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Hyaluronic acid (HA) is a natural polymer, produced endogenously by the human body, which has unique physicochemical and biological properties, exhibiting desirable biocompatibility and biodegradability. Therefore, it has been widely studied for possible applications in the area of inflammatory diseases. Although exogenous HA has been described as unable to restore or replace the properties and activities of endogenous HA, it can still provide satisfactory pain relief. This review aims to discuss the advances that have been achieved in the treatment of inflammatory diseases using hyaluronic acid as a key ingredient, essentially focusing on studies carried out between the years 2017 and 2021.

The high incidence of fungal infections has become a worrisome public health issue, having been aggravated by an increase in host predisposition factors. Despite all the drugs available on the market to treat these diseases, their efficiency is questionable, and their side effects cannot be neglected. Bearing that in mind, it is of upmost importance to synthetize new and innovative carriers for these medicines not only to fight emerging fungal infections but also to avert the increase in drug-resistant strains. Although it has revealed to be a difficult job, new nano-based drug delivery systems and even new cellular targets and compounds with antifungal potential are now being investigated. This article will provide a summary of the state-of-the-art strategies that have been studied in order to improve antifungal therapy and reduce adverse effects of conventional drugs. The bidirectional relationship between Mycology and Nanotechnology will be also explained. Furthermore, the article will focus on new compounds from the marine environment which have a proven antifungal potential and may act as platforms to discover drug-like characteristics, highlighting the challenges of the translation of these natural compounds into the clinical pipeline.

The use of marine-origin polysaccharides has increased in recent research because they are abundant, cheap, biocompatible, and biodegradable. These features motivate their application in nanotechnology as drug delivery systems; in tissue engineering, cancer therapy, or wound dressing; in biosensors; and even water treatment. Given the physicochemical and bioactive properties of fucoidan and chitosan, a wide range of nanostructures has been developed with these polysaccharides per se and in combination. This review provides an outline of these marine polysaccharides, including their sources, chemical structure, biological properties, and nanomedicine applications; their combination as nanoparticles with descriptions of the most commonly used production methods; and their physicochemical and biological properties applied to the design of nanoparticles to deliver several classes of compounds. A final section gives a brief overview of some biomedical applications of fucoidan and chitosan for tissue engineering and wound healing.

Polymeric nanoparticles based on fucoidan and chitosan were developed to deliver quercetin as a novel functional food. Through the polyelectrolyte self-assembly method, fucoidan/chitosan (F/C) nanoparticles were obtained with three different weight ratios (1/1, 3/1, and 5/1). The content of quercetin in the fucoidan/chitosan nanoparticles was in the range 110 ± 3 to 335 ± 4 mg·mL−1, with the increase of weight ratio of fucoidan to chitosan in the nanoparticle. Physicochemically stable nanoparticles were obtained with a particle size within the 300–400 nm range and surface potential higher than +30 mV for the 1F/1C ratio nanoparticle and around −30 mV for the 3F/1C and 5F/1C ratios nanoparticles. The 1F/1C ratio nanoparticle became larger and more unstable as the pH increased from 2.5 to 7.4, while the 3F/1C and 5F/1C nanoparticles retained their initial characteristics. This result indicates that the latter nanoparticles were stable along the gastrointestinal tract. The quercetin-loaded fucoidan/chitosan nanoparticles showed strong antioxidant activity and controlled release under simulated gastrointestinal environments (in particular for the 3F/1C and 5F/1C ratios), preventing quercetin degradation and increasing its oral bioavailability.

Dendritic cells (DCs) are promising targets for drug delivery, as they can induce immunity or tolerance. The current study aims to examine the potential of using nanostructured lipid carriers (NLC) as delivery systems for human DC by evaluating nanoparticle internalization, cell labeling, and drug activity. NLC were formulated incorporating the fluorochrome fluorescein isothiocyanate (FITC-NLC) or the natural anti-inflammatory molecule resveratrol (rsv-NLC). Primary human DCs were differentiated from peripheral blood monocytes, and the innovative imaging flow cytometry technique was used to examine FITC-NLC internalization. The capacity of rsv-NLC to inhibit DC activation in response to proinflammatory cytokine tumor necrosis factor-α (TNF- α) was investigated by conventional flow cytometry. A combination of imaging and conventional flow cytometry was used to assess NLC cytotoxicity. The results obtained indicate that both NLC formulations were stable over time, with mean diameter <200 nm and highly negative zeta potential (about -30 mV). When DCs were placed in contact with NLC, imaging flow cytometry clearly showed that DCs efficiently internalized FITC-NLC, with nearly 100% of cells internalizing nanoparticles upon 1 hour of incubation. Both immature and mature DCs internalized NLC to high and comparable levels, and without cytotoxicity. Stimulating DC with TNF-α in the presence of rsv-NLC revealed that, using these nanoparticles, very small concentrations of rsv were sufficient to significantly decrease surface expression of activation marker CD83 (5 µM) and major histocompatibility complex-class II molecule human leukocyte antigen - antigen D related (10 µM), both upregulated in response to TNF-α stimulation. Rsv-NLC were compared with free rsv; at 5 µM, rsv-NLC were able to inhibit nuclear factor κ beta phosphorylation and significantly decrease the level of interleukin-12/23, both upregulated in response to TNF-α, while 10 µM free rsv were needed to promote a similar effect. Taken together, the results presented show that NLC are suitable carriers of fluorescent labels or bioactive molecules for human DCs, leading to inflammation modulation.

