Nanodelivery systems for cutaneous melanoma treatment.

Cutaneous melanoma (CM) is a multifactorial disease whose treatment still presents challenges: the rapid progression to advanced CM, which leads to frequent recurrences even after surgical excision and, notably, the low response rates and resistance to the available therapies, particularly in the case of unresectable metastatic CM. Thereby, alternative innovative therapeutic approaches for CM continue to be searched. In this review we discuss relevant preclinical research studies, and provide a broad-brush analysis of patents and clinical trials which involve the application of nanotechnology-based delivery systems in CM therapy. Nanodelivery systems have been developed for the delivery of anticancer biomolecules to CM, which can be administered by different routes. Overall, nanosystems could promote technological advances in several therapeutic modalities and can be used in combinatorial therapies. Nevertheless, the results of these preclinical studies have not been translated to clinical applications. Thus, concerted and collaborative research studies involving basic, applied, translational, and clinical scientists need to be performed to allow the development of effective and safe nanomedicines to treat CM.

Preclinical developments of natural-occurring halloysite clay nanotubes in cancer therapeutics.

The natural world holds useful resources that can be exploited to design effective therapeutic approaches. Ready-to-use tubular nanoclays, such as halloysite clay nanotubes (HNTs), are widely available, cost-effective, and sustainable submicron crystalline materials that have been showing great potential towards chronic multifactorial and malignant diseases, standing out as a promising anticancer nanotherapeutic strategy. Currently, several preclinical studies have reported the application of HNTs in cancer research, diagnosis, monitoring, and therapeutics. This groundbreaking review highlights the preclinical knowledge hitherto collected concerning the application of HNTs towards cancer therapy. Despite their reproducibility issues, HNTs were used as nanoarchitectonic platforms for the delivery of conventional chemotherapeutic, natural-occurring, biopharmaceutical, and phototherapeutic anticancer agents in a wide range of in vitro and in vivo solid cancer models. Overall, in different types of cancer mice models, the intratumoral and intravenous administration of HNTs-based nanoplatforms induced tumor growth inhibition without causing significant toxic effects. Such evidence raises a relevant question: does the therapeutic benefit of the parenteral administration of HNTs in cancer outweigh their potential toxicological risk? To answer this question further long-term absorption-distribution-metabolism-excretion studies in healthy and cancer animal models need to be performed. In cancer therapeutics, HNTs are envisaged as promising platforms for cancer multi-agent therapy, enabling the combination of different therapeutic modalities. Furthermore, HNTs might constitute suitable nanotheranostic platforms. Nevertheless, to confirm the potential and safety of the application of HNTs as nanodelivery systems for cancer therapy, it is necessary to perform in-depth in vivo pharmacokinetics and pharmacodynamic studies to further the translation to clinical trials.

Cyclodextrin-based delivery systems for in vivo-tested anticancer therapies.

Cyclodextrins (CDs) are naturally occurring macromolecules widely used as excipients on pharmaceutical formulations, evidencing a large spectrum of applications in the pharmaceutical industry. Their unique ability to act as molecular containers by entrapping a wide range of guest molecules in their internal cavity makes them a remarkable excipient to improve drug apparent solubility, stability, and bioavailability, and a valuable tool for the assembly of new drug delivery systems. These features are especially useful when it comes to chemotherapy, as most of the anticancer drugs present both low permeability and reduced water solubility. Therefore, guest-host inclusion complexes offer several potential advantages not only regarding the improvement of pharmaceutical formulations characteristics but also considering the reduction of drug toxic side effects. The combination of CDs with additional technologies and materials constitutes a potential strategy towards the development of advanced and multifunctional CD-based delivery systems. Paclitaxel, curcumin, camptothecin, doxorubicin, and cisplatin are among the most studied molecules with anticancer activities and have been successfully incorporated in such nanosystems. Exciting results using CDs and CD-based delivery systems have been obtained so far, paving the way towards the attainment of intelligent delivery systems to possibly address cancer therapeutics' unmet needs. In this review, a comprehensive exposition concerning in vivo-tested CD and CD-based delivery systems for anticancer therapy is undertaken. Additionally, the authors address the multivalent functionalities of CD-based delivery systems, namely the incorporation of active target ligands, stimuli-responsiveness components, surface functionalization, or further associations with other delivery systems, aiming at improved in vivo anticancer therapies. Graphical abstract.

