Encapsulation is a technique in which one or more ingredients are trapped within some form of matrix—microscopic or macroscopic, solid or liquid, homogenous or heterogenous. The encapsulated compound is considered the “active” part and the material from which the coating is made is called the “wall” or “carrier”. Usually, a delivery system can have nanometric (1–1000 nm) or micrometric (1–1000 μm) dimensions
[122]. There are three main reasons why Rv is encapsulated. First, this technique is needed to enhance oral bioavailability by increasing its solubility in gastrointestinal fluids, promoting its absorption by enterocyte cells, and reducing its metabolism prior to absorption. Second, the barrier to the low solubility of Rv in aqueous solutions must be overcome. Third, Rv needs to be protected from environmental factors that promote its chemical degradation such as ultraviolet light, pH, temperature, and oxygen
[123].
The main nanocarrier systems used in Rv encapsulation are solid lipid nanoparticles (SLNs), liposomes, niosomes, dendrimers, micelles, and nanocapsules (Figure 6).
SLNs are lipid-based delivery systems that occur in many sizes in the range from 30 to 1000 nm
[124]. Their structure includes a mix of solid lipids stabilized by surfactants in an aqueous media. SLNs and nanostructured lipid carriers (NLCs) loaded with Rv were successfully produced to improve the bioavailability of the compound. With a size between 150 and 250 nm and an almost uniform spherical shape, the nanoparticles demonstrated an Rv encapsulation efficiency of 70%
[125]. Rv-loaded SLNs (248 nm) were dissolved in distilled water and administered orally by gavage daily in rats with type 2 diabetes for 1 month. The results of the study showed an improvement in insulin resistance through the upregulation of SNARE protein complex, suggesting that this type of transport of the polyphenol may be a therapeutic method of interest
[126].
Another nanosystem that has gained attention in the scientific world consists of an aqueous core surrounded by one or more layers of phospholipids and cholesterol that form a lipid bilayer and are called liposomes
[127]. With a structure similar to that of cell membranes, this nanosystem is much more biocompatible than other synthetic materials. Moreover, its surface can be easily functionalized, for example with PEG, to facilitate targeted delivery
[127]. Rv-loaded liposomes showed promising results regarding their therapeutic potential when tested in vivo for the management of breast cancer
[128], glioblastoma
[129], hepatocellular carcinoma
[130], and Parkinson’s disease
[131]. In an experiment related to DR, 200 nm Rv-loaded nanoliposomal formulations showed prolonged antioxidant activity against oxidative stress for 24 h and reduced the glucose levels significantly in pancreatic β TC cells
[132].
Niosomes are vesicles consisting of an aqueous core enclosed within a non-ionic surfactant bilayer, thus forming a closed bilayer structure. They are similar to liposomes from a structural point of view, being a stable and less expensive alternative version of those
[133]. On the other hand, there is a possibility that the vesicles may fuse and the encapsulated drug may leak or be hydrolyzed. Moreover, the synthesis process of niosomal carriers is time-consuming and requires special equipment
[134]. Good ocular tolerance of Rv-loaded chitoniosomes formulation without any inflammatory response to the rabbit eyes was obtained by El-Haddad et al., 2021. With a therapeutic encapsulation efficiency of 85% and a size below 500 nm, they were tested
in vivo on adult male albino rabbits. The anti-inflammatory effects after 3 days of treatment revealed reduced gene expressions of TNFα and IL-6, down to 49% and 55% respectively, in the treated groups compared to the control group
[135].
Dendrimers are synthetic polymers with a layered structure and dimensions below 15 nm. Their surface can be easily conjugated with various drugs or nucleic acids
[136]. They are mainly used in the delivery of genes and drugs, having the advantage of being connected to liposomes, carbon nanotubes, or various nanoparticles. Dendrimers are biocompatible and can be easily eliminated from the body. In contrast, they may exhibit cytotoxicity that contributes to the destruction of normal cells
[127].
This system named micelles is made of amphipathic linear polymers formed spontaneously by self-assembly in water and a hydrophobic core in which the drug is encapsulated
[137]. With a size ranging from 20 to 100 nm, they have a low volume of distribution and accumulate in body areas with compromised vasculature where they behave like carrier systems for drug targeting as they can carry specific ligands on their surface
[138]. According to in vivo experiments, the level of expression of the inflammatory markers IL-6, TNFα, and COX-1 decreased significantly after treatment of the inflamed cornea with micelle ophthalmic solution containing resveratrol. At the same time, the mRNAs corresponding to the antioxidant enzymes SOD and haem oxygenase 1 (HO-1) and the protein SIRT1 increased significantly under the same experimental conditions
[139].
