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Elucidation of physical-chemical characteristics of investigational medicinal products should be established with suitable methodology. Characterization of nanomedicines and nanocarriers in clinical trials may require the definition of additional specific properties depending on the nature of the nanostructures or nanomaterials composing the investigational medicinal product. The availability of regulatory requirements and guidelines is investigated focusing on critical quality attributes for nanomedicines and nanocarriers, mapping them in a clinical trial setting. Current regulatory challenges and issues are highlighted. The increasing complexity of nanostructures, the innovative connotation of applied nanotechnology, and the lack in capillarity or misalignment of relevant guidelines and terminology may lead to a potential not standardized approach in the characterization of nanomedicines and nanocarriers in clinical trials and delays in the approval process. Further efforts and a proactive approach from a regulatory standpoint would be desirable to surf the wave of innovation that impact nanomedicines and nanocarriers in clinical trials, in order to support clinical drug development capitalizing on technological advances and still ensuring a strong regulatory framework.

Nanoscale echogenic bubbles (NBs), can be used as a theranostic platform for the localizeddelivery of encapsulated drugs. However, the generation of NBs is challenging, because they havelifetimes as short as milliseconds in solution. The aim of this work has been the optimization of apreparation method for the generation of stable NBs, characterized by measuring: a) acousticefficiency, b) nano-size, to ensure passive tumour targeting, c) stability during storage and afterinjection d) ability to entrap drugs. NBs are monodisperse and ultra-stable, their stability achievedby generation of an amphiphilic multilamellar shell able to efficiently retain the PFC gas. The NBsperform as good acoustic enhancers over a wide frequency range and out of resonant conditions,as tested in both in vitro and in vivo experiments, proving to be a potential platform for theproduction of versatile carriers to be used in ultrasound-assisted diagnostic, therapeutic andtheranostic applications.

Marianecci C, Rinaldi F, Di Marzio L, et al. Int J Nanomedicine. 2014;9(1):635–651. The Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised regarding the alleged duplication of TEM images in Figure 1. Specifically, Figure 1A, F1, appears to have been duplicated with the same image for Figure 1C, F3 and Figure 1D, F3AG. The authors did respond to our queries but were unable to explain how the duplication of images occurred, nor were they able to provide the original TEM images from the reported study. The decision was made to retract the article and the authors were notified of this. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Federica Rinaldi,1,* Patrizia Nadia Hanieh,1,* Linda Maurizi,2 Catia Longhi,2 Daniela Uccelletti,3 Emily Schifano,3 Elena Del Favero,4 Laura Cantù4 ,†Caterina Ricci,4 Maria Grazia Ammendolia,5 Donatella Paolino,6 Francesca Froiio,6 Carlotta Marianecci,1 Maria Carafa1 1Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Rome, Italy; 2Dipartimento di Sanità pubblica e Malattie infettive, Sapienza Università di Roma, Rome, Italy; 3Dipartimento di Biologia e Biotecnologie Charles Darwin, Sapienza Università di Roma, Rome, Italy; 4Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università di Milano, Milan, Italy; 5Centro Nazionale Tecnologie Innovative in Sanità Pubblica, Istituto Superiore di Sanità , Rome, Italy; 6Dipartimento di Medicina Sperimentale e Clinica, Università Magna Graecia di Catanzaro, Campus Universitario “S. Venuta”, Catanzaro, Italy*These authors contributed equally to this work†Professor Laura Cantù passed away on August 05, 2022Correspondence: Maria Carafa; Carlotta Marianecci, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, Roma, 00185, Italy, Tel +390649913603 ; +390649913970, Fax +39064913133, Email maria.carafa@uniroma1.it; carlotta.marianecci@uniroma1.itPurpose: Vitamin E (VitE) may be classified in “the first line of defense” against the formation of reactive oxygen species. Its inclusion in nanoemulsions (NEs) is a promising alternative to increase its bioavailability. The aim of this study was to compare O/W NEs including VitE based on Almond or Neem oil, showing themselves antioxidant properties. The potential synergy of the antioxidant activities of oils and vitamin E, co-formulated in NEs, was explored.Patients and Methods: NEs have been prepared by sonication and deeply characterized evaluating size, ζ-potential, morphology (TEM and SAXS analyses), oil nanodroplet feature, and stability. Antioxidant activity has been evaluated in vitro, in non-tumorigenic HaCaT keratinocytes, and in vivo through fluorescence analysis of C. elegans transgenic strain. Moreover, on healthy human volunteers, skin tolerability and anti-inflammatory activity were evaluated by measuring the reduction of the skin erythema induced by the application of a skin chemical irritant (methyl-nicotinate).Results: Results confirm that Vitamin E can be formulated in highly stable NEs showing good antioxidant activity on keratinocyte and on C. elegans. Interestingly, only Neem oil NEs showed some anti-inflammatory activity on healthy volunteers.Conclusion: From the obtained results, Neem over Almond oil is a more appropriate candidate for further studies on this application.Graphical Abstract: Keywords: O/W nanodispersion, α-tocopherol, anti-inflammatory activity, HaCaT, C. elegans, healthy volunteers

