Co-delivering of oleuropein and lentisk oil in phospholipid vesicles as an effective approach to modulate oxidative stress, cytokine secretion and promote skin regeneration

Oleuropein is a phenolic compound naturally occurring in Oleaceae, Cornales, and Gentianales family [1], while from the chemical point of view, it is an ester of elenolic acid and hydroxytyrosol (3, 4-dihydroxyphenylethanol), Fig. 1 [2].

It is present in high amount (up to 14 %) in the stem of olive tree and it is responsible for the bitter and spicy taste of extra virgin olive oil [1]. However, rather than in the fruit it is particularly concentrated in the leaves, reaching 60–90 mg/g of dried source [3]. Several studies confirmed the biological properties of oleuropein such as anti-inflammatory, antibacterial, antifungal, analgesic, antiallergic, radioprotective and anticarcinogenic [4], [5]. Like most of the polyphenols, oleuropein is a strong antioxidant, capable of counteracting reactive oxygen species (ROS), thanks to its ortho-diphenol group, which neutralizes ROS through the donation of hydrogen atoms, and stabilizes oxygen radicals by means of an intramolecular hydrogen bond [6]. Thanks to this activity, it inhibits the cascade of processes connected with oxidative stress and inflammation thus promoting skin homeostasis and repair when topically applied [7]. Indeed, the daily application, in in vivo models, of a cream containing oleuropein favoured the wound contraction and increased hydroxyproline and glutathione level over time [8], [9], [10]. Its beneficial properties can be improved by the synergic activity of other molecules with complementary chemical properties and biological activity. Indeed, in a previous study, the extract obtained from olive oil leaves and rich in oleuropein has been associated to tocopherol aiming at obtaining an effective system capable of alleviating the cardiac toxicity induced by doxorubicin in rats [11]. It was also associated with doxorubicin to potentiate its activity in the treatment of breast cancer [12]. An extract rich in oleuropein has been added to other phytocomplexes as well, to synergically attenuate hypertension and insulin resistance in rats [13].

In general, the association of different phytochemicals, to synergically or complementarily improve the efficacy, is a valuable strategy to design new and effective formulations. The same strategy can be applied to oleuropein, aiming at potentiating its effectiveness in the treatment of skin lesions, and the oil obtained from the berries of Pistacia lentiscus appears to be a good candidate considering its synergic ability to promote the repair of skin lesions and inhibit lipid oxidation and depletion of antioxidant defence enzymes [14]. This oil was commonly used in folk medicine for the treatment of scabies or topically to treat sores, wounds and burns [15], [16]. Its regenerative effect at skin level is especially related to its unsaponifiable fraction, predominantly hydrocarbons, monoterpenes and sesquiterpenes, associate with polyunsaturated fatty acids and polyphenols. The total amount of unsaturated fatty acid contained in the lentisk oil is 74 %, mainly represented by oleic acid (51 %), linoleic acid (21 %) and palmitic acid (24 %), while the most abundant terpenes are α-pinene, β-pinene, limonene, terpinen-4-ol and α-terpineol [17]. These monoterpenes act as cyclooxygenases, as they exert anti-inflammatory activity when orally and topically administered and reduce the levels of cytokines and proinflammatory proteins through the inhibition of the nuclear factor kB (NF-kB) pathway [18].

The association of oleuropein and lentisk oil in a unique formulation can be achieved by their simultaneous loading in phospholipid vesicles, as previously confirmed using other molecules [19]. In addition, these carriers have themselves anti-inflammatory effect and can stimulate cell proliferation, and, above all, they can simultaneously deliver several molecules with different physiochemical properties, improving their bioavailability, especially when topically used [20].

In the present work, to obtain an antioxidant, anti-inflammatory and regenerative effect, oleuropein and lentisk oil were combined and co-loaded in phospholipid vesicles tailored for the treatment of skin lesions. Liposomes were prepared and then modified by the addition of tween 80 or hyaluronic acid. Hyaluronic acid has been chosen thanks to its ability to interact with phosphatidylcholine on the bilayer surface leading the formation of immobilized vesicles [21], [22], while the choice of Tween 80 is mainly connected with its ability to improve the deformability of the vesicular bilayer, thus facilitating the deposition and passage of the bioactives into and through the skin [23], [24], [25].

The main physico-chemical properties of the vesicles (i.e., mean size, surface charge, entrapment efficiency) were evaluated. Formulations were freeze-dried with or without cryoprotectant to improve their stability on storage. Finally, a deep in vitro evaluation of the biological properties of these formulations was performed measuring their biocompatibility and efficacy to inhibit the production of proinflammatory markers, along with their ability to improve cell proliferation and migration in a wounded cell monolayer.

留言 (0)

沒有登入
gif