscreen dose having penetrated into different stratum corneum layers was measured. RESULTS AND CONCLUSION: For the cream with the nonencapsulated sunscreen agent, the percentage of the applied EHT dose diffused into the stratum corneum was 21.9 ± 4.9%, not significantly different from that of the smaller-molecular-weight OMC (22.2 ± 7.6%) and BMDBM (20.5 ± 3.7%). A marked (45.7%) and statistically significant reduction in the in vivo skin penetration of EHT was attained with the cream containing microencapsulated EHT. The decreased percutaneous penetration provided by the LMs should favor the efficacy of EHT and limit potential toxicological risks.

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 (1.75% w/v chitosan solution) and LMs-Res-Ch-plus (8.75% w/v chitosan solution) were prepared by adding a chitosan solution to the formed particles. The mean diameter of the particles were 68.5 ±â€¯3.1 µm, 76.3 ±â€¯5.2 µm and 84.5 ±â€¯8.1 µm for LMs-Res, LMs-Res-Ch and LMs-Res-Ch-plus respectively, suitable for nasal delivery. Chitosan coating changed the particle surface charge from a negative zeta potential value (-12.7 ±â€¯2.1 mV) for the uncoated particles to a higher positive values respectively, 24.0 ±â€¯4.7 and 44.6 ±â€¯3.1 mV for the chitosan coated LM-Res-Ch and LM-Res-Ch-plus. Permeation studies across human NCM460 cell monolayers demonstrated that their transepithelial electrical resistance (TEER) values were not modified in the presence of free resveratrol, unloaded LMs, loaded LMs-Res or LMs-Res-Ch. On the other hand, the TEER values decreased from 150 ±â€¯7 to 41 ±â€¯3 Ω cm2 in the presence of LMs-Res-Ch-plus, which corresponded to a significant increase in the apparent permeability (Papp) of resveratrol from 518 ±â€¯8 × 10-4 cm/min to 750 ±â€¯98 × 10-4 cm/min. In vivo studies demonstrated that no resveratrol was detected in the rat cerebrospinal fluid (CSF) after an intravenous infusion of the polyphenol. Conversely, the nasal delivery of resveratrol in a chitosan suspension or encapsulated in uncoated LMs-Res dispersed in water achieved the uptake of resveratrol in the CSF with Cmax after 60 min of 1.30 ±â€¯0.30 µg/ml and 0.79 ±â€¯0.15 µg/ml, respectively. However, a dramatic increase in the levels of resveratrol reaching the CSF was attained by the administration of an aqueous suspension of LMs-Res-Ch-plus with a Cmax after 60 min of 9.7 ±â€¯1.9 µg/ml. This marked increase in the CSF bioavailability was achieved without any distribution in the systemic circulation, demonstrating a direct and specific nose to brain delivery.

Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic Respiratory Biofilm Infection.

PURPOSE: The failure of chronic therapy with antibiotics to clear persistent respiratory infection is the key morbidity and mortality factor for patients with chronic lung diseases, primarily due to the presence of biofilm in the lungs. It is hypothesised that carbon sources, such as mannitol, could stimulate the metabolic activity of persister cells within biofilms and restore their susceptibility to antibiotics. The aims of the current study are to: (1) establish a representative in vitro model of Pseudomonas aeruginosa biofilm lung infection, and (2) investigate the effects of nebulised mannitol on antibiotic efficacy, focusing on ciprofloxacin, in the eradication of biofilm. METHOD: Air interface biofilm was cultured onto Snapwell inserts incorporated into a modified pharmacopeia deposition apparatus, the Anderson Cascade Impactor (ACI). Three different formulations including mannitol only, ciprofloxacin only and combined ciprofloxacin and mannitol were nebulised onto the P. aeruginosa biofilm using the modified ACI. Antibacterial effectiveness was evaluated using colony-forming units counts, biofilm penetration and scanning electron microscopy. RESULTS: Nebulised mannitol promotes the dispersion of bacteria from the biofilm and demonstrated a synergistic enhancement of the antibacterial efficacy of ciprofloxacin compared to delivery of antibiotic alone. CONCLUSIONS: The combination of ciprofloxacin and mannitol may provide an important new strategy to improve antibiotic therapy for the treatment of chronic lung infections. Furthermore, the development of a representative lung model of bacterial biofilm could potentially be used as a platform for future new antimicrobial pre-clinical screening.

