Rhamnolipids: A biosurfactant for the development of lipid-based nanosystems for food applications.

Biosurfactants (surfactants synthesized by microorganisms) are produced by microorganisms and are suitable for use in different areas. Among biosurfactants, rhamnolipids are the most studied and popular, attracting scientists, and industries' interest. Due to their unique characteristics, the rhamnolipids have been used as synthetic surfactants' alternatives and explored in food applications. Besides the production challenges that need to be tackled to guarantee efficient production and low cost, their properties need to be adjusted to the final application, where the pH instability needs to be considered. Moreover, regulatory approval is needed to start being used in commercial applications. One characteristic of interest is their capacity to form oil-in-water nanosystems. Some of the most explored have been nanoemulsions, solid-lipid nanoparticles and nanostructured lipid carriers. This review presents an overview of the main properties of rhamnolipids, asserts the potential and efficiency of rhamnolipids to replace the synthetic surfactants in the development of nanosystems, and describes the rhamnolipids-based nanosystems used in food applications. It also discusses the main characteristics and methodologies used for their characterization and in the end, some of the main challenges are highlighted.

Synthetic and Nanotechnological Approaches for a Diagnostic Use of Manganese.

The development of multimodal imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) allows the contemporary obtaining of metabolic and morphological information. To fully exploit the complementarity of the two imaging modalities, the design of probes displaying radioactive and magnetic properties at the same time could be very beneficial. In this regard, transition metals offer appealing options, with manganese representing an ideal candidate. As nanosized imaging probes have demonstrated great value for designing advanced diagnostic/theranostic procedures, this work focuses on the potential of liposomal formulations loaded with a new synthesized paramagnetic Mn(II) chelates. Negatively charged liposomes were produced by thin-layer hydration method and extrusion. The obtained formulations were characterized in terms of size, surface charge, efficiency of encapsulation, stability over time, relaxivity, effective magnetic moment, and in vitro antiproliferative effect on human cells by means of the MTT assay. The negatively charged paramagnetic liposomes were monodisperse, with an average hydrodynamic diameter not exceeding 200 nm, and they displayed good stability and no cytotoxicity. As determined by optical emission spectroscopy, manganese complexes are loaded almost completely on liposomes maintaining their paramagnetic properties.

Ellagic Acid Containing Nanostructured Lipid Carriers for Topical Application: A Preliminary Study.

Ellagic acid (EA) is a potent antioxidant substance of natural origin characterized by poor biopharmaceutical properties and low solubility in water that limit its use. The aim of the present study was to develop lipid-based nanoparticle formulations able to encapsulate EA for dermal delivery. The EA-loaded nanoparticles were prepared using two different lipid compositions, namely tristearin/tricaprylin (NLC-EA1) and tristearin/labrasol (NLC-EA2). The influence of formulations on size, entrapment efficiency, and stability of EA-loaded nanoparticles was investigated. Cryo-TEM and small-angle X-ray scattering (SAXS) analyses showed that no morphological differences are evident among all the types of loaded and unloaded nanostructured lipid carriers (NLCs). The macroscopic aspect of both NLC-EA1 and NLC-EA2 did not change with time. No difference in size was appreciable between empty and drug-containing NLC, thus the nanoparticle diameter was not affected by the presence of EA and in general no variations of the diameters occurred during this time. The entrapment efficiency of both EA-loaded nanoparticles was almost quantitative. In addition, NLC-EA1 maintained EA stability for almost two months, while NLC-EA2 up to 40 days. FRAP (Ferric reducing ability of plasma) assay showed an antioxidant activity around 60% for both the loaded NLC, as compared to the solution. Although both types of NLC are characterized by some toxicity on HaCaT cells, NLC-EA1 are less cytotoxic than NLC-EA2. Taken together these results demonstrated that the inclusion of EA within NLC could improve the water solubility, allowing for a reduction of the dosage. Moreover, both types of NLC-EA maintained a high antioxidant effect and low toxicity.

Lipid-based nanosystems for wound healing.

INTRODUCTION: Wounds, resulting from traumas, surgery, burns or diabetes, are important medical problems due to the complexity of wound healing process regarding healing times and healthcare costs. Nanosystems have emerged as promising candidates in this field thank to their properties and versatile applications in drugs delivery. AREAS COVERED: Lipid-based nanosystems (LBN) are described for wound treatment, highlighting their different behaviors when interacting with the cutaneous tissue. The role of nanosystems in delivering mostly natural compounds on skin as well as the technological and engineering strategies to increase their efficiency in wound healing effect are reviewed. Finally, in vitro, ex-vivo and in vivo studies are reported. EXPERT OPINION: LBN have shown promise in addressing the challenges of wound healing as they can improve the stability of drugs used in wound therapy, leading to higher efficacy and fewer adverse effects as compared to traditional formulations. LBNs being involved in the inflammatory and proliferation stages of the wound healing process, enable the modification of wound healing through multiple ways. In addition, the use of new technologies, including 3D bioprinting and photobiomodulation, may lead to potential breakthroughs in wound healing. This would provide clinicians with more potent forms of therapy for wound healing.