Hypothesis. Isoniazid is one of the primary drugs used in tuberculosis treatment. Isoniazid encapsulation in liposomal vesicles can improve drug therapeutic index and minimize toxic and side effects. In this work, we consider mixtures of hydrogenated soy phosphatidylcholine/phosphatidylglycerol (HSPC/DPPG) to get novel biocompatible liposomes for isoniazid pulmonary delivery. Our goal is to understand if the entrapped drug affects bilayer structure. Experiments. HSPC-DPPG unilamellar liposomes are prepared and characterized by dynamic light scattering, $\zeta$-potential, fluorescence anisotropy and Transmission Electron Microscopy. Isoniazid encapsulation is determined by UV and Laser Transmission Spectroscopy. Calorimetry, light scattering and Surface Pressure measurements are used to get insight on adsorption and thermodynamic properties of lipid bilayers in the presence of the drug. Findings. We find that INH-lipid interaction can increase the entrapment capability of the carrier due to isoniazid adsorption. The preferential INH-HSPC dipole-dipole interaction promotes modification of lipid packing and ordering and favors the condensation of a HSPC-richer phase in molar excess of DPPG. Our findings highlight the importance of fundamental investigations of drug-lipid interactions for the optimal design of liposomal nanocarriers., Comment: 28 pages (main manuscript + supplementary information)

The chemopreventive potential of Resveratrol (RV) against bladder cancer and its mechanism of action have been widely demonstrated. The physicochemical properties of RV, particularly its high reactivity and low solubility in aqueous phase, have been limiting factors for its bioavailability and in vivo efficacy. In order to overcome these limitations, its inclusion in drug delivery systems needs to be taken into account. In particular, oil-in-water (O/W) nanoemulsions (NEs) have been considered ideal candidates for RV encapsulation. Since surfactant and oil composition can strongly influence NE features and their application field, a ternary phase diagram was constructed and evaluated to select a suitable surfactant/oil/water ratio. The selected sample was deeply characterized in terms of physical chemical features, stability, release capability and cytotoxic activity. Results showed a significant decrease in cell viability after the incubation of bladder T24 cancer cells with RV-loaded NEs, compared to free RV. The selected NE formulation was able to preserve and improve RV cytotoxic activity by a more rapid drug uptake into the cells. O/W NEs represent an effective approach to improve RV bioavailability.

