Natural product-based nanomedicine applied to fungal infection treatment: A review of the last 4 years.

Fungal infections are one of the main public health problems, especially in immunocompromised patients, nosocomial environments, patients with chronic diseases, and transplant recipients. These diseases are increasingly frequent and lethal because the microorganism has a high capacity to acquire resistance to available therapy. The main resistance factors are the emergence of new strains and the uncontrolled use of antifungals. It is, therefore, important to develop new methods that contribute to combating fungal diseases in the clinical area. Natural products have considerable potential for the development of new drugs with antifungal activity, mainly due to their biocompatibility and low toxic effect. This promising antimicrobial activity of natural products is mainly due to the presence of flavonoids, terpenes, and quinones, which explains their antifungal potential. Pharmaceutical nanotechnology has been explored to enhance the delivery, selectivity, and clinical efficacy of these products. Nanotechnological systems provide a safe and selective environment for various substances, such as natural products, improving antifungal activity. However, further safety experiments (in vivo or clinical trials) need to be carried out to prove the therapeutic action of natural products, since they may have undesirable, toxic, and mutagenic effects. Therefore, this review article addresses the main nanotechnological methods using natural products for effective future treatment against the main fungal diseases.

A Critical Review of Analytical Methods for Quantification of Amphotericin B in Biological Samples and Pharmaceutical Formulations.

Amphotericin B (AmB) is an important antifungal agent available in the clinical practice with the action mechanism related to the inhibition of ergosterol molecule present in the fungal cell wall. Given this, in order to expand AmB knowledge, this review article gathers important information of the AmB physical, chemical, and biological properties. In addition, the main analytical methods for quantifying and determining the AmB were also reported in this review, such as high-performance liquid chromatography (HPLC), liquid chromatography, tandem mass spectrophotometry (LC-MS/MS), immunoenzymatic assay (ELISA), capillary zone electrophoresis (CE) stands out and among others. Based in this review article, the scientific community will have important information to choose the best method for analysis in their scientific or clinical research, providing greater security and reliability in the obtained results.

Hydroalcoholic Extract of Myrcia bella Loaded into a Microemulsion System: A Study of Antifungal and Mutagenic Potential.

Myrcia bella is a medicinal plant used for the treatment of diabetes, hemorrhages, and hypertension in Brazilian folk medicine. Considering that plant extracts are attractive sources of new drugs, the aim of the present study was to verify the influence of incorporating 70% hydroalcoholic of M. bella leaves in nanostructured lipid systems on the mutagenic and antifungal activities of the extract. In this work, we evaluated the antifungal potential of M. bella loaded on the microemulsion against Candida sp for minimum inhibitory concentration, using the microdilution technique. The system was composed of polyoxyethylene 20 cetyl ether and soybean phosphatidylcholine (10%), grape seed oil, cholesterol (10%: proportion 5/1), and purified water (80%). To investigate the mutagenic activity, the Ames test was used with the Salmonella Typhimurium tester strains. M. bella, either incorporated or free, showed an important antifungal effect against all tested strains. Moreover, the incorporation surprisingly inhibited the mutagenicity presented by the extract. The present study attests the antimicrobial properties of M. bella extract, contributing to the search for new natural products with biological activities and suggesting caution in its use for medicinal purposes. In addition, the results emphasize the importance of the use of nanotechnology associated with natural products as a strategy for the control of infections caused mainly by the genus Candida sp.

Galleria mellonella for systemic assessment of anti-Candida auris using amphotericin B loaded in nanoemulsion.