Fighting Epilepsy with Nanomedicines-Is This the Right Weapon?

Epilepsy is a chronic and complex condition and is one of the most common neurological diseases, affecting about 50 million people worldwide. Pharmacological therapy has been, and is likely to remain, the main treatment approach for this disease. Although a large number of new antiseizure drugs (ASDs) has been introduced into the market in the last few years, many patients suffer from uncontrolled seizures, demanding the development of more effective therapies. Nanomedicines have emerged as a promising approach to deliver drugs to the brain, potentiating their therapeutic index. Moreover, nanomedicine has applied the knowledge of nanoscience, not only in disease treatment but also in prevention and diagnosis. In the current review, the general features and therapeutic management of epilepsy will be addressed, as well as the main barriers to overcome to obtain better antiseizure therapies. Furthermore, the role of nanomedicines as a valuable tool to selectively deliver drugs will be discussed, considering the ability of nanocarriers to deal with the less favourable physical-chemical properties of some ASDs, enhance their brain penetration, reduce the adverse effects, and circumvent the concerning drug resistance.

Intranasal delivery of lipid-based nanosystems as a promising approach for brain targeting of the new-generation antiepileptic drug perampanel.

Perampanel (PER), a new-generation antiepileptic drug effective against different types of seizures, has already demonstrated a potential in status epilepticus therapy. Considering the growing interest of intranasal (IN) administration for nose-to-brain delivery, PER could be envisioned as a good candidate for this route, especially if formulated in a lipid-based nanosystem. With that purpose, a hydrophobic formulation (FO1.2) and a self-microemulsifying drug delivery system (SMEDDS) (FH5) loaded with PER were developed and characterized. Following PER IN administration (1 mg/kg) to mice, its pharmacokinetics was characterized and compared with intravenous and oral routes. Histopathological toxicity was also examined after a 7-day repeated dose study. FH5 homogeneously formed nanodroplets upon dispersion (20.07 ± 0.03 nm), showing a sustained in vitro PER release profile up to 4 h. By IN route, PER brain delivery was more extensive with FH5 (Cmax and AUC of 52.32 ng/g and 190.35 ng.h/g for FO1.2; 93.87 ng/g and 257.75 ng.h/g for FH5). Maximum brain concentration and total brain exposure were higher than those obtained after oral dosage, with maximum PER concentrations reached significantly faster than post-oral administration (15 min vs 2 h). An improvement in PER plasmatic concentration was also obtained, demonstrated by high relative bioavailability values (134.1% for FH5 and 107.8% for FO1.2). PER absolute plasma bioavailability after IN delivery was 55.5% for FH5 and 44.6% for FO1.2, ensuring a somewhat improved targeting of PER to the brain by the IN route compared to the IV route. No signs of toxicity were found by histopathologic evaluation. Results suggest that IN administration of PER might be a feasible and safe approach for acute and chronic epilepsy management, especially using delivery systems as SMEDDS.

Fundamental Aspects of Lipid-Based Excipients in Lipid-Based Product Development.

Poor aqueous solubility of drugs is still a foremost challenge in pharmaceutical product development. The use of lipids in designing formulations provides an opportunity to enhance the aqueous solubility and consequently bioavailability of drugs. Pre-dissolution of drugs in lipids, surfactants, or mixtures of lipid excipients and surfactants eliminate the dissolution/dissolving step, which is likely to be the rate-limiting factor for oral absorption of poorly water-soluble drugs. In this review, we exhaustively summarize the lipids excipients in relation to their classification, absorption mechanisms, and lipid-based product development. Methodologies utilized for the preparation of solid and semi-solid lipid formulations, applications, phase behaviour, and regulatory perspective of lipid excipients are discussed.

Lipid-Based Nanocarriers as Topical Drug Delivery Systems for Intraocular Diseases.

Effective drug delivery to intraocular tissues remains a great challenge due to complex anatomical and physiological barriers that selectively limit the entry of drugs into the eye. To overcome these challenges, frequent topical application and regular intravitreal injections are currently used to achieve the desired drug concentrations into the eye. However, the repetitive installation or recurrent injections may result in several side effects. Recent advancements in the field of nanoparticle-based drug delivery have demonstrated promising results for topical ophthalmic nanotherapies in the treatment of intraocular diseases. Studies have revealed that nanocarriers enhance the intraocular half-life and bioavailability of several therapies including proteins, peptides and genetic material. Amongst the array of nanoparticles available nowadays, lipid-based nanosystems have shown an increased efficiency and feasibility in topical formulations, making them an important target for constant and thorough research in both preclinical and clinical practice. In this review, we will cover the promising lipid-based nanocarriers used in topical ophthalmic formulations for intraocular drug delivery.