Hyaluronic acid (HA) is one of the most used biopolymers in the development of drug delivery systems, due to its biocompatibility, biodegradability, non-immunogenicity and intrinsic-targeting properties. HA specifically binds to CD44, this property combined to the EPR effect could provide an option for reinforced active tumor targeting by nanocarriers, improving drug uptake by the cancer cells via the HA-CD44 receptor-mediated endocytosis pathway. Moreover, HA can be easily chemically modified to tailor its physico-chemical properties in view of specific applications. The derivatization with cholesterol confers to HA an amphiphilic character, and then the ability of anchoring to niosomes. HA-Chol was then used to coat Span® or Tween® niosomes providing them with an intrinsic targeting shell. The nanocarrier physico-chemical properties were analyzed in terms of hydrodynamic diameter, ζ-potential, and bilayer structural features to evaluate the difference between naked and HA-coated niosomes. Niosomes stability was evaluated over time and in bovine serum. Moreover, interaction properties of HA-coated nanovesicles with model membranes, namely liposomes, were studied, to obtain insights on their interaction behavior with biological membranes in future experiments. The obtained coated systems showed good chemical physical features and represent a good opportunity to carry out active targeting strategies.

Advances, perspectives and innovation in drug delivery have increased in recent years, however, there is limited information available regarding the actual presence of surfactants, nanomedicines and nanocarriers in investigational medicinal products submitted as part of a request for authorization of clinical trials, particularly for those authorized in the European Economic Area. We retrieve, analyze and report data available at the Clinical Trial Office of the Italian Medicines Agency (AIFA), increasing the transparency and availability of relevant information. An analysis of quality documentation submitted along with clinical trials authorized by the AIFA in 2018 was carried out, focusing on the key terms “surfactant”, “nanomedicine” and “nanocarrier”. Results suggest potential indications and inputs for further reflection and actions for regulators to actively and safely drive innovation from a regulatory perspective and to transpose upcoming evolution of clinical trials within a strong regulatory framework.

S100B protein bridges chronic mucosal inflammation and colorectal cancer given its ability to activate NF‐kappaB transcription via RAGE signalling and sequestrate pro‐apoptotic wtp53. Being an S100B inhibitor, pentamidine antagonizes S100B‐wtp53 interaction, restoring wtp53‐mediated pro‐apoptotic control in cancer cells in several types of tumours. The expression of S100B, pro‐inflammatory molecules and wtp53 protein was evaluated in human biopsies deriving from controls, ulcerative colitis and colon cancer patients at baseline (a) and (b) following S100B targeting with niosomal PENtamidine VEhiculation (PENVE), to maximize drug permeabilization in the tissue. Cultured biopsies underwent immunoblot, EMSA, ELISA and biochemical assays for S100B and related pro‐inflammatory/pro‐apoptotic proteins. Exogenous S100B (0.005‐5 μmol/L) alone, or in the presence of PENVE (0.005‐5 μmol/L), was tested in control biopsies while PENVE (5 μmol/L) was evaluated on control, peritumoral, ulcerative colitis and colon cancer biopsies. Our data show that S100B level progressively increases in control, peritumoral, ulcerative colitis and colon cancer enabling a pro‐inflammatory/angiogenic and antiapoptotic environment, featured by iNOS, VEGF and IL‐6 up‐regulation and wtp53 and Bax inhibition. PENVE inhibited S100B activity, reducing its capability to activate RAGE/phosphor‐p38 MAPK/NF‐kappaB and favouring its disengagement with wtp53. PENVE blocks S100B activity and rescues wtp53 expression determining pro‐apoptotic control in colon cancer, suggesting pentamidine as a potential anticancer drug.

Satureja montana essential oil (SEO) presents a wide range of biological activities due to its high content of active phytochemicals. In order to improve the essential oil’s (EO) properties, oil in water nanoemulsions (NEs) composed of SEO and Tween-80 were prepared, characterized, and their antimicrobial and antibiofilm properties assayed against Escherichia coli strains isolated from healthy chicken. Since surfactant and oil composition can strongly influence NE features and their application field, a ternary phase diagram was constructed and evaluated to select a suitable surfactant/oil/water ratio. Minimal inhibitory concentration and minimal bactericidal concentration of NEs, evaluated by the microdilution method, showed that the SEO NE formulation exhibited higher inhibitory effects against planktonic E. coli than SEO alone. The quantification of biofilm production in the presence of NEs, assessed by crystal violet staining and scanning electron microscopy, evidenced that sub-MIC concentrations of SEO NEs enable an efficient reduction of biofilm production by the strong producer strains. The optimized nanoemulsion formulation could ensure food safety quality, and counteract the antibiotic resistance of poultry associated E. coli, if applied/aerosolized in poultry farms.

