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Abstract The success of many drugs in ophthalmic treatments is hindered by their physico-chemical properties and the limited precorneal retention time. Here, lyotropic liquid crystals are proposed as a new ophthalmic drug delivery system. Acyclovir was chosen as model drug for its solubility and its controlled release from cubic phase was achieved. We demonstrated the effortless application of lamellar phase on corneal surface and its ability to convert itself in cubic phase in situ. While the complex viscosity of lamellar phase was affected by temperature (5.1 ± 1.4 kPa·s at 25 °C and 0.12 ± 0.001 Pa·s at 35 °C, respectively), the cubic phase shown no changes in viscosity values and shear thinning behaviour at both temperatures and even in presence of the drug The degradation kinetic of drug-loaded cubic phase was slightly slower than the empty formulation, recording 27.92 ± 1.43% and 33.30 ± 3.11% of weight loss after 8 h. Ex vivo studies conducted on porcine eyeballs and isolated cornea confirmed the instantaneous transition to cubic phase, its ability to resist to gravity force, and forced dripping of simulated tear fluid. Histopathological investigation showed how treated cornea did not report changes in epithelial and stroma structures. In summary, lyotropic liquid crystals could represent an advantageous ophthalmic drug delivery system.

As many natural origin antioxidants, resveratrol is characterized by non-suitable physicochemical properties for its topical application. To allow its benefits to manifest on human skin, resveratrol has been entrapped within liquid crystal nanocarriers (LCNs) made up of glyceryl monooleate, a penetration enhancer, and DSPE-PEG 750. The nanosystems have been more deeply characterized by using dynamic light scattering and Turbiscan Lab® Expert optical analyzer, and they have been tested in vitro on NCTC 2544. The improved antioxidant activity of entrapped resveratrol was evaluated on keratinocyte cells as a function of its concentration. Finally, to really propose the resveratrol-loaded LCNs for topical use, the systems were gelled by using two different gelling agents, poloxamer P407 and carboxymethyl cellulose, to improve the contact time between skin and formulation. The rheological features of obtained gels were evaluated using two important methods (microrheology at rest and dynamic rheology), before testing their safety profile on human healthy volunteers. The obtained results showed the ability of LCNs to improve antioxidant activity of RSV and the gelled LCNs showed good rheological profiles. In conclusion, the results confirmed the potentiality of gelled resveratrol-loaded nanosystems for skin disease, mainly related to their antioxidant effects.

A biodegradable and biocompatible polymeric matrix made up of poly(d,l-lactide-co-glycolide) (PLGA) was used for the simultaneous delivery of rutin and the (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide derivative (URB894). The goal was to exploit the well-known radical scavenging properties of rutin and the antioxidant features recently reported for the molecules belonging to the class of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors, such as URB894. The use of the compounds, both as single agents or in association promoted the development of negatively-charged nanosystems characterized by a narrow size distribution and an average diameter of ~200 nm when 0.2–0.6 mg/mL of rutin or URB894 were used. The obtained multidrug carriers evidenced an entrapment efficiency of ~50% and 40% when 0.4 and 0.6 mg/mL of rutin and URB894 were associated during the sample preparation, respectively. The multidrug formulation evidenced an improved in vitro dose-dependent protective effect against H2O2-related oxidative stress with respect to that of the nanosystems containing the active compounds as a single agent, confirming the rationale of using the co-encapsulation approach to obtain a novel antioxidant nanomedicine.

Doxorubicin hydrochloride (DOX) is a well-known antitumor drug used as first line treatment for many types of malignancies. Despite its clinical relevance, the administration of the compound is negatively affected by dose-dependent off-target toxicity phenomena. Nanotechnology has helped to overcome these important limitations by improving the therapeutic index of the bioactive and promoting the translation of novel nanomedicines into clinical practice. Herein, nanoparticles made up of wheat gliadin and stabilized by polyoxyethylene (2) oleyl ether were investigated for the first time as carriers of DOX. The encapsulation of the compound did not significantly affect the physico-chemical features of the gliadin nanoparticles (GNPs), which evidenced a mean diameter of ~180 nm, a polydispersity index < 0.2 and a negative surface charge. The nanosystems demonstrated great stability regarding temperature (25–50 °C) and were able to retain high amounts of drug, allowing its prolonged and sustained release for up to a week. In vitro viability assay performed against breast cancer cells demonstrated that the nanoencapsulation of DOX modulated the cytotoxicity of the bioactive as a function of the incubation time with respect to the free form of the drug. The results demonstrate the potential use of GNPs as carriers of hydrophilic antitumor compounds.