Galleria mellonella is a model that uses adult larvae to assess the prophylactic, therapeutic, and acute toxic potential of substances. Given their benefits, G. mellonella models are being employed in investigations of systemic infections caused by highly resistant microorganisms. Among the multiresistant microorganisms, we highlight Candida auris, a yeast with high mortality potential and resistance. Among the potential drugs, amphotericin B (AmB) stands out; however, microbial resistance episodes and side effects caused by low selectivity have been observed. The incorporation of AmB into a nanoemulsion (NE) can contribute to the control of C. auris infections and resistance as well as decrease the side effects of this drug. This study aimed to develop AmB-loaded NE (NEA) and evaluate its antifungal action against C. auris in G. mellonella. NEs were obtained by using sunflower oil and cholesterol as the oily phase, polyoxyethylene 20 cetyl ether (Brij® 58) and soy phosphatidylcholine as the surfactant system, and PBS buffer as the aqueous phase. An alternative in vivo assay with G. mellonella for acute toxicity and infection was performed using adult stage larvae (200 mg to 400 mg). According to the obtained results, NE and NEA exhibited sizes of 43 and 48 nm, respectively. The PDI was 0.285 and 0.389 for NE and NEA, respectively. The ZP showed electronegativity for both systems, with -3.77 mV and -3.80 mV for NE and NEA, respectively. Acute toxicity showed that free AmB had greater acute toxicity potential than NEA. The survival assay showed high larval viability. NEA had a better antifungal profile against systemic infection in G. mellonella. It is concluded that the alternative model proved to be an efficient in vivo assay to determine the toxicity and evaluate the therapeutic property of free AmB and NEA in systemic infections caused by C. auris.

Exploiting drug delivery systems for oral route in the peptic ulcer disease treatment.

Peptic ulcer disease (PUD) is a common condition that is induced by acid and pepsin causing lesions in the mucosa of the duodenum and stomach. The pathogenesis of PUD is a many-sided scenario, which involves an imbalance between protective factors, such as prostaglandins, blood flow, and cell renewal, and aggressive ones, like alcohol abuse, smoking, Helicobacter pylori colonisation, and the use of non-steroidal anti-inflammatory drugs. The standard oral treatment is well established; however, several problems can decrease the success of this therapy, such as drug degradation in the gastric environment, low oral bioavailability, and lack of vectorisation to the target site. In this way, the use of strategies to improve the effectiveness of these conventional drugs becomes interesting. Currently, the use of drug delivery systems is being explored as an option to improve the drug therapy limitations, such as antimicrobial resistance, low bioavailability, molecule degradation in an acid environment, and low concentration of the drug at the site of action. This article provides a review of oral drug delivery systems looking for improving the treatment of PUD.

Metronidazole-Loaded Polyethyleneimine and Chitosan-Based Liquid Crystalline System for Treatment of Staphylococcal Skin Infections.

Staphylococcus aureus is a common gram-positive bacterium of the human skin microbiota. It is also a dangerous pathogen that can cause serious and even lethal skin infections. The topical administration of metronidazole via nanotechnology-based drug delivery systems, such as liquid crystalline systems, can modulate both the drug permeation and activity, decreasing its side effects and increasing the drug potent activity against the gram-positive bacteria. This study aimed at: (1) structurally developing and characterizing a liquid crystalline systems composed of chitosan and polyethyleneimine dispersion as the aqueous phase, oleic acid as the oily phase, and ethoxylated and propoxylated cetyl alcohol as the surfactant (FPC) for metronidazole incorporation (0.5% w/w); (2) evaluating the in vitro release and skin permeation and retention properties of the metronidazole-loaded liquid crystalline systems (FPC-M); (3) investigating the in vitro antibacterial activity of FPC-M against Staphylococcus aureus. Polarised light microscopy indicated that both FPC and FPC-M are hexagonal systems. Rheological, texture, and bioadhesion assays showed that both are elastic and bioadhesive systems. According to the results of the in vitro release, permeation, and retention assays, FPC can modulate metronidazole release and allow metronidazole to stay for a longer time on the skin. The determination of FPC-M activity against Staphylococcus aureus showed that it could target the bacterial cell. In conclusion, the liquid crystalline systems developed in this study can improve the clinical performance of metronidazole in the treatment of staphylococcal skin infections.

Zinc oxide 3D microstructures as an antimicrobial filler content for composite resins.