Electro-responsive controlled drug delivery from melanin nanoparticles.

Electro-responsive controlled drug delivery has been receiving an increasing interest as one of the on-demand drug delivery systems, aiming the improvement of the therapeutics efficacy by controlling the amount of drug release at a specific time and target site. Herein, we report a simple method to develop an electro-responsive controlled drug delivery system using functionalized melanin nanoparticles (FMNPs) with polydopamine and polypyrrole to precisely control the release of dexamethasone (Dex). Optimized FMNPs showed 376.77 ± 62.05 nm of particle size, a polydispersity index of 0.26 ± 0.09 and a zeta-potential (ZP) of -32.59 ± 3.61 mV. FMNPs evidenced a spherical shape, which was confirmed by scanning electron microscopy. Fourier-transform infrared spectrometry analysis confirmed the deposition of the polymers on the FMNPs' surface. The incorporation efficiency of the optimized Dex-loaded FMNPs was 94.45 ± 0.63% and the increase of ZP to -40.34 ± 4.65 mV was attributed to the anionic nature of Dex. In vitro Dex release studies without stimuli revealed a maximum Dex release below 10%. Applying electrical stimulation, Dex release was augmented, with a maximum of ca. 32% after 24 h. The designed FMNPs provide a powerful biomaterial-based technological tool for electro-responsive controlled drug delivery, capable of surpassing the associated lack of efficiency and stability of current carriers.

Nanotechnological breakthroughs in the development of topical phytocompounds-based formulations.

Cosmeceuticals are a type of cosmetic products distinguished by the presence of active ingredients that, in addition to their cosmetic effects, also hold therapeutic outcomes. This review is focused on phytocompounds (PHYTOCs)-based cosmeceuticals, an established segment of cosmetic industry, due to the great demand for vitamins and plant-derived products. PHYTOCs beauty and health-related applications are due to their anti-oxidant, anti-bacterial, wound-healing, anti-aging, sun protection, cytoprotective, anticarcinogenic and anti-inflammatory activities. However, PHYTOCs present disadvantages, precisely the poor solubility, instability, reduced skin permeation and low skin retention time, which strongly restrict their topical application. Therefore, and since the cosmetic industry constantly pursues groundbreaking technological products, nanotechnology emerges as an innovative strategy to tackle the PHYTOCs recognized limitations. Nanotechnology manipulates and reduces materials size to 1 and 100 nm, creating structures able to encapsulate active ingredients, such as PHYTOCs, with the purpose of overcoming their limitations and delivering them in a controlled manner to the skin. This review highlights the potential properties of PHYTOCs loaded in several types of nanocarriers (liposomes, niosomes, ethosomes, transferosomes, cubosomes, phytosomes, nanoemulsions, nanocrystals, polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, carbon nanotubes, fullerenes, and dendrimers) used to overcome PHYTOCs free form limitations and potentiate their cosmeceutical properties. An approach to the "green" chemical synthesis of metallic nanoparticles taking advantage of PHYTOCS as natural reducing agents is exposed as well. Nanocosmeceuticals toxicity concerns and regulatory aspects are also addressed.

Sonication-assisted Layer-by-Layer self-assembly nanoparticles for resveratrol delivery.