The manuscript describes the development of zein nanoparticles containing paclitaxel (PTX) and the bromo-and extra-terminal domain inhibitor (S)-tertbutyl2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepin-6-yl)acetate (JQ1) together with their cytotoxicity on triple-negative breast cancer cells. The rationale of this association is that of exploiting different types of cancer cells as targets in order to obtain increased pharmacological activity with respect to that exerted by the single agents. Zein, a protein found in the endosperm of corn, was used as a biomaterial to obtain multidrug carriers characterized by mean sizes of ˂200 nm, a low polydispersity index (0.1–0.2) and a negative surface charge. An entrapment efficiency of ~35% of both the drugs was obtained when 0.3 mg/mL of the active compounds were used during the nanoprecipitation procedure. No adverse phenomena such as sedimentation, macro-aggregation or flocculation occurred when the nanosystems were heated to 37 °C. The multidrug nanoformulation demonstrated significant in vitro cytototoxic activity against MDA-MB-157 and MDA-MB-231 cancer cells by MTT-test and adhesion assay which was stronger than that of the compounds encapsulated as single agents. The results evidence the potential application of zein nanoparticles containing PTX and JQ1 as a novel nanomedicine.

Hydrogels have been extensively investigated to identify innovative formulations that can fulfill all the necessary purposes to improve local vaginal therapy through the mucosa. Herein, we propose in situ-forming lyotropic liquid crystals (LLCs) derived from a cheap and GRAS (generally recognized as safe) ingredient as an intravaginal delivery system. The system consists of a precursor solution loaded with sertaconazole nitrate as a model drug, which is able to easily swell in a stable three-dimensional structure by absorbing simulated vaginal fluid. Under polarized light microscopy the precursor solution and the formed phase of LLCs showed the typical textures belonging to anisotropic and an isotropic mesophases, respectively. A deep rheological investigation by Kinexus® Pro proved the stability and strength of the cubic phase, as well as its potential in mucoadhesion. In vitro degradation studies showed a slow matrix erosion, consistent with data obtained from lipophilic drug release studies in simulated vaginal fluid. Therefore, the suggested cubic phase based on lyotropic liquid crystals could represent a valid proposal as a vaginal drug delivery system due to its characteristics of resistance, adhesion and the possibility of providing a slow and controlled release of drugs directly at the administration site.

Background: Cancer is a common disease in dogs, with a growing incidence related to the age of the animal. Nanotechnology is being employed in the veterinary field in the same manner as in human therapy. Aim: This review focuses on the application of biocompatible nanocarriers for the treatment of canine cancer, paying attention to the experimental studies performed on dogs with spontaneously occurring cancer. Methods: The most important experimental investigations based on the use of lipid and non-lipid nanosystems proposed for the treatment of canine cancer, such as liposomes and polymeric nanoparticles containing doxorubicin, paclitaxel and cisplatin, are described and their in vivo fate and antitumor features discussed. Conclusions: Dogs affected by spontaneous cancers are useful models for evaluating the efficacy of drug delivery systems containing antitumor compounds.

For many years, corneal transplantation has been the first-choice treatment for irreversible damage affecting the anterior part of the eye. However, the low number of cornea donors and cases of graft rejection highlighted the need to replace donor corneas with new biomaterials. Tissue engineering plays a fundamental role in achieving this goal through challenging research into a construct that must reflect all the properties of the cornea that are essential to ensure correct vision. In this review, the anatomy and physiology of the cornea are described to point out the main roles of the corneal layers to be compensated and all the requirements expected from the material to be manufactured. Then, a deep investigation of alginate as a suitable alternative to donor tissue was conducted. Thanks to its adaptability, transparency and low immunogenicity, alginate has emerged as a promising candidate for the realization of bioengineered materials for corneal regeneration. Chemical modifications and the blending of alginate with other functional compounds allow the control of its mechanical, degradation and cell-proliferation features, enabling it to go beyond its limits, improving its functionality in the field of corneal tissue engineering and regenerative medicine.

Advances in nanotechnology have favored the development of novel colloidal formulations able to modulate the pharmacological and biopharmaceutical properties of drugs. The peculiar physico-chemical and technological properties of nanomaterial-based therapeutics have allowed for several successful applications in the treatment of cancer. The size, shape, charge and patterning of nanoscale therapeutic molecules are parameters that need to be investigated and modulated in order to promote and optimize cell and tissue interaction. In this review, the use of polymeric nanoparticles as drug delivery systems of anticancer compounds, their physico-chemical properties and their ability to be efficiently localized in specific tumor tissues have been described. The nanoencapsulation of antitumor active compounds in polymeric systems is a promising approach to improve the efficacy of various tumor treatments.