Inhaled simvastatin nanoparticles for inflammatory lung disease.

AIM: Current inhaled treatments are not adequate to treat all lung diseases. In this study, a promising nanotechnology has been developed to deliver a potential anti-inflammatory and muco-inhibitory compound, simvastatin, for treatment of inflammatory lung diseases via inhalation. MATERIALS & METHODS: Simvastatin nanoparticles (SV-NPs) encapsulated with poly(lactic-co-glycolic) acid were fabricated using the solvent and anti-solvent precipitation method. RESULTS: SV-NPs were found to be stable up to 9 months at 4°C in a freeze-dried form prior to reconstitution. The amount of mucus produced was significantly reduced after SV-NPs treatment on inflammation epithelial cell models and were effective in suppressing the proinflammatory marker expression. CONCLUSION: This study suggests that SV-NPs nebulization could potentially be used for the treatment of chronic pulmonary diseases.

Novel nano-cellulose excipient for generating non-Newtonian droplets for targeted nasal drug delivery.

PURPOSE: Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post-administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips. METHODS: Nasal sprays containing nano-cellulose at different concentrations were investigated for the additive's potential as an excipient. The formulations were characterized for their rheological and aerosol properties. This was then compared to conventional nasal spray formulation containing the single-component hydroxyl-propyl methyl cellulose (HPMC) viscosity enhancing excipient. RESULTS: The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray. CONCLUSIONS: Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size, and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners.

Pulmonary delivery systems for polyphenols.

This review reports on the beneficial pharmacological properties of naturally occurring polyphenols for the treatment of inflammatory pulmonary diseases. In addition, it presents an overview of the different types of inhalable formulations which have been developed in order to achieve efficient delivery of polyphenols to the respiratory tract. The main biological activities of polyphenols (anti-oxidant and anti-inflammatory) are covered, with particular emphasis on the studies describing their therapeutic effects on different factors and conditions characteristic of lung pathologies. Special focus is on the technological aspects which influence the pulmonary delivery of drugs. The various polyphenol-based inhalable formulations reported in the literature are examined with specific attention to the preparation methodologies, aerosol performance, lung deposition and in vitro and in vivo polyphenol uptake by the pulmonary epithelial cells.

Resveratrol solid lipid microparticles as dry powder formulation for nasal delivery, characterization and in vitro deposition study.

This study focuses on development and in vitro characterisation of a nasal delivery system based on uncoated or chitosan-coated solid lipid microparticles (SLMs) containing resveratrol, a natural anti-inflammatory molecule, as an effective alternative to the conventional steroidal drugs. The physico-chemical characteristics of the SLMs loaded with resveratrol were evaluated in terms of morphology, size, thermal behaviour and moisture sorption. The SLMs appeared as aggregates larger than 20 µm. In vitro nasal deposition was evaluated using a USP specification Apparatus E 7-stage cascade impactor equipped with a standard or a modified nasal deposition apparatus. More than 95% of resveratrol was recovered onto the nasal deposition chamber and stage 1 of impactor, suggesting that the SLMs mostly deposited in the nasal cavity. Additionally, the SLMs were not toxic on RPMI 2650 nasal cell line up to a concentration of approximately 40 µM of resveratrol.

Co-spray dried resveratrol and budesonide inhalation formulation for reducing inflammation and oxidative stress in rat alveolar macrophages.

Oxidative stress is instrumental in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies that target macrophages, based on the use of antioxidant compounds, could be explored to improve corticosteroid responses in COPD patients. In this study, inhalable microparticles containing budesonide (BD) and resveratrol (RES) were prepared and characterized. This approach was undertaken to develop a multi-drug inhalable formulation with anti-oxidant and anti-inflammatory activities for treatment of chronic lung diseases. The inhalable microparticles containing different ratios of BD and RES were prepared by spray drying. The physico-chemical properties of the formulations were characterized in terms of surface morphology, particle size, physical and thermal stability. Additionally, in vitro aerosol performances of these formulations were evaluated with the multi-stage liquid impinger (MSLI) at 60 and 90 l/min, respectively. The cytotoxicity effect of the formulations was evaluated using rat alveolar macrophages. The biological responses of alveolar macrophages in terms of cytokine expressions, nitric oxide (NO) production and free radical scavenging activities were also tested. The co-spray dried (Co-SD) microparticles of all formulations exhibited morphologies appropriate for inhalation administration. Analysis of the deposition profiles showed an increase in aerosol performance proportional to BD concentration. Cell viability assay demonstrated that alveolar macrophages could tolerate a wide range of RES and BD concentrations. In addition, RES and BD were able to decrease the levels of tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS) induced alveolar macrophages. This study has successfully established the manufacture of Co-SD formulations of RES and BD with morphology and aerosol properties suitable for inhalation drug delivery, negligible in vitro toxicity and enhanced efficacy to control inflammation and oxidative stress in LPS-induced alveolar macrophages.