The aim of this study was to evaluate the antibacterial activity of a composite resin modified by 3D zinc oxide (ZnO) microstructures and to verify possible alterations on its mechanical properties. ZnO was synthesized by hydrothermal approach and characterized by X-ray diffraction (XRD), surface area by Brunauer, Emmett and Teller (BET), Fourier transform infrared spectroscopy (FTIR) and Field emission scanning electron microscopy (FESEM). The minimum inhibitory concentrations of ZnO against Streptococcus mutans, Escherichia coli, Staphylococcus aureus, and Candida albicans were determinated. The composite resin FiltekTM Z350XT (3M of Brazil) was blended with 0.2%, 0.5%, and 1% in weight of ZnO and submitted to antibacterial assay by direct contact test against S. mutans, the leading cause of dental caries and the most cariogenic oral streptococci. Additionally, it was performed compressive and diametral tensile strength tests of the modified composite resin. Microrods and hollow microrods of ZnO were obtained and its MIC values were found to be 125 µg/mL for S. mutans, 500 µg/mL for C. albicans and 62.5 µg/mL for S. aureus. For the tested concentrations, it was not found MIC against E. coli. The direct contact test showed a significant antibacterial capacity of modified composite resin (p > 0.05 for all concentrations). The compressive and diametral tensile strength remains no changed after inclusion of microparticles (p > 0.05 for all concentrations). The modification of the composite resin with small amounts of ZnO microparticles significantly inhibited the S. mutans growth on resin surface without significant alterations of its mechanical strength.

Essential Oil of Cymbopogon nardus (L.) Rendle: A Strategy to Combat Fungal Infections Caused by Candida Species.

BACKGROUND: The incidence of fungal infections, especially those caused by Candida yeasts, has increased over the last two decades. However, the indicated therapy for fungal control has limitations. Hence, medicinal plants have emerged as an alternative in the search for new antifungal agents as they present compounds, such as essential oils, with important biological effects. Published data demonstrate important pharmacological properties of the essential oil of Cymbopogon nardus (L.) Rendle; these include anti-tumor, anti-nociceptive, and antibacterial activities, and so an investigation of this compound against pathogenic fungi is interesting. OBJECTIVE: The aim of this study was to evaluate the chemical composition and biological potential of essential oil (EO) obtained from the leaves of C. nardus focusing on its antifungal profile against Candida species. METHODS: The EO was obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS). Testing of the antifungal potential against standard and clinical strains was performed by determining the minimal inhibitory concentration (MIC), time-kill, inhibition of Candida albicans hyphae growth, and inhibition of mature biofilms. Additionally, the cytotoxicity was investigated by the IC50 against HepG-2 (hepatic) and MRC-5 (fibroblast) cell lines. RESULTS: According to the chemical analysis, the main compounds of the EO were the oxygen-containing monoterpenes: citronellal, geranial, geraniol, citronellol, and neral. The results showed important antifungal potential for all strains tested with MIC values ranging from 250 to 1000 µg/mL, except for two clinical isolates of C. tropicalis (MIC > 1000 µg/mL). The time-kill assay showed that the EO inhibited the growth of the yeast and inhibited hyphal formation of C. albicans strains at concentrations ranging from 15.8 to 1000 µg/mL. Inhibition of mature biofilms of strains of C. albicans, C. krusei and C. parapsilosis occurred at a concentration of 10× MIC. The values of the IC50 for the EO were 96.6 µg/mL (HepG-2) and 33.1 µg/mL (MRC-5). CONCLUSION: As a major virulence mechanism is attributed to these types of infections, the EO is a promising compound to inhibit Candida species, especially considering its action against biofilm.

Nanostructured lipid system as a strategy to improve the anti-Candida albicans activity of Astronium sp.

The genus Astronium (Anacardiaceae) includes species, such as Astronium fraxinifolium, Astronium graveolens, and Astronium urundeuva, which possess anti-inflammatory, anti-ulcerogenic, healing, and antimicrobial properties. Nanostructured lipid systems are able to potentiate the action of plant extracts, reducing the required dose and side effects and improving antimicrobial activity. This work aims to evaluate a nanostructured lipid system that was developed as a strategy to improve the anti-Candida albicans activity of hydroethanolic extracts of stems and leaves from Astronium sp. The antifungal activity against C. albicans (ATCC 18804) was evaluated in vitro by a microdilution technique. In addition to the in vitro assays, the Astronium sp. that showed the best antifungal activity and selectivity index was submitted to an in vivo assay using a model of vulvovaginal candidiasis infection. In these assays, the extracts were either used alone or were incorporated into the nanostructured lipid system (comprising 10% oil phase, 10% surfactant, and 80% aqueous phase). The results indicated a minimal inhibitory concentration of 125.00 µg/mL before incorporation into the nanostructured system; this activity was even more enhanced when this extract presented a minimal inhibitory concentration of 15.62 µg/mL after its incorporation. In vivo assay dates showed that the nanostructure-incorporated extract of A. urundeuva leaves was more effective than both the unincorporated extract and the antifungal positive control (amphotericin B). These results suggest that this nanostructured lipid system can be used in a strategy to improve the in vitro and in vivo anti-C. albicans activity of hydroethanolic extracts of Astronium sp.

