Highlights

Although flavonones have beneficial effects in both cosmetic and medicinal treatments, they have low bioavailability and solubility. In that regard, nanotechnological formulations have been proposed to improve their efficacy.

This report is an overview of the most recent contributions on flavanones into nanosystems since there are few reports addressing these compounds into drug delivery systems for skin delivery.

This report could be useful in directing further research. Mainly to chronic skin diseases, more effective treatments are important to improve patients quality of life.

Introduction

Citrus fruits are a rich source of flavonoids, which are found in all parts of the plant body. In plant metabolism, these compounds provide protection against ultraviolet radiation, defense against pathogens. Also, flavonoids play a role as signaling molecules⁽¹⁾. More than a hundred flavonoids have been identified in citrus fruits, mainly flavonones. Glycosylated flavonones are more abundant than aglycone forms. The three most common aglycones are hesperetin, naringenin and eriodictyol. Glycoside flavonones are classified into rutinoside flavonones and neohesperidoside flavonones. Rutinoside flavanones include hesperidin (hesperitin rutinoside), narirutin (naringenin rutinoside), and eriocitrin (eriodictyol rutinoside) while neohesperidoside flavonones include neohesperidin (hesperitin neohesperidoside), naringin (narigenin neohesperidoside) and neoeriocitrin (eriodictyol neohesperidoside). Hesperidin and narutin are found in higher contents in sweet oranges, mandarins, tangors and lemons. Neohesperidoside flavones are related to bitter taste in some citrus species of which neohesperidin and neoeriocitrin highlights. Both are mostly found in grapefruit and sour oranges. On the other hand, hesperidin is the most abundant flavonoid in orange juice and its concentration can vary between 31 and 122 mg L^-1 depending on the cultivar^(1)-(3).

Plant phytochemicals are increasingly employed in the development of skin care products⁽⁴⁾, including flavonoids, with several health benefits, where antioxidant activity is one of the most important properties⁽⁵⁾. In Citrus species, flavonones are a valuable class of flavonoids due to anti-inflammatory and anti-tumor activity. Therefore, these compounds may be applied in the treatment of various skin disorders⁽⁶⁾. As nanotechnology improves formulations performance, plant compounds have been loaded into nanosystems⁽⁷⁾ to increase their solubility^(8),(9) and their skin penetration⁽¹⁰⁾. Hence, this review aims to arrange the current knowledge and state of the art of flavanones loaded in nanocarriers for cutaneous application, with an approach about limitations and challenges to be overcome in the development of phyto-nanomedicines.

Methods

The selection of articles was performed on a search for original articles covering flavanones in nanosystems for topical application, in the Scopus database. The articles were selected by searching for the terms: flavonoids AND nano* AND skin. A total of 300 articles were retrieved. Then, a second search was conducted for each flavanone by “searching within results” option of Scopus database, as shown in Figure 1.

Figure 1. Schematic representation of the search for articles in the Scopus database. 

The following inclusion criteria were employed:

1) a nanosystem containing either hesperidin, hesperitin, naringin or naringenin for cutaneous application; 2) articles written in english and published between 2018 and 2023; 3) reports approaching skin penetration or biological evaluation, 4) research articles.

The exclusion criteria included:1) articles prior to 2013; B) review articles, books, conference reviews, book chapters and conference papers reports; C) reports that do not address the use of flavanones in nanosystems, D) reports articles approaching solely with physicochemical characterization or optimization of nanoformulations.

Results

A total of 15 articles were selected after applying the inclusion criteria. Table 1 summarizes the flavonones loaded-nanocarriers for skin delivery, with emphasis to wound healing^(11)-(16). Naringenin^{(11),(12),(17)-(20)} and hesperidin^{(13)-(16),(21)} were the most encapsulated flavanones. Regard to nanocarrier, lipid carriers^{(12),(17),(19),(22)-(24))} are the most important ones.

Flavonones were applied for cosmetic or therapeutic purposes. In cosmetics, naringenin is the most important one. In this sense, association of physical sunscreens nanoparticles and naringenin nanoparticles improved photoprotection⁽¹⁸⁾ due to the ultraviolet scattering ability of lipid nanoparticles. Sunscreen use is essential for preventing skin diseases such as skin cancer⁽²⁵⁾. Besides, both hesperidin and naringenin had anti-aging activity. Hesperidin nanocrystals were able to chelate copper and zinc, important cofactors of enzymes related to skin aging⁽²¹⁾. In other report, sericin gel bearing naringenin microemulsions reduced ultraviolet radiation-induced wrinkles⁽¹⁹⁾.

About therapeutic purpose, flavonones in nanosystems are used for atopic dermatitis⁽¹⁷⁾ and for wound healing^{(11)-(13),(15),(16),(26)}. In the treatment of inflammatory skin diseases, naringenin may be employed to reduce inflammatory markers^(27),(28). Thereby, solid lipid nanoparticles containing linoleic acid, cyclosporine and naringenin were able to reduce inflammation due to the anti-inflammatory synergistic of these compounds⁽¹⁷⁾. Likewise, naringenin loaded in liposomes reduced skin edema indicating its anti-inflammatory activity⁽²³⁾. Beyond that, liposomes improved hesperitin ability to scavenge reactive oxygen radicals. As several skin diseases increase free radicals, an antioxidant approach would be very useful⁽²⁴⁾.