Brain infections as meningitis and encephalitis are attracting a great interest. Challenges in the treatment of these diseases are mainly represented by the blood brain barrier (BBB) that impairs the efficient delivery of even very potent drugs to reach the brain. The nose to the brain administration route, is a non-invasive alternative for a quick onset of action, and enables the transport of numerous medicinal agents straight to the brain thus workarounding the BBB through the highly vascularized olfactory region. In this report, Thymus vulgaris and Syzygium aromaticum essential oils (EOs) were selected to be included in chitosan coated nanoemulsions (NEs). The EOs were firstly analyzed to determine their chemical composition, then used to prepare NEs, that were deeply characterized in order to evaluate their use in intranasal administration. An in vitro evaluation against a collection of clinical isolated bacterial strains was carried out for both free and nanoemulsioned EOs. Chitosan coated NEs showed to be a potential and effective intranasal formulation against multi-drug resistant Gram-negative bacteria such as methicillin-susceptible Staphylococcus aureus and multi-drug resistant Gram-negative microorganisms including carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae.

All-Trans Retinoic Acid (ATRA) is the most active metabolite of vitamin A. It is critically involved in the regulation of multiple processes, such as cell differentiation and apoptosis, by activating specific genomic pathways or by influencing key signaling proteins. Furthermore, mounting evidence highlights the anti-tumor activity of this compound. Notably, oral administration of ATRA is the first choice treatment in Acute Promyelocytic Leukemia (APL) in adults and NeuroBlastoma (NB) in children. Regrettably, the promising results obtained for these diseases have not been translated yet into the clinics for solid tumors. This is mainly due to ATRA-resistance developed by cancer cells and to ineffective delivery and targeting. This up-to-date review deals with recent studies on different ATRA-loaded Drug Delivery Systems (DDSs) development and application on several tumor models. Moreover, patents, pre-clinical, and clinical studies are also reviewed. To sum up, the main aim of this in-depth review is to provide a detailed overview of the several attempts which have been made in the recent years to ameliorate ATRA delivery and targeting in cancer.

PubMed: 28965424, The aim of the present work is to develop nanoemulsions (NEs), nanosized emulsions, manufactured for improving the delivery of active pharmaceutical ingredients. In particular, nanoemulsions composed of Neem seed oil, contain rich bioactive components, and Tween 20 as nonionic surfactant were prepared. A mean droplet size ranging from 10 to 100 nm was obtained by modulating the oil/surfactant ratio. Physicochemical characterisation was carried out evaluating size, ?-potential, microviscosity, polarity and turbidity of the external shell and morphology, along with stability in simulated cerebrospinal fluid (CSF), activity of Neem oil alone and in NEs, HEp-2 cell interaction and cytotoxicity studies. This study confirms the formation of NEs by Tween 20 and Neem oil at different weight ratios with small and homogenous dimensions. The antioxidant activity of Neem oil alone and in NEs was comparable, whereas its cytotoxicity was strongly reduced when loaded in NEs after interaction with HEp-2 cells. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group., Università degli Studi di Milano, EDF thanks BIOMETRA Dept., University of Milan, for financial support (Piano sostegno ricerca – Linea B 2016).