The natural healing capacity of the tendon tissue is limited due to the hypovascular and cellular nature of this tissue. So far, several conventional approaches have been tested for tendon repair to accelerate the healing process, but all these approaches have their own advantages and limitations. Regenerative medicine and tissue engineering are interdisciplinary fields that aspire to develop novel medical devices, innovative bioscaffold, and nanomedicine, by combining different cell sources, biodegradable materials, immune modulators, and nanoparticles for tendon tissue repair. Different studies supported the idea that bioscaffolds can provide an alternative for tendon augmentation with an enormous therapeutic potentiality. However, available data are lacking to allow definitive conclusion on the use of bioscaffolds for tendon regeneration and repairing. In this review, we provide an overview of the current basic understanding and material science in the field of bioscaffolds, nanomedicine, and tissue engineering for tendon repair.

The incidence of cancer is increasing dramatically, affecting all ages of the population and reaching an ever higher worldwide mortality rate. The lack of therapies’ efficacy is due to several factors such as a delay in diagnosis, tumor regrowth after surgical resection and the occurrence of multidrug resistance (MDR). Tumor-associated immune cells and the tumor microenvironment (TME) deeply affect the tumor’s progression, leading to several physicochemical changes compared to physiological conditions. In this scenario, macrophages play a crucial role, participating both in tumor suppression or progression based on the polarization of onco-suppressive M1 or pro-oncogenic M2 phenotypes. Moreover, much evidence supports the pivotal role of macrophage-derived extracellular vesicles (EVs) as mediators in TME, because of their ability to shuttle the cell–cell and organ–cell communications, by delivering nucleic acids and proteins. EVs are lipid-based nanosystems with a broad size range distribution, which reflect a similar composition of native parent cells, thus providing a natural selectivity towards target sites. In this review, we discuss the impact of macrophage-derived EVs in the cancer’s fate as well as their potential implications for the development of personalized anticancer nanomedicine.

Bergamot essential oil (BEO) and Ammonium glycyrrhizinate (AG), naturally derived compounds, have remarkable anti-inflammatory properties, thus making them suitable candidates for the treatment of skin disorders. Despite this, their inadequate physicochemical properties strongly compromise their topical application. Ultradeformable nanocarriers containing both BEO and AG were used to allow their passage through the skin, thus maximizing their therapeutic activity. Physicochemical characterization studies were performed using Zetasizer Nano ZS and Turbiscan Lab®. The dialysis method was used to investigate the release profile of the active compounds. In vivo studies were performed on human healthy volunteers through the X-Rite spectrophotometer. The nanosystems showed suitable features for topical cutaneous administration in terms of mean size, surface charge, size distribution, and long-term stability/storability. The co-delivery of BEO and AG in the deformable systems improved both the release profile kinetic of ammonium glycyrrhizinate and deformability properties of the resulting nanosystems. The topical cutaneous administration on human volunteers confirmed the efficacy of the nanosystems. In detail, BEO and AG-co-loaded ultradeformable vesicles showed a superior activity compared to that recorded from the ones containing AG as a single agent. These results are promising and strongly encourage a potential topical application of AG/BEO co-loaded nanocarriers for anti-inflammatory therapies.

N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that preferentially catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide, which has been shown to exhibit neuroprotective and antinociceptive properties by engaging peroxisome proliferator-activated receptor-α. A few potent NAAA inhibitors have been developed, including α-acylamino-β-lactone derivatives, which are very strong and effective, but they have limited chemical and plasmatic stability, compromising their use as systemic agents. In the present study, as an example of a molecule belonging to the chemical class of N-(2-oxo-3-oxetanyl)amide NAAA inhibitors, URB866 was entrapped in poly(lactic-co-glycolic acid) nanoparticles in order to increase its physical stability. The data show a monomodal pattern and a significant time- and temperature-dependent stability of the molecule-loaded nanoparticles, which also demonstrated a greater ability to effectively retain the compound. The nanoparticles improved the photostability of URB866 with respect to that of the free molecule and displayed a better antioxidant profile on various cell lines at the molecule concentration of 25 μM. Overall, these results prove that the use of polymeric nanoparticles could be a useful strategy for overcoming the instability of α-acylamino-β-lactone NAAA inhibitors, allowing the maintenance of their characteristics and activity for a longer time.

The regeneration of cardiac tissue is a multidisciplinary research field aiming to improve the health condition of the post-heart attack patient. Indeed, myocardial tissue has a poor ability to self-regenerate after severe damage. The scientific efforts focused on the research of a biomaterial able to adapt to heart tissue, thus guaranteeing the in situ release of active substances or growth promoters. Many types of hydrogels were proposed for this purpose, showing several limitations. The aim of this study was to suggest a new usage for glyceryl monooleate-based lyotropic liquid crystals (LLCs) as a biocompatible and inert material for a myocardial application. The main advantages of LLCs are mainly related to their easy in situ injection as lamellar phase and their instant in situ transition in the cubic phase. In vivo studies proved the biocompatibility and the inertia of LLCs after their application on the myocardial tissue of mice. In detail, the cardiac activity was monitored through 28 days, and no significant alterations were recorded in the heart anatomy and functionality. Moreover, gross anatomy showed the ability of LLCs to be bio-degraded in a suitable time frame. Overall, these results permitted us to suppose a potential use of LLCs as materials for cardiac drug delivery.