This paper advances the development of a novel drug nanodelivery solution to the oral administration of resveratrol (RSV), a low soluble drug whose recognized therapeutic applications are circumscribed when administered in the free compound form. Layer-by-Layer (LbL) self-assembly is an emergent nanotechnology proposed to address this concern with means to afford control over key formulation parameters, which are able to ultimately promote an improved pharmacokinetics. LbL self-assembly consists in the sequential adsorption of oppositely charged polyelectrolytes upon a low soluble drug nanoparticle (NP) template, giving rise to onion-like multilayered nanoarchitectures. In this work, RSV nanoprecipitation followed by LbL self-assembly of polyelectrolytes, led by a washless approach, was carried out by using the cationic poly(allylamine hydrochloride) (PAH) and the anionic dextran sulfate (DS) as polyelectrolytes towards the nanoencapsulation of RSV. Each saturated polyelectrolyte layer deposition involved the rigorous polyelectrolyte concentration assessment which was accomplished by tracing titration curves. This way, aqueous RSV nanocores and RSV LbL nanoformulations with a distinct number of PAH/DS bilayers were developed, including 2.5 (RSV-(PAH/DS)2.5 NPs), 5.5 (RSV-(PAH/DS)5.5 NPs) and 7.5 (RSV-(PAH/DS)7.5 NPs) bilayered nanoformulations. Homogenous particle size distributions at the desired nanoscale interval (ca. 116-220 nm; polydispersity index below 0.15), good colloidal (zeta potential magnitudes ca. ± 20-30 mV) and chemical stabilizations, high encapsulation efficiency (above 90%) together with an excellent cytocompatibility with Caco-2 cells (cell viability above 90%) were observed for all the nanoformulations. Eventfully, LbL NPs promoted a controlled release of RSV pursuant to the number of polyelectrolyte bilayers under simulated gastrointestinal conditions, particularly in the intestine medium, emphasizing their biopharmaceutical advantage. Our findings manifestly pinpoint that LbL PAH/DS NPs constitute a promising nanodelivery system for the oral delivery of RSV, providing a rational strategy to enlarge the implementation range of this interesting polyphenol, which is possibly the most actively investigated phytochemical worldwide.

Biomedical potential of clay nanotube formulations and their toxicity assessment.

Introduction: Halloysite clay nanotubes (HNTs) are a naturally abundant and biocompatible aluminosilicate material with a structure able to encapsulate 10-20% of drugs. These features are attractive toward the clinical application in controlled drug delivery, tissue engineering and regenerative medicine. Areas covered: We describe the application of HNTs as a viable method for clinical purposes, particularly developing formulations for prophylaxis, diagnosis and therapeutics, having a special attention to these nanotubes bio-safety. HNTs may be used for pharmaceuticals, biopharmaceuticals, wound healing, bone regeneration, dental repair, hair surface engineering and biomimetic applications. Expert opinion: HNTs are a versatile, safe and biocompatible nanomaterial used for drug encapsulation for numerous clinical applications. The studies here reviewed confirm the HNTs biocompatibility, describing their low toxicity. Further developments will be made regarding the long-term efficacy of halloysite-based treatments in humans, concentrating mostly on topical applications.

Evolution of Hair Treatment and Care: Prospects of Nanotube-Based Formulations.

A new approach for hair treatment through coating with nanotubes loaded with drugs or dyes for coloring is suggested. This coating is produced by nanotube self-assembly, resulting in stable 2-3 µm thick layers. For medical treatment such formulations allow for sustained long-lasting drug delivery directly on the hair surface, also enhanced in the cuticle openings. For coloring, this process allows avoiding a direct hair contact with dye encased inside the clay nanotubes and provides a possibility to load water insoluble dyes from an organic solvent, store the formulation for a long time in dried form, and then apply to hair as an aqueous nanotube suspension. The described technique works with human and other mammal hairs and halloysite nanoclay coating is resilient against multiple shampoo washing. The most promising, halloysite tubule clay, is a biocompatible natural material which may be loaded with basic red, blue, and yellow dyes for optimized hair color, and also with drugs (e.g., antilice care-permethrin) to enhance the treatment efficiency with sustained release. This functionalized nanotube coating may have applications in human medical and beauty formulations, as well as veterinary applications.

Targeting Cancer Via Resveratrol-Loaded Nanoparticles Administration: Focusing on In Vivo Evidence.