Optical properties of orthodontic aligners--spectrophotometry analysis of three types before and after aging.

BACKGROUND: The aim was to assess and compare absorbance and transmittance values of three types of clear orthodontic aligners before and after two cycles of in vitro aging. METHODS: Nine samples of orthodontic aligners from three different manufacturers (Invisalign, Align Technology, Santa Clara, CA, USA; All-In, Micerium, Avegno, GE, Italy; F22 Aligner, Sweden & Martina, Due Carrare, PD, Italy) were selected, and each sample was subjected to spectrophotometry analysis of both its transmittance and absorbance a total of 27 times. Samples were subsequently aged in vitro at a constant temperature in artificial saliva supplemented with food colouring for two cycles of 14 days each. The spectrophotometry protocol was then repeated, and the resulting data were analysed and compared by means of ANOVA (p < 0.05). RESULTS: All types of aligners tested yielded lower transmittance and higher absorbance values after aging, but the difference was not significant in any case. That being said, the F22 aligners were found to be most transparent, both before and after aging, followed by Invisalign and All-In, and these differences were statistically significant. CONCLUSIONS: Commercial aligners possess significantly different optical, and therefore aesthetic, properties, both as delivered and following aging.

Enhancement of in vivo human skin penetration of resveratrol by chitosan-coated lipid microparticles.

In this study, lipid microparticles (LMs) uncoated or coated with chitosan, and containing the antioxidant polyphenol, resveratrol were developed in order to enhance its in vivo skin permeation. The LMs loaded with resveratrol were prepared by melt emulsification and sonication, using tristearin as lipidic material and hydrogenated phosphatidylcholine as the surfactant. Two different methods were examined for the coating of the LMs: chitosan addition during LM preparation or treatment of already formed LMs with a chitosan solution. The latter method achieved a better modulation of the in vitro release of resveratrol and hence was used for subsequent studies. The resveratrol loading and mean diameter of the LMs were 4.1 ± 0.3% (w/w) and 5.7 µm and 3.8 ± 0.2 % (w/w) and 6.1 µm for the uncoated and the chitosan-coated LMs, respectively. Chitosan coating changed the LM surface charge, from a negative zeta potential value (-17.8 ± 4.8 mV) for the uncoated particles, to a higher positive values (+64.2 ± 4.4 mV) for the chitosan-coated ones. Creams containing resveratrol free, encapsulated in the uncoated or chitosan-coated LMs were applied to the forearm of human volunteers and the penetration of the polyphenol in the stratum corneum was investigated in vivo by the tape stripping technique. Uncoated LMs did not produce any significant increase in the fraction of the applied resveratrol dose diffused in the stratum corneum (32.8 ± 8.9 %) compared to the control cream containing the non-encapsulated polyphenol (26.2 ± 5.6 % of the applied dose). On the other hand, application of the cream containing the chitosan-coated LMs produced a significant enhancement in the in vivo permeation of resveratrol to 49.3 ± 5.9% of the applied dose, the effect being more marked in the upper region of the horny layer. The observed improvement in the human stratum corneum penetration of resveratrol achieved by the LMs coated with chitosan should favour the efficiency of its topical application.

In vitro biological activity of resveratrol using a novel inhalable resveratrol spray-dried formulation.

The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of chronic obstructive pulmonary disease (COPD). Resveratrol, with a spherical morphology and particle diameter less than 5 µm, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9 ± 1.1% and 3.7 ± 0.1 µm, respectively, when assessed with an Andersen cascade impactor (ACI) at 60 l/min. The cytotoxicity results of resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160 µM). In addition, in transport experiments using Snapwells, it was observed that more than 80% of the deposited dry powder was transported across the Calu-3 cells to the basal chamber within four hours. The expression of interleukin-8 (IL-8) from Calu-3 induced with tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-ß1) and lipopolysaccharide (LPS) were significantly reduced after treatment with spray-dried resveratrol. The antioxidant assay (radical scavenging activity and nitric oxide production) showed spray-dried resveratrol to possess an equivalent antioxidant property as compared to vitamin C. Results presented in this investigation suggested that resveratrol could potentially be developed as a dry powder for inhalation for the treatment of inflammatory lung diseases like COPD.