The evaluation of the physico-chemical features of nanocarriers is fundamental because the modulation of these parameters can influence their biological and in vivo fate. This work investigated the feasibility of saline, 5% w/v glucose and phosphate-buffered saline solution, as polar media for the development of nanoparticles made up of two vegetal proteins, zein from corn and gliadin from wheat, respectively. The physico-chemical features of the various systems were evaluated using dynamic and multiple light scattering techniques, and the results demonstrate that the 5% w/v glucose solution is a feasible medium to be used for their development. Moreover, the best formulations were characterized by the aforementioned techniques following the freeze-drying procedure. The aggregation of the zein nanoparticles prepared in water or glucose solution was prevented by using various cryoprotectants. Mannose confirmed its crucial role in the cryopreservation of the gliadin nanosystems prepared in both water and glucose solution. Sucrose and glucose emerged as additional useful excipients when they were added to gliadin nanoparticles prepared in a 5% glucose solution. Specifically, their protective effect was in the following order: mannose > sucrose > glucose. The results obtained when using specific aqueous media and cryoprotectants permitted us to develop stable zein or gliadin nanoparticles as suspension or freeze-dried formulations.

Ethosomes® are one of the main deformable vesicles proposed to overcome the stratum corneum. They are composed of lecithin, ethanol and water, resulting in round vesicles characterized by a narrow size distribution and a negative surface charge. Taking into account their efficiency to deliver drugs into deeper skin layers, the current study was designed to evaluate the influence of different lipids on the physico-chemical features of traditional ethosomes in the attempt to influence their fate. Three lipids (DOPE, DSPE and DOTAP) were used for the study, but only DOTAP conferred a net positive charge to ethosomes, maintaining a narrow mean size lower than 300 nm and a good polydispersity index. Stability and in vitro cytotoxic studies have been performed using Turbiscan Lab analysis and MTT dye exclusion assay, respectively. Data recorded demonstrated the good stability of modified ethosomes and a reasonable absence of cell mortality when applied to human keratinocytes, NCTC 2544, which are used as a cell model. Finally, the best formulations were selected to evaluate their ability to encapsulate drugs, through the use of model compounds. Cationic ethosomes encapsulated oil red o and rhodamine b in amounts comparable to those recorded from conventional ethosomes (over 50%). Results recorded from this study are encouraging as cationic ethosomes may open new opportunities for skin delivery.

Paclitaxel (PTX) is one of the most successful antineoplastic drugs and is widely used for the treatment of many forms of advanced and refractory cancer. Unfortunately, various drawbacks including non-selective cytotoxicity, poor water solubility and low bioavailability limit its clinical use. The aim of this study was to characterize a novel colloidal system made up of the natural protein zein, that would be able to efficiently retain the anticancer compound and increase its in vitro pharmacological effects. In fact, zein has promising characteristics that render it a potential material to be used in drug delivery application. The influences of temperature, pH and serum incubation on the stability of these particles, entrapment efficiency of PTX and in vitro toxicity on different cancer cell lines were evaluated. The nanosystems containing PTX demonstrated suitable storage stability, and were not destabilized by temperatures of up to 50 °C, pH alterations, the freeze-drying process or serum proteins. The encapsulation of PTX did not destabilize the structure of the zein nanoparticles and a suitable drug entrapment efficiency resulted. PTX-loaded zein nanoparticles showed an increased toxicity on different cancer cell lines with respect to the free drug, confirming its potential application in preclinical and clinical investigations.

Ethosomes® have been proposed as potential intra-articular drug delivery devices, in order to obtain a longer residence time of the delivered drug in the knee joint. To this aim, the conventional composition and preparation method were modified. Ethosomes® were prepared by using a low ethanol concentration and carrying out a vesicle extrusion during the preparation. The modified composition did not affect the deformability of ethosomes®, a typical feature of this colloidal vesicular topical carrier. The maintenance of sufficient deformability bodes well for an effective ethosome® application in the treatment of joint pathologies because they should be able to go beyond the pores of the dense collagen II network. The investigated ethosomes® were inserted in a three-dimensional network of thermo-sensitive poloxamer gel (EtoGel) to improve the residence time in the joint. Rheological experiments evidenced that EtoGel could allow an easy intra-articular injection at room temperature and hence transform itself in gel form at body temperature into the joint. Furthermore, EtoGel seemed to be able to support the knee joint during walking and running. In vitro studies demonstrated that the amount of used ethanol did not affect the viability of human chondrocytes and nanocarriers were also able to suitably interact with cells.