Chemical fingerprints of four different Satureja montana L. essential oils (SEOs) were assayed by an untargeted metabolomics approach based on Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) coupled with either electrospray ionization or atmospheric pressure chemical ionization ion sources. Analysis and relative quantification of the non-polar volatile fraction were conducted by gas chromatography (GC) coupled to MS. FT-ICR MS confirmed significant differences in the polar metabolite composition, while GC-MS analyses confirmed slight fluctuations in the relative amount of major terpenes and terpenoids, known to play a key role in antimicrobial mechanisms. Oil in eater (O/W) nanoemulsions (NEs) composed by SEOs and Tween 20 or Tween 80 were prepared and analyzed in terms of hydrodynamic diameter, &zeta, potential and polydispersity index. The results confirm the formation of stable NEs homogeneous in size. Minimum inhibitory and minimum bactericidal concentrations of SEOs were determined towards Gram-positive (Listeria monocytogenes, Staphylococcus aureus, Staphylococcus haemolyticus) and Gram-negative clinical isolates (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens). Commercial SEO showed strongest antibacterial activity, while SEO 3 was found to be the most active among the lab made extractions. MIC and MBC values ranged from 0.39 to 6.25 mg&middot, mL&minus, 1. Furthermore, a SEO structured in NEs formulation was able to preserve and improve antimicrobial activity.

Ibuprofen is one of the non-steroidal anti-inflammatory drugs (NSAIDs) widely used to treat pain conditions. NSAIDs encounter several obstacles to passing across biological membranes. To overcome these constraints, we decided to study the effects of a new pH-sensitive formulation of niosomes containing Polysorbate 20 derivatized by Glycine and loaded with ibuprofen (NioIbu) in several animal models of pain in mice. We performed two tests commonly used to study acute antinociceptive activity, namely the writhing test and the capsaicin test. Our results demonstrated that NioIbu, administered 2 h before testing, reduced nociception, whereas the free form of ibuprofen was ineffective. In a model of inflammatory pain, hyperalgesia induced by zymosan, NioIbu induced a long-lasting reduction in hyperalgesia in treated mice. In a model of neuropathic pain induced by sciatic nerve chronic constriction, NioIbu reduced both neuropathy-induced allodynia and hyperalgesia. The results obtained in our experiments suggest that pH-sensitive niosomes containing Polysorbate 20 derivatized by Glycine is an effective model for NSAIDs delivery, providing durable antinociceptive effects and reducing the incidence of side effects.

pH-sensitive nonionic surfactant vesicles (niosomes) by polysorbate-20 (Tween-20) or polysorbate-20 derivatized by glycine (added as pH sensitive agent), were developed to deliver Ibuprofen (IBU) and Lidocaine (LID). For the physical-chemical characterization of vesicles (mean size, size distribution, zeta potential, vesicle morphology, bilayer properties and stability) dynamic light scattering (DLS), small angle X-ray scattering and fluorescence studies were performed. Potential cytotoxicity was evaluated on immortalized human keratinocyte cells (HaCaT) and on immortalized mouse fibroblasts Balb/3T3. In vivo antinociceptive activity (formalin test) and anti-inflammatory activity tests (paw edema induced by zymosan) in murine models were performed on drug-loaded niosomes. pH-sensitive niosomes were stable in the presence of 0 and 10% fetal bovine serum, non-cytotoxic and able to modify IBU or LID pharmacological activity in vivo. The synthesis of stimuli responsive surfactant, as an alternative to add pH-sensitive molecules to niosomes, could represent a promising delivery strategy for anesthetic and anti-inflammatory drugs.

The blood-brain barrier (BBB) plays a fundamental role in protecting and maintaining the homeostasis of the brain. For this reason, drug delivery to the brain is much more difficult than that to other compartments of the body. In order to bypass or cross the BBB, many strategies have been developed: invasive techniques, such as temporary disruption of the BBB or direct intraventricular and intracerebral administration of the drug, as well as noninvasive techniques. Preliminary results, reported in the large number of studies on the potential strategies for brain delivery, are encouraging, but it is far too early to draw any conclusion about the actual use of these therapeutic approaches. Among the most recent, but still pioneering, approaches related to the nasal mucosa properties, the permeabilization of the BBB via nasal mucosal engrafting can offer new potential opportunities. It should be emphasized that this surgical procedure is quite invasive, but the implication for patient outcome needs to be compared to the gold standard of direct intracranial injection, and evaluated whilst keeping in mind that central nervous system diseases and lysosomal storage diseases are chronic and severely debilitating and that up to now no therapy seems to be completely successful.