Resveratrol is a polyphenol found in grapes and red wines. Interest in this polyphenol has increased due to its pharmacological cardio- and neuroprotective, chemopreventive, and antiaging effects, among others. Nevertheless, its pharmacokinetic properties are less favorable, since the compound has poor bioavailability, low water solubility, and is chemically unstable. To overcome these problems, we developed two novel resveratrol nanodelivery systems based on lipid nanoparticles to enhance resveratrol's oral bioavailability for further use in medicines, supplements, and nutraceuticals. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) loaded with resveratrol were successfully produced by a modified hot homogenization technique. These were completely characterized to evaluate the quality of the developed resveratrol-loaded nanoparticles. Cryo-scanning electron microscopy morphology studies showed spherical and uniform nanoparticles with a smooth surface. An average resveratrol entrapment efficiency of ~70% was obtained for both SLNs and NLCs. Dynamic light scattering measurements gave a Z-average of 150-250 nm, polydispersity index of ~0.2, and a highly negative zeta potential of around -30 mV with no statistically significant differences in the presence of resveratrol. These characteristics remained unchanged for at least 2 months, suggesting good stability. Differential scanning calorimetry studies confirmed the solid state of the SLNs and NLCs at both room and body temperatures. The NLCs had a less ordered crystalline structure conferred by the inclusion of the liquid lipid, since they had lower values for phase transition temperature, melting enthalpy, and the recrystallization index. The presence of resveratrol induced a disorder in the crystal structure of the nanoparticles, suggesting a favoring of its entrapment. The in vitro release studies on conditions of storage showed a negligible resveratrol release over several hours for both nanosystems and the in vitro simulation of gastrointestinal transit showed that the resveratrol remained mostly associated with the lipid nanoparticles after their incubation in digestive fluids. Both nanodelivery systems can be considered suitable carriers for oral administration, conferring protection to the incorporated resveratrol and allowing a controlled release after uptake.

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Understanding how nanoparticles’ properties influence their cellular interactions is a bottleneck for improving the design of carriers. Macrophage polarization governs their active role in solving infections or tissue repair. To unravel the effect of carbohydrate-targeting mannose receptors on the macrophage surface, drug-free fucoidan/chitosan nanoparticles were functionalized using mannose (M) and mannan (Mn). Polyelectrolyte complex nanoparticles were obtained upon chitosan self-assembly using fucoidan. The functionalized nanoparticles were characterized in terms of their physicochemical characteristics, chemical profile, and carbohydrate orientation. The nanoparticles varied in size from 200 to 400 nm, were monodisperse, and had a stable negative zeta potential with a low aggregation tendency. The nonfunctionalized and functionalized nanoparticles retained their properties for up to 12 weeks. Cell viability and internalization studies were performed for all the designed nanoparticles in the THP-1 monocytes and THP-1-differentiated macrophages. The expression of the mannose receptor was verified in both immune cells. The carbohydrate-functionalized nanoparticles led to their activation and the production of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α. Both M- and Mn-coated nanoparticles modulate macrophages toward an M1-polarized state. These findings demonstrate the tailoring of these nanoplatforms to interact and alter the macrophage phenotype in vitro and represent their therapeutic potential either alone or in combination with a loaded drug for future studies.

This work aimed to design, develop, and characterize a lipid nanocarrier system for the selective delivery of rifabutin (RFB) to alveolar macrophages. Lipid nanoparticles, specifically nanostructured lipid carriers (NLC), were synthetized by the high-shear homogenization and ultrasonication techniques. These nanoparticles were designed to exhibit both passive and active targeting strategies to be efficiently internalized by the alveolar macrophages, traffic to the acidified phagosomes and phagolysosomes, and release bactericidal concentrations of the antituberculosis drug intracellularly. NLC that could entrap RFB were prepared, characterized, and further functionalized with mannose. Particles' diameter, zeta potential, morphology, drug% entrapping efficiency, and drug release kinetics were evaluated. The mannose coating process was confirmed by Fourier transform infrared. Further, the cytotoxicity of the formulations was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay in A549, Calu-3, and Raw 264.7 cells. The diameter of NLC formulations was found to be in the range of 175-213 nm, and drug entrapping efficiency was found to be above 80%. In addition, high storage stability for the formulations was expected since they maintained the initial characteristics for 6 months. Moreover, the drug release was pH-sensitive, with a faster drug release at acidic pH than at neutral pH. These results pose a strong argument that the developed nanocarrier can be explored as a promising carrier for safer and more efficient management of tuberculosis by exploiting the pulmonary route of administration.

Rheumatoid arthritis (RA) is the most common joint-related autoimmune disease and one of the most severe. Despite intensive investigation, the RA inflammatory process remains largely unknown and finding effective and long lasting therapies that specifically target RA is a challenging task. This study proposes a different approach for RA therapy, taking advantage of the new emerging field of nanomedicine to develop a targeted theranostic system for intravenous administration, using solid lipid nanoparticles (SLN), a biocompatible and biodegradable colloidal delivery system, surface-functionalized with an anti-CD64 antibody that specifically targets macrophages in RA. Methotrexate (MTX) and superparamagnetic iron oxide nanoparticles (SPIONs) were co-encapsulated inside the SLNs to be used as therapeutic and imaging agents, respectively. All the formulations presented sizes under 250 nm and zeta potential values lower than −16 mV, suitable characteristics for intravenous administration. Transmission electron microscopy (TEM) photographs indicated that the SPIONs were encapsulated inside the SLN matrix and MTX association efficiency values were higher than 98%. In vitro studies, using THP-1 cells, demonstrated that all formulations presented low cytotoxicity at concentrations lower than 500 μg/mL. It was proven that the proposed NPs were not cytotoxic, that both a therapeutic and imaging agent could be co-encapsulated and that the SLN could be functionalized for a potential future application such as anti-body specific targeting. The proposed formulations are, therefore, promising candidates for future theranostic applications.