Linoleic and oleic acids are natural unsaturated fatty acids involved in several biological processes and recently studied as structural components of innovative nanovesicles. The use of natural components in the pharmaceutical field is receiving growing attention from the scientific world. The aim of this research work is to design, to perform physico-chemical characterization and in vitro/in vivo studies of unsaturated fatty acids vesicles containing ammonium glycyrrhizinate, obtaining a new topical drug delivery system. The chosen active substance is well known as an anti-inflammatory compound, but its antioxidant activity is also noteworthy. In this way, the obtained nanocarriers are totally natural vesicles and they have shown to have suitable physico-chemical features for topical administration. Moreover, the proposed nanocarriers have proven their ability to improve the in vitro percutaneous permeation and antioxidant activity of ammonium glycyrrhizinate on human keratinocytes (NCTC 2544 cells). In vivo studies, carried out on human volunteers, have demonstrated the biocompatibility of unsaturated fatty acid vesicles toward skin tissue, indicating a possible clinical application of unsaturated fatty acid vesicles for the treatment of topical diseases.

Periodontal diseases are multifactorial disorders, mainly due to severe infections and inflammation which affect the tissues (i.e., gum and dental bone) that support and surround the teeth. These pathologies are characterized by bleeding gums, pain, bad breath and, in more severe forms, can lead to the detachment of gum from teeth, causing their loss. To date it is estimated that severe periodontal diseases affect around 10% of the population worldwide thus making necessary the development of effective treatments able to both reduce the infections and inflammation in injured sites and improve the regeneration of damaged tissues. In this scenario, the use of 3D scaffolds can play a pivotal role by providing an effective platform for drugs, nanosystems, growth factors, stem cells, etc., improving the effectiveness of therapies and reducing their systemic side effects. The aim of this review is to describe the recent progress in periodontal regeneration, highlighting the influence of materials’ properties used to realize three-dimensional (3D)-scaffolds, their bio-physical characteristics and their ability to provide a biocompatible platform able to embed nanosystems.

In the last few decades, the combination between nanotechnology and nutraceutics has gained the attention of several research groups. Nutraceuticals are considered as active compounds, abundant in natural products, showing beneficial effects on human health. Unfortunately, the uses, and consequently the health benefits, of many nutraceutical products are limited by their unsuitable chemico-physical features. For example, many nutraceuticals are characterized by low water solubility, low stability and high susceptibility to light and oxygen, poor absorption and potential chemical modifications after their administration. Based on the potential efficacy of nutraceuticals and on their limiting features, nanotechnology could be considered a revolutionary innovation in empowering the beneficial properties of nutraceuticals on human health, thus enhancing their efficacy in several diseases. For this reason, nanotechnology could represent a new frontier in supplementary food. In this review, the most recent nanotechnological approaches are discussed, focusing on their ability to improve the bioavailability of the most common nutraceuticals, providing an overview regarding both the advantages and the possible limitations of the use of several nanodelivery systems. In fact, although the efficacy of smart nanocarriers in improving health benefits deriving from nutraceuticals has been widely demonstrated, the conflicting opinions on the mechanism of action of some nanosystems still reduce their applicability in the therapeutic field.

The discovery of paclitaxel (PTX) has been a milestone in anti-cancer therapy and has promoted the development and marketing of various formulations that have revolutionized the therapeutic approach towards several malignancies. Despite its peculiar anti-cancer activity, the physico-chemical properties of PTX compromise the administration of the compound in polar media. Because of this, since the development of the first Food and Drug Administration (FDA)-approved formulation (Taxol®), consistent efforts have been made to obtain suitable delivery systems able to preserve/increase PTX efficacy and to overcome the side effects correlated to the presence of some excipients. The exploitation of natural polymers as potential materials for drug delivery purposes has favored the modulation of the bioavailability and the pharmacokinetic profiles of the drug, and in this regard, several formulations have been developed that allow the controlled release of the active compound. In this mini-review, the recent advances concerning the design and applications of natural polymer-based hydrogels containing PTX-loaded biocompatible nanocarriers are discussed. The technological features of these formulations as well as the therapeutic outcome achieved following their administration will be described, demonstrating their potential role as innovative systems to be used in anti-tumor therapy.

Ferulic acid is a derivative of cinnamic acid showing efficacious anti-oxidant activity. It catalyzes the stable phenoxy radical formation, upon absorption of ultraviolet light, giving the strength to ferulic acid for terminating free radical chain reactions. Ultraviolet rays are one of the most dangerous factors that daily assault the skin, causing excessive generation of reactive oxygen species (ROS), which are regarded to be important contributors to a variety of cutaneous alterations. The skin possesses endogenous antioxidant defense systems, but the excess of ROS leads to an oxidant–antioxidant imbalance. Although ferulic acid is daily introduced in human organism with the diet, its bioavailability after oral administration is poor, particularly in the skin. The aim of this investigation was to evaluate three types of emulsions (W/O/W multiple emulsions and two simple emulsions) as suitable formulations for topical application of the active compound. In vitro studies were performed to investigate the stability and release profiles of these systems. Multiple emulsions showed great stability and the best ability to carry and release ferulic acid. In vivo evaluations highlighted their best capability to treat UV-B-induced erythema. These findings suggested multiple emulsions as an innovative and more efficient vehicle for topical application of ferulic acid.