Nanocapsules are a commonly used delivery system that comes in various forms: polymeric nanocapsules, silica nanocapsules, and gold or silver nanocapsules. Due to the presence of numerous silanol groups on their surface, silica nanocapsules can be easily modified in order to have different functionalities
[140]. Gold and silver nanoparticles demonstrated good biocompatibility, with those below 50 nm diameter having the ability to cross the blood–brain barrier
[141]. Gold nanoparticles (AuNPs) containing Rv were administered orally on streptozotocin (STZ) induced diabetic rats for a period of 3 months (once/day with 200 or 300 mg / kg quantity of AuNPs in a volume of 1.5 mL/kg purified water). After this period, these AuNPs with an average size of 10 nm showed a reduction in the level of mRNA corresponding to VEGF-1, IL-6, Tumor Necrosis Factor (TNFα), Monocyte Chemotactic Proteins-1 (MCP-1), and Intercellular Adhesion Molecules-1 (ICAM-1). Furthermore, a reduction in Nf-kB phosphorylation was observed
[142]. Chitosan—pectin core—shell nanoparticles loaded with Rv have been tested for their antioxidant activity compared to free resveratrol and have shown better antioxidant potential. Additionally, the release of Rv from the nanosystem was obtained in the acidic pH of the stomach but also in the alkaline pH of the intestine for almost 30 h
[143]. In another example, the topical release of Rv from the natural seed butter (SLN) of
Theobroma grandiflorum was tested. Homogeneous nanospheres obtained with a size ranging from 150 nm to 200 nm demonstrated an Rv encapsulation efficiency of approximately 74% and an increase in antioxidant activity in a dose-dependent manner. Additionally, the release of polyphenols was done gradually, in 24 h, reaching 80.48 ± 12.20% Rv
[144]. Pure
trans-resveratrol nanoparticles with a mean size of 170 nm with an absolute bioavailability of 25.2%, tested on rats, were fabricated by a supercritical antisolvent (SAS) process
[145]. Reduction of intraocular pressure was demonstrated in a normotensive eye rabbit model following the application of Rv (1 mg/mL) chitosan nanoparticles with dimensions below 100 nm
[146]. The use of poly (lactic-co-glycolic-acid) nanoparticles was proposed for the delivery of resveratrol. The delivery system was efficient in reducing the expression of VEGF in ARPE-19 cells, and, therefore, could be a useful strategy for the treatment of neovascular AMD
[147]. Resveratrol-loaded mucoadhesive lecithin/chitosan nanoparticles were topically instilled into the lower conjunctival sac of the left eye of albino rabbits in order to test the lower drug retention to the eye’s anterior portion, an area of primary interest for the ocular drug delivery system. The nanoparticles had an average size of 163.3 nm and an RV encapsulation efficiency of 97.03%. By interacting with the mucus layer, these nanoparticles exerted a long-term release of the therapeutic agent
[148].
Microsystems are another category of Rv delivery systems that have been studied extensively in recent years (Figure 6). Like the nanosystems described above, they fall into several categories, each with its own characteristics, advantages, and disadvantages.
Drugs can be encapsulated in microparticles or microspheres with targeted delivery achieved by binding ligands to their surface. So far, much of the research conducted in this area has been focused on seeking biodegradable and biocompatible polymer materials
[149]. Both synthetic and natural polymers can be used individually or in different combinations to build the system’s walls
[150]. In terms of encapsulation techniques, there is a rich variety of approaches: the layer-by-layer (Lbl) technique, spray drying, freeze-drying, ionic gelation, co-precipitation, and coacervation
[151][152][153][154][155][156]. Lecithin-polysaccharide self-assembled microspheres with a dimension of 12 μm entrapped Rv with an efficiency of 92% and maintained an elevated bioavailability of the compound during in vitro simulated digestion
[157]. Rv can be added in gastro-resistant pectin-alginate-coated microcapsules with an encapsulation efficiency of 41.72% ± 1.92% and release efficiency of the compound of about 70% of the total, within 24 h and pH 7.4
[158]. An encapsulation efficiency of 96.8% was obtained for Rv entrapped between the walls of a polyelectrolyte multilayer system that was designed to be delivered inside retina-pigmented epithelial cells. Having a diameter of 3.5 μm, these microcarriers were monitored inside D407 retina-pigmented epithelial cells due to the fluorescent rhodamine 6G dye
[159]. Another fluorescent dye, fluorescein isothiocyanate, was introduced inside near-infrared (NIR) responsive polymeric microcapsules carrying resveratrol in tandem with gold nanobipyramids to observe the internalization process in D407 cells. These microcarriers, with a diameter of 2.5 μm, were able to release the therapeutic agent and showed no cytotoxicity toward the tested cells
[160].
Hydrogels, three-dimensional cross-linked networks of polymer chains, are potential materials for drug delivery owing to their similarity with extra cell matrix, softness, hydrophilicity, viscoelasticity, biodegradability, and biocompatibility. They can also be modified to respond to various stimuli such as light, temperature, pH, magnetic or electric field, pressure, or ionic power
[161]. Moreover, their toxicity is negligible
[162]. Rv was encapsulated in high molecular weight chitosan-based nanogels measuring approximately 140 nm and a round overall morphology. These nanogels were rapidly internalized in ARPE-19 cells where they showed no cytotoxicity and escaped from the endo/lysosomal acidic compartments, demonstrating their safety and applicability in ocular treatments
[163].
10. Conclusions and Future Perspectives
Despite the fact that there is a considerable number of studies that have investigated the therapeutic potential of Rv in the treatment of eye diseases, there is a gap between the scientific results that prevents the establishment of well-defined conclusions. It is necessary to focus on studies that have an experimental design in which the administered dose, treatment period, and adverse effects are well documented. Moreover, knowing the mechanism of action of Rv and its target molecules are other key aspects that must be taken into account to implement a successful treatment. In improving the stability and bioavailability of Rv there are different types of resveratrol delivery systems that have been manufactured and have succeeded.