The majority of active agents do not readily permeate into brain due to the presence of the blood-brain barrier and blood-cerebrospinal fluid barrier. Currently, the most innovative and promising non-invasive strategy in brain delivery is the design and preparation of nanocarriers, which can move through the brain endothelium. Niosomes can perform brain delivery, in fact polysorbates, can act as an anchor for apolipoprotein E from blood plasma. The particles mimic LDL and interact with the LDL receptor leading to the endothelial cells uptake. The efficacy of niosomes for anticancer therapeutic applications was correlated to their physicochemical and drug delivery properties. Dimensions and ζ-potential were characterized using dynamic light scattering and asymmetric flow-field fractionation system. Lipid bilayer was characterized measuring the fluidity, polarity and microviscosity by fluorescent probe spectra evaluation. Morphology and homogeneity were characterized using atomic force microscopy. Physicochemical stability and serum stability (45% v/v fetal bovine and human serum) were evaluated as a function of time using dynamic light scattering. U87-MG human glioblastoma cells were used to evaluate vesicle cytotoxicity and internalisation efficiency. From the obtained data, the systems appear useful to perform a prolonged (modified) release of biological active substances to the central nervous system.

Efficient and safe drug delivery has always been a challenge in theraphy and diagnostics. The use of nanotechnology, as well as the development of nanocarriers for drug delivery, received great attention according to the evidence that they can theoretically act as “magic bullets” capable to hit the target cells while sparing normal tissues and organs. Since 1980 the formulation of vesicular carriers became a tool to improve drug delivery. Liposomes and niosomes are self assembled nanocarriers obtained by hydration of amphiphilic molecules and appropriate amounts of cholesterol. Vesicular carriers can be unilamellar or multilamellar, are suitable as carriers of both hydrophilic and lipophilic drugs and are able to deliver drugs to the target site. The vesicle properties are specifically dictated by size, shape, and surface chemistry which are able to modify the intrinsic pharmacokinetics of the drug and, eventually, drug targeting to the pathological areas. This up-to-date review deals with the importance of various vesicular carriers in drug delivery with particular emphasis on innovative liposomes and niosomes developed at the Department of Drug Chemistry and Technologies at “Sapienza” University of Rome.

Span-20 non-ionic surfactant vesicles (niosomes), designed for future applications in brain drug delivery through intranasal route, are prepared and coated with chitosan glutamate, a mucoadhesive agent specifically proposed for brain delivery and for an optimal interaction with nasal mucin, with the aim to promote the vesicles residence time in the nasal cavity. The understanding of the interaction between chitosan coated niosomes with mucin is of great relevance as it can influence their in vivo distribution and physiological behaviour. Complementary and different techniques are then used in a non-conventional combined approach to study this phenomenon. The integrated use of dynamic light scattering (DLS), fluorimetric and spectrophotometric assays, small-angle X-ray scattering (SAXS), atomic force microscopy (AFM) and high speed brightfield microscopy (BFM) allows to shed new light on the physico-chemical behaviour of the mucin-niosomes system, addressing this complex phenomenon by different perspectives.