Resveratrol (RSV) is a polyphenol endowed with potential therapeutic effects in chronic diseases, particularly in cancer, the second leading cause of death worldwide in the twenty-first century. The advent of nanotechnology application in the field of drug delivery allows to overcome the constrains associated with the conventional anticancer treatments, in particular chemotherapy, reducing its adverse side effects, off target risks and surpassing cancer multidrug chemoresistance. Moreover, the use of nanotechnology-based carriers in the delivery of plant-derived anticancer agents, such as RSV, has already demonstrated to surpass the poor water solubility, instability and reduced bioavailability associated with phytochemicals, improving their therapeutic activity, thus prompting pharmaceutical developments. This review highlights the in vivo anticancer potential of RSV achieved by nanotherapeutic approaches. First, RSV physicochemical, stability and pharmacokinetic features are described. Thereupon, the chemotherapeutic and chemopreventive properties of RSV are underlined, emphasizing the RSV numerous cancer molecular targets. Lastly, a comprehensive analysis of the RSV-loaded nanoparticles (RSV-NPs) developed and administered in different in vivo cancer models to date is presented. Nanoparticles (NPs) have shown to improve RSV solubility, stability, pharmacokinetics and biodistribution in cancer tissues, enhancing markedly its in vivo anticancer activity. RSV-NPs are, thus, considered a potential nanomedicine-based strategy to fight cancer; however, further studies are still necessary to allow RSV-NP clinical translation.

Nanotechnology-based formulations for resveratrol delivery: Effects on resveratrol in vivo bioavailability and bioactivity.

Resveratrol (RES), also known as 3,5,4'-trihydroxystilbene, is a polyphenolic phytoalexin that has been widely researched in the past decade due to its recognized numerous biological activities. Despite the potential benefits of RES, its effective use is limited due to its poor solubility, photosensitivity and rapid metabolism, which strongly undermine RES bioavailability and bioactivity. Thereby, recently, nanotechnology appeared as a potential strategy to circumvent RES physicochemical and pharmacokinetics constrains. However, only few studies have addressed the crucial in vivo suitability of the developed delivery systems to improve RES efficacy. Facing this scenario, in the present review, it is intended to present and discuss the in vivo resveratrol bioavailability and bioactivity, following its encapsulation or conjugation in nanotechnology-based carriers, contemplating their pharmacokinetics effectiveness.

First-time oral administration of resveratrol-loaded layer-by-layer nanoparticles to rats - a pharmacokinetics study.

trans-Resveratrol (RSV) is a plant-derived polyphenol endowed with a broad spectrum of promising therapeutic activities. The applicability of RSV in vivo has, however, had limited success so far, largely due to its inefficient systemic delivery resulting from its low water solubility. Layer-by-Layer (LbL) nanotechnology constitutes an innovative formulation strategy to address this concern, and is based on the design of tunable onion-like multilayered nanoarchitectures on the surface of low solubility drug nanocores, such as RSV. The purpose of this study was the investigation of the bioavailability of an LbL nanoformulation composed of 5.5 bilayers of polyallylamine hydrochloride (PAH) and dextran sulfate (DS) (LbL NPs) by pharmacokinetic studies following oral dosing to Wistar rats (20 mg kg-1). The systemic exposure of LbL NPs was compared to the respective nanoformulation without LbL coatings (RSV nanocores) and the free RSV suspension. The results demonstrated that both LbL NPs and RSV nanocores significantly enhanced, respectively, 1.76-fold and 2.74-fold the systemic exposure of RSV compared to the free RSV suspension, emphasizing their biopharmaceutical advantage. Surprisingly, besides the modified drug release potential of the LbL NPs, these exhibited a slightly lower systemic exposure (0.36-fold) in comparison with non-LbL modified RSV nanocores. These results were justified only by the electrostatic interactions composition of the LbL shell composition, requiring further research towards the application of stronger interactions. For this study, due to the key role of the bioanalytical method in the in vivo data acquisition, a rapid, selective, and sensitive HPLC-DAD method has been successfully optimized and fully validated to confidently quantify RSV levels in the rat plasma matrix, together with the optimization of the sample preparation procedure. Moreover, the chemical stability of RSV was evaluated for 24 h in simulated gastric and intestinal fluids with enzymes. Overall, our findings suggest that LbL NPs should be given great attention, representing a potential drug delivery system for RSV in view of the application of RSV not solely as a supplement but also as a therapeutic drug.

Nanotechnology for the development of new cosmetic formulations.