Synthesis and therapeutic delivery approaches for praziquantel: a patent review (2010-present).

INTRODUCTION: : Among all the anti-schistosomal drugs, praziquantel has been the most widely used. However, some major challenges have been faced using the drug in the treatment of schistosome infections. AREAS COVERED: : Several approaches used in the synthesis of praziquantel aimed at reducing the time and cost of production, the toxicity and experimental harsh conditions are discussed. Also, patented methods involved in the pharmaceutical reformulation of praziquantel in the treatment of diverse endoparasitic infestations are reported. Additionally, future perspectives in terms of nanomedicine approach in the formulation of praziquantel are highlighted. EXPERT OPINION: : Lipid-based nanosystems (LBNSs) formulations can be used to overcome the shortcomings associated with the use of praziquantel in the schistosomiasis treatment due to their amphipathic nature. This could be a promising vehicle for the delivery of praziquantel, which could in turn improve the bioavailability, as well as reduce the frequent dose of the drug and improve patient compliance. This may sustain the release of the drug and improve the rapid conversion of the drug into inactive metabolite due to rapid metabolism. Additionally, LBNSs approach could increase and improve the lipophilicity of the drug, which could make it easier to interact with the hydrophobic cores of the worm tegument.

Lipid Nanoparticulate Drug Delivery Systems: Recent Advances in the Treatment of Skin Disorders.

The multifunctional role of the human skin is well known. It acts as a sensory and immune organ that protects the human body from harmful environmental impacts such as chemical, mechanical, and physical threats, reduces UV radiation effects, prevents moisture loss, and helps thermoregulation. In this regard, skin disorders related to skin integrity require adequate treatment. Lipid nanoparticles (LN) are recognized as promising drug delivery systems (DDS) in treating skin disorders. Solid lipid nanoparticles (SLN) together with nanostructured lipid carriers (NLC) exhibit excellent tolerability as these are produced from physiological and biodegradable lipids. Moreover, LN applied to the skin can improve stability, drug targeting, occlusion, penetration enhancement, and increased skin hydration compared with other drug nanocarriers. Furthermore, the features of LN can be enhanced by inclusion in suitable bases such as creams, ointments, gels (i.e., hydrogel, emulgel, bigel), lotions, etc. This review focuses on recent developments in lipid nanoparticle systems and their application to treating skin diseases. We point out and consider the reasons for their creation, pay attention to their advantages and disadvantages, list the main production techniques for obtaining them, and examine the place assigned to them in solving the problems caused by skin disorders.

Advances in ophthalmic preparation: the role of drug nanocrystals and lipid-based nanosystems.

Nanocrystals and lipid-based nanosystems have the potential to play a crucial role in a significant shift in the treatment of ophthalmic diseases. These drug delivery systems allow overcoming the barriers imposed by anatomy and physiology of the organ of vision. This review aims to present new perspectives for these innovative preparations, emphasising the applications of the nanocrystal and lipid-based nanosystem while outlining their advantages and the drawbacks. The in vivo performance of the lipid-based nanosystems was highlighted. Lipid-based nanosystems and nanocrystals showed a prolonged effect, improved ocular bioavailability, upper therapeutic efficacy, higher permeation, prolonged residence time, and sustained drug release, compared to the current applications. Well-established and innovative developments updates of these systems are highlighted herein.

Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis.

Epileptic seizures and anxiety crisis are severe conditions that require fast and effective treatment, targeting the brain. Current emergency antiepiletics and anxiolytics have limited brain bioavailability, following oral, intravenous or rectal administration. This relates with the limited extent at which these drugs bypass the blood brain barrier (BBB). Thereby, the development of strategies that significantly improve the brain bioavailability of these drugs, along with a simple and safe administration by patients, attenuating and/or preventing epileptic seizures or anxiety crisis, are still a major need. In this respect, the nasal/intranasal route has been suggested as a promising strategy for drug targeting to the brain, thus avoiding the BBB. Besides, the use of lipid-based nanosystems, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), liposomes, nanoemulsions and microemulsions, have been demonstrating high efficiency for nose-to-brain transport. This review highlights the potential of using lipid-based nanosystems in the management of epilepsy and anxiety, by means of the nasal/intranasal route. So far, the reported studies have shown promising results, being required more in vivo experiments to further advance for clinical trials. Furthermore, toxicological concerns related to the need of evaluate the impairment on the mucociliary clearance mechanism have been pointed.

Emergent Nanotechnological Strategies for Systemic Chemotherapy against Melanoma.