A curcumin-loaded liquid crystal precursor mucoadhesive system for the treatment of vaginal candidiasis.

Women often develop vaginal infections that are caused primarily by organisms of the genus Candida. The current treatments of vaginal candidiasis usually involve azole-based antifungals, though fungal resistance to these compounds has become prevalent. Therefore, much attention has been given to molecules with antifungal properties from natural sources, such as curcumin (CUR). However, CUR has poor solubility in aqueous solvents and poor oral bioavailability. This study attempted to overcome this problem by developing, characterizing, and evaluating the in vitro antifungal action of a CUR-loaded liquid crystal precursor mucoadhesive system (LCPM) for vaginal administration. A low-viscosity LCPM (F) consisting of 40% wt/wt polyoxpropylene-(5)-polyoxyethylene-(20)-cetyl alcohol, 50% wt/wt oleic acid, and 10% wt/wt chitosan dispersion at 0.5% with the addition of 16% poloxamer 407 was developed to take advantage of the lyotropic phase behavior of this formulation. Notably, F could transform into liquid crystal systems when diluted with artificial vaginal mucus at ratios of 1:3 and 1:1 (wt/wt), resulting in the formation of F30 and F100, respectively. Polarized light microscopy and rheological studies revealed that F behaved like an isotropic formulation, whereas F30 and F100 behaved like an anisotropic liquid crystalline system (LCS). Moreover, F30 and F100 presented higher mucoadhesion to porcine vaginal mucosa than F. The analysis of the in vitro activity against Candida albicans revealed that CUR-loaded F was more potent against standard and clinical strains compared with a CUR solution. Therefore, the vaginal administration of CUR-loaded LCPMs represents a promising platform for the treatment of vaginal candidiasis.

Nanotechnological strategies for vaginal administration of drugs--a review.

Women frequently develop disorders related to the vaginal area, including problems with the immune system, hygiene, genetic aspects and sexually transmitted diseases. Compared with other mucosal application sites, the vagina represents local effect as well as systemic drug delivery and is able to avoid the first-pass effect due to its large surface area, high blood supply and permeability to many active ingredients. It has been widely proposed that the use of drugs to treat vaginal disorders be combined with nanotechnology because nanosystems often potentiate the action of most active constituents, reducing the required dosage and side effects and improving the resulting activity in comparison with conventional treatments. Following the trend of using drug delivery systems based on nanotechology, many studies have encouraged the scientific community to turn to the development of new strategies for the vaginal administration of drugs. This study proposes to review the most common nanotechnology-based drug delivery systems that have been used to improve the effectiveness of active compounds administrated to treat vaginal disorders.

Nanotechnology-based drug delivery systems and herbal medicines: a review.

Herbal medicines have been widely used around the world since ancient times. The advancement of phytochemical and phytopharmacological sciences has enabled elucidation of the composition and biological activities of several medicinal plant products. The effectiveness of many species of medicinal plants depends on the supply of active compounds. Most of the biologically active constituents of extracts, such as flavonoids, tannins, and terpenoids, are highly soluble in water, but have low absorption, because they are unable to cross the lipid membranes of the cells, have excessively high molecular size, or are poorly absorbed, resulting in loss of bioavailability and efficacy. Some extracts are not used clinically because of these obstacles. It has been widely proposed to combine herbal medicine with nanotechnology, because nanostructured systems might be able to potentiate the action of plant extracts, reducing the required dose and side effects, and improving activity. Nanosystems can deliver the active constituent at a sufficient concentration during the entire treatment period, directing it to the desired site of action. Conventional treatments do not meet these requirements. The purpose of this study is to review nanotechnology-based drug delivery systems and herbal medicines.