Ufasomes are unsaturated fatty acid liposomes made up of oleic and linoleic acids, natural components required in various biological processes. This kind of nanocarrier is characterized by a simple and dynamic structure and is able to improve the bioavailability of unsaturated fatty acids. The aim of this investigation was to evaluate ufasomes as natural compound delivery systems to deliver oleuropein and improve its antioxidant activity. Oleuropein is a phenolic compound mainly present in olives and olive oil, with several biological properties, such as the antioxidant activity. However, to improve their biological activity, antioxidant compounds should be able to cross cell membranes and uniformly incorporate in cells. Because of the great similarity between their constituents and cell membranes, ufasomes could be advantageous carriers for oleuropein delivery. The physico-chemical characteristics of ufasomes were investigated. A regular shape was shown by transmission electron microscopy studies, while the mean sizes were dependent on the ufasomes composition. In vitro studies highlighted that empty ufasomes did not lead to cell mortality at the tested concentrations and a good carrier internalization in CaCo-2 cells, further studies in vitro studies demonstrated that oleuropein-loaded ufasomes were able to enhance the antioxidant activity of the free active substance making this carrier a suitable one for nutraceutical application.

The topical administration of active compounds represents an advantageous strategy to reach the various skin components as well as its appendages. Pilosebaceous follicles are skin appendages originating in the deeper skin layers. They are very difficult to target, and hence higher active dosages are generally required to achieve effective biological responses, thus favoring the rise of side effects. The aim of this work was to design a supramolecular colloidal carrier, i.e., a liquid crystal nanocarrier, for the selective delivery of active compounds into the pilosebaceous follicle. This nanocarrier showed mean sizes of ~80 nm, a good stability, a negative surface charge, and great safety properties. In vitro studies highlighted its ability to contain and release different substances and to successfully permeate the skin. Minoxidil was encapsulated in the nanocarriers and the in vivo biological effect was compared with a conventional dosage form. Minoxidil-loaded liquid crystal nanocarrier was able to selectively reach the pilosebaceous follicle, thus allowing an increased biological effectiveness of the delivered active in terms of biological response, duration of the biological effects, and reduction of collaterals. Our investigation showed that liquid crystal nanocarriers represent a promising device for the treatment of different pilosebaceous follicular impairments/diseases.

The controlled release of a compound entrapped in a biocompatible formulation is a sought-after goal in modern pharmaceutical technology. Zein is a hydrophobic protein which has several advantageous properties that make it suitable for use as a biocompatible and degradable material under physiological conditions. It is, therefore, proposed for different biomedical and pharmaceutical applications. In particular, due to its gelling properties, it can be used to form a polymeric network able to preserve biomolecules from harsh environments. The current study was designed to investigate the influence of different probes on the rheological properties of gels made up of zein, in order to characterize the systems as a function of the polymer concentration. Four model compounds characterized by different physico-chemical properties were entrapped in zein gels, and different behaviors (viscoelastic or pronounced solid-like characteristics) of the systems were observed. Zein-based gels showed various release profiles of the encapsulated compounds, suggesting that there are different interaction rates between the probes and the polymeric matrix.

Mesoporous silicon microparticles (MSMPs) can incorporate drug-carrying nanoparticles (NPs) into their pores. An NP-loaded MSMP is a multistage vector (MSV) that forms a Matryoshka-like structure that protects the therapeutic cargo from degradation and prevents its dilution in the circulation during delivery to tumor cells. We developed an MSV constituted by 1 µm discoidal MSMPs embedded with PEGylated liposomes containing oxaliplatin (oxa) which is a therapeutic agent for colorectal cancer (CRC). To obtain extra-small liposomes able to fit the 60 nm pores of MSMP, we tested several liposomal formulations, and identified two optimal compositions, with a prevalence of the rigid lipid 1,2-distearoyl-sn-glycero-3-phosphocholine and of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. To improve the MSV assembly, we optimized the liposome-loading inside the MSMP and achieved a five-fold increase of the payload using an innovative lyophilization approach. This procedure also increased the load and limited dimensional changes of the liposomes released from the MSV in vitro. Lastly, we found that the cytotoxic efficacy of oxa-loaded liposomes and-oxa-liposome-MSV in CRC cell culture was similar to that of free oxa. This study increases knowledge about extra-small liposomes and their loading into porous materials and provides useful hints about alternative strategies for designing drug-encapsulating NPs.