Melanoma is an aggressive form of skin cancer, being one of the deadliest cancers in the world. The current treatment options involve surgery, radiotherapy, targeted therapy, immunotherapy and the use of chemotherapeutic agents. Although the last approach is the most used, the high toxicity and the lack of efficacy in advanced stages of the disease have demanded the search for novel bioactive molecules and/or efficient drug delivery systems. The current review aims to discuss the most recent advances on the elucidation of potential targets for melanoma treatment, such as aquaporin-3 and tyrosinase. In addition, the role of nanotechnology as a valuable strategy to effectively deliver selective drugs is emphasized, either incorporating/encapsulating synthetic molecules or natural-derived compounds in lipid-based nanosystems such as liposomes. Nanoformulated compounds have been explored for their improved anticancer activity against melanoma and promising results have been obtained. Indeed, they displayed improved physicochemical properties and higher accumulation in tumoral tissues, which potentiated the efficacy of the compounds in pre-clinical experiments. Overall, these experiments opened new doors for the discovery and development of more effective drug formulations for melanoma treatment.

Current Trends in Cancer Nanotheranostics: Metallic, Polymeric, and Lipid-Based Systems.

Theranostics has emerged in recent years to provide an efficient and safer alternative in cancer management. This review presents an updated description of nanotheranostic formulations under development for skin cancer (including melanoma), head and neck, thyroid, breast, gynecologic, prostate, and colon cancers, brain-related cancer, and hepatocellular carcinoma. With this focus, we appraised the clinical advantages and drawbacks of metallic, polymeric, and lipid-based nanosystems, such as low invasiveness, low toxicity to the surrounding healthy tissues, high precision, deeper tissue penetration, and dosage adjustment in a real-time setting. Particularly recognizing the increased complexity and multimodality in this area, multifunctional hybrid nanoparticles, comprising different nanomaterials and functionalized with targeting moieties and/or anticancer drugs, present the best characteristics for theranostics. Several examples, focusing on their design, composition, imaging and treatment modalities, and in vitro and in vivo characterization, are detailed herein. Briefly, all studies followed a common trend in the design of these theranostics modalities, such as the use of materials and/or drugs that share both inherent imaging (e.g., contrast agents) and therapeutic properties (e.g., heating or production reactive oxygen species). This rationale allows one to apparently overcome the heterogeneity, complexity, and harsh conditions of tumor microenvironments, leading to the development of successful targeted therapies.

Evaluation of the biocompatibility and skin hydration potential of vitamin E-loaded lipid nanosystems formulations: In vitro and human in vivo studies.

Lipid-based nanosystems, such as nanostructured lipid carriers (NLC) and nanoemulsions (NE) have been described as promising alternatives to conventional formulations for increase skin hydration. Besides, these systems have been used as efficient vehicles for lipophilic molecules that improve skin properties (e.g. vitamin E). In this study, we performed comparative investigations between hydrogels formulations containing vitamin E-loaded NLC (HG-NLCVE) and vitamin E-loaded nanoemulsion (HG-NEVE). The experiments started with particle size measurements, which showed no significant differences between nanoparticles/nanodroplets sizes after incorporation in the hydrogel net (386 nm vs. 397 nm for HG-NLCVE and 402 nm vs. 514 nm for HG-NEVE). Afterwards, in vitro biocompatibility studies in human keratinocytes were carried out, being observed that the lipid-based nanosystems were more cytotoxic for the cells before incorporation in the hydrogel. Finally, the formulations hydration potential and sensory attributes for skin application were evaluated by in vitro occlusion tests and in vivo human experiments. The results showed that the HG-NLCVE exhibited the best occlusive properties, whereas the HG-NEVE performed a faster skin hydration effect. Furthermore, the latter was selected as the most attractive for skin application, although the HG-NLCVE was described as more suitable to obtain a long-lasting effect. This study demonstrated the in vitro and in vivo safety and hydration potential of hydrogels containing vitamin E-loaded lipid-based nanosystems. These results establish a basis to assess the cutaneous use of these systems, despite more in vivo experiments, for longer periods and in more volunteers, are required before commercialization.

Recent advances in vaccine delivery.

The field of vaccination is moving from the use of attenuated or inactivated pathogens to safer but less immunogenic protein and peptide antigens, which require stronger adjuvant compositions. Antigen delivery carriers appear to play an important role in vaccine development, providing not only antigen protection and controlled release but also an intrinsic adjuvant potential. Among them, carriers based on polymers and lipids are the most representative ones. Patent applications in this area have disclosed, either the design and preparation methods for new biocompatible antigen delivery systems or the application of the previously developed systems for the delivery of novel antigens. Some of them have also reported the use of these technologies for modern therapeutic vaccination approaches.