The ability of some surfactants to self-assemble in a water/oil bi-phase environment thus forming supramolecular structure leading to the formation of w/o/w multiple emulsions was investigated. The w/o/w multiple emulsions obtained by self-assembling (one-step preparation method) were compared with those prepared following the traditional two-step procedure. Methyl-nicotinate was used as a hydrophilic model drug. The formation of the multiple emulsion structure was evidenced by optical microscopy, which showed a mean size of the inner oil droplets of 6 μm and 10 μm for one-step and two-step multiple emulsions, respectively. The in vitrobiopharmaceutical features of the various w/o/w multiple emulsion formulations were evaluated by means of viscosimetry studies, drug release and in vitro percutaneous permeation experiments through human stratum corneum and viable epidermis membranes. The self-assembled multiple emulsions allowed a more gradual percutaneous permeation (a zero-order permeation rate) than the two-step ones. The in vivotopical carrier properties of the two different multiple emulsions were evaluated on healthy human volunteers by using the spectrophotometry of reflectance, an in vivonon invasive method. These multiple emulsion systems were also compared with conventional emulsion formulations. Our findings demonstrated that the multiple emulsions obtained by self-assembling were able to provide a more sustained drug delivery into the skin and hence a longer therapeutic action than two-step multiple emulsions and conventional emulsion formulations. Finally, our findings showed that the supramolecular micro-assembly of multiple emulsions was able to influence not only the biopharmaceutical characteristics but also the potential in vivotherapeutic response.

The aim of the present paper is to highlight the potential of nasal mucosa as an administration route for targeting the central nervous system, in particular, the brain. Among the formulation strategies for enhance nose to brain drug delivery, the use of colloidal carriers has became a revolutionary approach. These systems should be able to entrap drugs in the desired amount, to penetrate through anatomical barriers, to efficiently release the loaded drugs in the site of action and moreover to show a good physicochemical, biological stability and good biocompatibility. The use of vesicular systems (liposomes and niosomes) together with the use of micelles, in nose to brain delivery are here presented. Vesicle structure is characterized by the presence of a hydrophobic bilayer and an aqueous core that is absent in micelles. Amphiphilic molecules are responsible for soft nanocarriers formation, in particular: liposomes are formed by phospholipids, while niosomes by non-ionic surfactant and micelles by amphiphilic polymers.

Ultradeformable liposomes represent useful formulations able to increase the skin permeation of drug compounds. In this study, resveratrol- and 5-fluorouracil-loaded ultradeformable liposomes were investigated for the potential treatment of non-melanoma skin cancer. The in vitro anticancer activity of ultradeformable liposomes was tested on human skin cancer cells through viability-, cell cycle- and apoptosis-analysis. Furthermore, we tested the percutaneous permeation of ultradeformable liposomes using human stratum corneum and viable epidermis. The co-encapsulation of resveratrol and 5-fluorouracil (multi-drug carrier) in ultradeformable liposomes improved their anticancer activity on skin cancer cells as compared to both the free drug form and the single entrapped agents. These multi-drug ultradeformable liposomes arrest cell proliferation in G1/S, thus modifying the action of 5-fluorouracil and increasing the activity of resveratrol. This effect might depend on the ultradeformable liposomes, which may accumulate in deeper skin layers, thus generating a cutaneous depot from which resveratrol and 5-fluorouracil are gradually released. Resveratrol and 5-fluorouracil co-loaded ultradeformable liposomes could be a new nanomedicine for the treatment of squamous cell carcinoma, i.e., actinic keratosis, Bowen's disease, and keratoacanthoma.

Nanodiamonds are a novel class of nanomaterials which have raised much attention for application in biomedical field, as they combine the possibility of being produced on large scale using relatively inexpensive synthetic processes, of being fluorescent as a consequence of the presence of nitrogen vacancies, of having their surfaces functionalized, and of having good biocompatibility. Among other applications, we mainly focus on drug delivery, including cell interaction, targeting, cancer therapy, gene and protein delivery. In addition, nanodiamonds for bone and dental implants and for antibacterial use is discussed. Techniques for detection and imaging of nanodiamonds in biological tissues are also reviewed, including electron microscopy, fluorescence microscopy, Raman mapping, atomic force microscopy, thermal imaging, magnetic resonance imaging, and positron emission tomography, either in vitro, in vivo, or ex vivo. Toxicological aspects related to the use of nanodiamonds are also discussed. Finally, patents, preclinical and clinical trials based on the use of nanodiamonds for biomedical applications are reviewed.