Rutin is a flavone glycoside contained in many plants, and exhibits antioxidant, anti-inflammatory, anticancer, and wound-healing properties. The main disadvantage related to the use of this molecule for pharmaceutical application is its poor bioavailability, due to its low solubility in aqueous media. Poloxamer 407-hydrogels show interesting thermo-sensitive properties that make them attractive candidates as pharmaceutical formulations. The hydrophobic domains in the chemical structure of the copolymer, a polymer made up of two or more monomer species, are useful for retaining poorly water-soluble compounds. In this investigation various poloxamer 407-based hydrogels containing rutin were developed and characterized as a function of the drug concentration. In detail, the Turbiscan stability index, the micro- and dynamic rheological profiles and in vitro drug release were investigated and discussed. Rutin (either as a free powder or solubilized in ethanol) did not modify the stability or the rheological properties of these poloxamer 407-based hydrogels. The drug leakage was constant and prolonged for up to 72 h. The formulations described are expected to represent suitable systems for the in situ application of the bioactive as a consequence of their peculiar versatility.

Poloxamer 407 copolymer is a versatile and widely used thermo-reversible material. Its use has many advantages, such as bio-adhesion, enhanced solubilization of poorly water-soluble drugs and many applications fields like oral, rectal, topical, nasal drug administration. Hydrogels made up of Poloxamer 407 are characterized by specific rheological features, which are affected by temperature, concentration and presence of other compounds. A strategic approach in topical therapeutic treatments may be the inclusion of drug delivery systems, such as ethosomes, transfersomes and niosomes, into hydrogel poloxamer formulation. The evaluation of the interaction between colloidal carriers and the Poloxamer 407 hydrogel network is essential for a suitable design of an innovative topical dosage form. For this reason, the Rheolaser Master™, based on diffusing wave spectroscopy, and a Kinexus Rotational Rheometer were used to evaluate the influence of nanocarriers on the microrheological features of hydrogels. The advantages of the Rheolaser Master™ analyzer are: (i) its ability to determine viscoelastic parameter, without altering or destroying the sample and at rest (zero shear); (ii) possibility of aging analysis on the same sample. This study provide evidence that vesicular systems do not influence the rheological features of the gel, supporting the possibility to encapsulate an innovative system into a three-dimensional network.

The introduction of nanotechnology into pharmaceutical application revolutionized the administration of antitumor drugs through the modulation of their accumulation in specific organs/body compartments, a decrease in their side-effects and their controlled release from innovative systems. The use of plant-derived proteins as innovative, safe and renewable raw materials to be used for the development of polymeric nanoparticles unlocked a new scenario in the drug delivery field. In particular, the reduced size of the colloidal systems combined with the peculiar properties of non-immunogenic polymers favored the characterization and evaluation of the pharmacological activity of the novel nanoformulations. The aim of this review is to describe the physico-chemical properties of nanoparticles composed of vegetal proteins used to retain and deliver anticancer drugs, together with the most important preparation methods and the pharmacological features of these potential nanomedicines.

Polyethylene glycol (PEG)-phospholipids in long-circulating liposomes cause non-specific immune reactions; mainly attributable to negatively-charged phosphoryl s at the interface of PEG and phospholipid. We investigated a novel lipopolymer, by which a superhydrophilic polymer (SHP) is conjugated to a non-phospholipid N1-(2-aminoethyl)-N4-hexadecyl-2-tetradecylsuccinamide (HDAS). The modification of preformed liposomes HDAS-SHP, HDAS-PEG2000, and DSPE-PEG2000 were performed by post-insertion techniques. The efficiency of post-insertion and desorption rates, from the liposome surface, were determined. HDAS-SHP micelles showed highly positive zeta potential (+28.4 mV); zeta potentials of DSPE-PEG2000 and HDAS-PEG2000 micelles were −34.4 mV, and −3.7 mV, respectively. Critical micelle concentration predicted amphiphilicity of HDAS-SHP (CMC 2.58 µM) as close to that of DSPE-PEG2000 (CMC 2.44 µM). Both HDAS-SHP and HDAS-PEG2000 post-inserted with comparable efficiency (79%, and 73%, respectively), but noticeably lower than DSPE-PEG2000 (90%). The desorption rate of HDAS-SHP was close to that of DSPE-PEG2000 (0.53%/h, and 0.45%/h, respectively); the desorption rate for HDAS-PEG2000 was slightly more at 0.67%/h. Compared to plain liposomes, both HDAS-SHP- and DSPE-PEG2000-liposomes showed significant leakage of encapsulated Na-fluorescein isothiocyanate (FITC) upon incubation with serum. At the same time, both modified liposomes were found to suppress serum levels of the complement proteins, Bb and C4d. We infer that HDAS-SHP is a viable alternative to commonly-used PEG-phospholipid derivatives for stealth purposes.