INTRODUCTION: Nanotechnology is an increasingly widespread area of research for its various applications and advantages. Accordingly, nanotechnology has been the focus of investment in different areas of science, namely as a technological strategy for the development of cosmetics formulations. Nanosystems allow for a profit skin penetration and an effective release profile of ingredients, which contributes to superior technological and cosmetic effects. The applications of nanocosmetics are numerous, from anti-aging care, make-up, nails, deodorants, oral care, sunscreens, and hair care. However, as an area of emerging knowledge, it has now begun to encourage investigations into its toxicology profile, particularly regarding health damage and environmental pollution. Also, the regulatory area saw its adaptation concerning the use of formulations containing nanotechnology. AREAS COVERED: A description of the nanosystems so far applied in the development of cosmetics is presented. Moreover, an outline concerning lipid-based-nanosystems, polymeric-based nanoparticles, metal-based nanoparticles, silica nanoparticles, and additional nanosystems (dendrimers, nanocrystals, fullerenes, nanodiamonds, and cyclodextrins) towards the obtainment of effective cosmetic outcomes is addressed. The concerning toxicological as well as the regulatory aspects are also discussed. EXPERT OPINION: This innovative and timely review emphasizes that nanosystems constitute a highly promising technology strategy towards the obtainment of superior and ground-breaking cosmetic formulations.

Linalool bioactive properties and potential applicability in drug delivery systems.

The medicinal properties of essential oils from aromatic plants are known since antiquity. Currently, the technological innovation enabled the reinvention of the ancient plant knowledge leading to the identification and extraction of organic compounds present in essential oils. These organic compounds belong mainly to the terpene group and are accountable for the wide range of bioactive properties attributed to essential oils. Linalool (C10H18O), so-called 3,7-dimethyl-1,6-octadien-3-ol, is a monoterpene alcohol broadly present as a major constituent of plant essential oils, particularly lavender and coriander. Linalool per se is non-toxic and, according to recent in vitro and in vivo scientific studies, it has demonstrated to have a comprehensive range of bioactive properties, which can be exploited for pharmaceutic and cosmetic applications. The present review focuses on the anti-inflammatory, anticancer, anti-hyperlipidemic, antimicrobial, antinoceptive, analgesic, anxiolytic, antidepressive and neuroprotective properties of linalool. The advantages of the loading in nanotechnology-based drug delivery systems, with the purpose of enhancing its bioactive properties are also discussed.

Optimization of linalool-loaded solid lipid nanoparticles using experimental factorial design and long-term stability studies with a new centrifugal sedimentation method.

Linalool (C10H18O), also known as 3, 7-dimethyl-1, 6-octadien-3-ol, is the most common acyclic monoterpene tertiary alcohol present in essential oils of several aromatic plant species. Previous studies indicate that linalool is a valuable compound with a wide range of therapeutic properties. The promising therapeutic effects of linalool are however limited by its poor water solubility and volatility. Recently, the encapsulation of linalool in drug delivery systems, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) has demonstrated to overcome linalool physicochemical limitations. The present study aimed the production and optimization of linalool encapsulation in SLN applying the experimental full factorial design. The estimation of the long-term stability of the produced linalool-loaded SLN was carried out using a new centrifugal sedimentation method, LUMiSizer®. SLN dispersions were produced by the hot high pressure homogenization (HPH) method. The influence of the independent variables, surfactant and lipid concentrations on linalool-loaded SLN particle size, polydispersity index (PI) and zeta potential (ZP) was evaluated by a 22 factorial design composed of 2 variables which were set at 2-levels each. For each of the three dependent variables, analysis of the variance (ANOVA) was performed using a 95% confidence interval. The concentration of surfactant, as well as, the interaction between the different concentrations of lipid and surfactant, hada statistically significant effect on the particle size and PI. Experimental factorial design has been successfully employed to develop an optimal SLN dispersion, requiring a minimum of performed experiments. Based on the obtained results, the optimal linalool-loaded SLN dispersion was composed of 1% (w/v) linalool 2% (w/v) of solid lipid and 5% (w/v) of surfactant. Furthermore, the stability analysis revealed that the produced linalool-loaded SLN dispersions have limited storage stability which can be easily overcome through the assembly of a polymeric coating on the SLN surface. LUMiSizer® has been successfully used in the kinetic analysis of linalool-SLN during accelerated storage time.