Is the cellular uptake of respiratory aerosols delivered from different devices equivalent?

The study focuses on the application of a cell integrated modified Andersen Cascade Impactor (ACI) as an in vitro lung model for the evaluation of aerosols' behaviour of different formulation devices, containing the same active drug, specifically nebuliser, pressurised metered dose inhaler (pMDI) and dry powder inhaler (DPI). Deposition and transport profiles of the three different inhaled salbutamol sulphate (SS) formulations with clinically relevant doses were evaluated using a modified ACI coupled with the air interface Calu-3 bronchial cell model. Reproducible amounts of SS were deposited on Snapwells for the different formulations, with no significant difference in SS deposition found between the standard ACI plate and modified plate. The transport of SS aerosols produced from pMDI formulation had similar transport kinetics to nebulised SS but significantly higher compared to the DPI, which could have led to the differences in clinical outcomes. Furthermore, drug absorption of different inhaled formulation devices of the same aerodynamic fraction was found not to be equivalent due to their physical chemical properties upon aerosolisation. This study has established an in vitro platform for the evaluation of the different inhaled formulations in physiologically relevant pulmonary conditions.

Solid lipid microparticles as an approach to drug delivery.

INTRODUCTION: Solid lipid particles were introduced in the early 1990s as an alternative drug carrier system to emulsions, liposomes and polymeric microparticles. Although lipid nanoparticles have been the object of a substantial number of reviews, fewer are available on lipid microparticles (LMs), despite their distinct advantages, including biocompatibility, ease of production and characterisation, extended release properties and high loading. AREAS COVERED: This review presents an overview of the advantages and drawbacks of LMs, that is, lipid-based particles with dimensions in the micrometre range. Specific focus is on the role of the main excipients used for LM formulations, lipids and surfactants and their effects on LM properties. An update on preparation techniques and characterisation methods are also presented, with particular emphasis on more recent technologies. The interaction of LMs with biological systems and with cells in particular is reviewed. The various LM administration routes are examined, with special attention to most recent applications (i.e., pulmonary and nasal delivery). EXPERT OPINION: LMs represent attractive and versatile carrier systems; however, their pharmaceutical applicability has been rather limited. Investigation on the use of LMs for less-established administration routes, such as pulmonary delivery, may provide further interest within the area of LM-based systems, both in industry and in the clinic.

In vivo penetration of bare and lipid-coated silica nanoparticles across the human stratum corneum.

Skin penetration of silica nanoparticles (NP) currently used in pharmaceutical and cosmetic products is a topic of interest not only to evaluate their possible toxicity, but also to understand their behaviour upon contact with the skin and to exploit their potential positive effects in drug or cosmetic delivery field. Therefore, the present work aimed to elucidate the in vivo mechanism by which amorphous hydrophilic silica NP enter human stratum corneum (SC) through the evaluation of the role played by the nanoparticle surface polarity and the human hair follicle density. Two silica samples, bare hydrophilic silica (B-silica, 162±51nm in size) and hydrophobic lipid-coated silica (LC-silica, 363±74nm in size) were applied on both the volar and dorsal side of volunteer forearms. Twelve repetitive stripped tapes were removed from the human skin and evaluated for elemental composition by Energy Dispersive X-ray (EDX) analysis and for silicon content by Inductively Coupled Plasma quadrupole Mass Spectrometry (ICP-MS). All the stripped tapes revealed nanosized structures generally located in the broad spaces between corneocytes and characterized by the same elemental composition (relative weight percentage of silicon and silicon to oxygen weight ratio) than that of the applied samples. However, only about 10% B-silica permeated until the deepest SC layers considered in the study indicating a silica retention in the upper layers of SC, regardless of the hair follicle density. Otherwise, the exposure to LC-silica led to a greater silica skin penetration extent into the deeper SC layers (about 42% and 18% silica following volar and dorsal forearm application, respectively) indicating that the NP surface polarity played a predominant role on that of their size in determining the route and the extent of penetration.