Embedding of active substances in supramolecular systems has as the main goal to ensure the controlled release of the active ingredients. Whatever the final architecture or entrapment mechanism, modeling of release is challenging due to the moving boundary conditions and complex initial conditions. Despite huge diversity of formulations, diffusion phenomena are involved in practically all release processes. The approach in this paper starts, therefore, from mathematical methods for solving the diffusion equation in initial and boundary conditions, which are further connected with phenomenological conditions, simplified and idealized in order to lead to problems which can be analytically solved. Consequently, the release models are classified starting from the geometry of diffusion domain, initial conditions, and conditions on frontiers. Taking into account that practically all solutions of the models use the separation of variables method and integral transformation method, two specific applications of these methods are included. This paper suggests that “good modeling practice„ of release kinetics consists essentially of identifying the most appropriate mathematical conditions corresponding to implied physicochemical phenomena. However, in most of the cases, models can be written but analytical solutions for these models cannot be obtained. Consequently, empiric models remain the first choice, and they receive an important place in the review.

Hydrogels are three-dimensional networks of hydrophilic polymers able to absorb and retain a considerable amount of water or biological fluid while maintaining their structure. Among these, thermo-sensitive hydrogels, characterized by a temperature-dependent sol–gel transition, have been massively used as drug delivery systems for the controlled release of various bioactives. Poloxamer 407 (P407) is an ABA-type triblock copolymer with a center block of hydrophobic polypropylene oxide (PPO) between two hydrophilic polyethyleneoxide (PEO) lateral chains. Due to its unique thermo-reversible gelation properties, P407 has been widely investigated as a temperature-responsive material. The gelation phenomenon of P407 aqueous solutions is reversible and characterized by a sol–gel transition temperature. The nanoencapsulation of drugs within biocompatible delivery systems dispersed in P407 hydrogels is a strategy used to increase the local residence time of various bioactives at the injection site. In this mini-review, the state of the art of the most important mixed systems made up of colloidal carriers localized within a P407 hydrogel will be provided in order to illustrate the possibility of obtaining a controlled release of the entrapped drugs and an increase in their therapeutic efficacy as a function of the biomaterial used.

Poloxamer 407, also known by the trademark Pluronic® F127, is a water-soluble, non-ionic triblock copolymer that is made up of a hydrophobic residue of polyoxypropylene (POP) between the two hydrophilic units of polyoxyethylene (POE). Poloxamer 407-based hydrogels exhibit an interesting reversible thermal characteristic. That is, they are liquid at room temperature, but they assume a gel form when administered at body temperature, which makes them attractive candidates as pharmaceutical drug carriers. These systems have been widely investigated in the development of mucoadhesive formulations because they do not irritate the mucosal membranes. Based on these mucoadhesive properties, a simple administration into a specific compartment should maintain the required drug concentration in situ for a prolonged period of time, decreasing the necessary dosages and side effects. Their main limitations are their modest mechanical strength and, notwithstanding their bioadhesive properties, their tendency to succumb to rapid elimination in physiological media. Various technological approaches have been investigated in the attempt to modulate these properties. This review focuses on the application of poloxamer 407-based hydrogels for mucosal drug delivery with particular attention being paid to the latest published works.

Abstract  A novel niosome formulation is proposed for topical drug delivery of ammonium glycyrrhizinate, a natural compound with an efficacious anti-inflammatory activity. Niosomes were made up of a new non ionic surfactant, α,ω-hexadecyl-bis-(1-aza-18-crown-6) (Bola-surfactant)-Span 80-cholesterol (2:3:1 molar ratio). Niosome vesicles were prepared with the thin layer evaporation method and were physico-chemically characterized. The tolerability of Bola-surfactant both as free molecules or assembled ion niosome vesicles was evaluated in vitro on cultured of human keratinocyte cells (NCTC2544). Human tolerability was evaluated on volunteers. The ability of Bola-niosomes to promote intracellular delivery was evaluated by confocal laser scanning microscopy (CLSM) studies. Human stratum corneum and epidermis (SCE) membranes were used in vitro to investigate the percutaneous permeation. The anti-inflammatory activity of ammonium glycyrrhizinate was evaluated in vivo on human volunteers with a chemically induced erythema. Experimental data show that Bola-niosomes are characterized by a mean size of ∼400 nm and are able to provide an encapsulation efficiency of 40% with respect to the drug amount used during preparation. CLSM showed that Bola-niosomes were able to promote the intracellular uptake of the delivered substances. Bola-niosomes were also able to significantly improve (p in vitro and in vivo. Ammonium glycyrrhizinate-loaded Bola-niosomes determined a significant (p in vivo anti-inflammatory activity of the drug. An effective example of conjugating innovative colloidal carriers, coming from pharmaceutical nanotechnology, and therapeutically effective natural compounds, coming from traditional medicine, was reported. [ABSTRACT FROM AUTHOR]