Besides, both naringenin^(11),(12) and hesperidin^(13)-(16) are designed for wound healing, mainly hesperidin^(13)-(16). In that regard, nanoemulsions⁽¹²⁾, dendrimers⁽¹⁶⁾, silver nanoparticles⁽¹⁵⁾ and nanofibers^(11),(13) promoted wound contraction^{(11)-(13),(16)} and reduction of inflammatory cells^{(12),(13),(15)}. Further, a greater cell migration and a greater expression of beta Fibroblastic Growth Factor (bFGF) was detected for hydrogels containing silver nanoparticles in which hesperidin was employed as a reducing agent. A greater cell migration and expression of bFGF are indicative of a better healing and improved re-epithelialization, respectively⁽¹⁵⁾.

Furthermore, a nanohybrid hydrogel bearing metallic nanoparticles, cysteine complexed with chitosan, naringenin, and cellulose, improved anti-cancer ability over skin cancer cell line regarding naringenin. Although naringenin itself had cytotoxic effect, it was lower than nanohybrid⁽²⁰⁾. Then, the naringenin loaded into nanotechnological formulations may be interesting in the treatment of cancer.

Discussion

Nanocarriers employed for flavanones encapsulation include inorganic and organic ones^(7),(15). Although the most employed nanocarriers are organic^{(12),(17),(18),(19),(21),(22),(29)}, silver nanoparticles stand as an inorganic nanocarrier employed mainly due to their antibacterial activity on wound healing^(15)). Among organic nanoparticles, elastic liposomes^(22),(24), solid lipid nanoparticles⁽¹⁷⁾, nanoemulsions⁽¹²⁾, microemulsions⁽¹⁹⁾, polymeric nanoparticles⁽¹⁸⁾, nanocrystals⁽²¹⁾, hybrid systems^(14),(20) were employed to load either hesperidin, hesperitin, naringenin or naringin. Lipid carriers are widely used due to their biocompatibility with biological tissues. Among them, elastic liposomes improve drug penetration into skin⁽³⁰⁾. In that regard, hesperitin loaded in proposomal gels had a higher in vitro release regarding to non-nanotechnological hesperidin gels. Proposomes are liposomes containing polyethylene glycol, as an agent promoting skin permeation⁽²⁴⁾. Moreover, ethosomes emulsions bearing ethanol and naringin had an improved skin deposition. The increased in vitro release and increased skin retention of nanotechnological formulations is a desired effect that directly correlates to formulation efficacy⁽²²⁾.

Flavanones would bring benefits in the treatment of several skin disorders such as atopic dermatitis skin aging because of its antioxidant ability. In addition, skin health maintenance could also be achieved as well as the prevention of aging-related diseases^(31),(32). Beyond that, use of sunscreen goes beyond an aesthetic purpose, as it prevents the development of skin cancer⁽³³⁾. Moreover, the improved wound healing is of importance mainly in diabetic patients whose healing ability is compromised⁽³⁴⁾. For wound healing purposes, nanofibers are worthed, nanometric-sized structures⁽³⁵⁾ resembling biological tissues⁽³⁶⁾.

Hybrid systems are obtained by a mixture of different types of particles. Then, a hybrid may be a nanoparticle system formed by both polymers and lipids⁽¹⁴⁾. Also, a nanohybrid may be a mixture of inorganic and organic nanoparticles⁽²⁰⁾. Hybrid systems are a trend in nanotechnology systems as they can present better performance than non-hybrid nanotechnology systems^(14),(20).

As previously mentioned, naringenin shows cytotoxic effect. However, this effect is concentration-dependent. In the development of formulations designed for cancer treatment, the use of naringenin in higher concentrations is desirable as changes in cell viability were shown naringenin in higher concentrations is desirable as changes in cell viability were shown⁽³⁷⁾. In this sense, nanofibers bearing higher naringenin contents reduced cell viability of human carcinoma-derived cell culture⁽¹¹⁾. On the other hand, the antioxidant⁽¹⁴⁾ and wound contraction ability⁽¹⁶⁾ of hesperidin loaded in nanocarriers also relies on hesperidin content. Unlike cancer, in both cases, it is important to maintain cell viability. Therefore, flavonones may be used for cancer or not-cancer disorders. Nevertheless, it is required to better establish the ideal dose in for each skin disorder treatment.

Conclusions

Flavanones have been loaded in different nanocarriers, with emphasis to lipids, polymeric and hybrid ones. The majority of applications are aimed at treating skin diseases. However, anti-aging activity and sunscreen properties has been reported for naringenin and naringin. Furthermore, anti-inflammatory, antitumoral and wound healing effects must be highlighted which makes flavanones interesting to inflammatory skin diseases, cancer and wound healing treatments. Therefore, there is a promising application of flavanones to the improvement of human health, despite their low solubility and low skin permeability. Hence, their loading into nanocarriers may enable an improved efficacy treatment.