Plant-Derived Polyphenols to Prevent and Treat Oral Mucositis Induced by Chemo- and Radiotherapy in Head and Neck Cancers Management.

Oral Mucositis (OM) is the most common side effect due to chemotherapy and radiotherapy, which are the conventional treatment options for head and neck cancers. OM is a severe inflammatory condition characterized by multifactorial etiopathogenesis. It further negatively affects patients' quality of life by severe impairment of normal oral functions. Consequently, it is mandatory to identify new effective therapeutic approaches to both prevent and treat OM while also avoiding any recurrence. Polyphenols recently attracted the interest of the scientific community due to their low toxicity and wide range of biological activities making them ideal candidates for several applications in the odontostomatological field, particularly against OM. This review collects the in vivo studies and the clinical trials conducted over the past 13 years evaluating the preventive and curative effects of several polyphenolic compounds towards chemo- and radiotherapy-induced OM, both when administered alone or as a plant-extracted phytocomplex. The literature fully confirms the usefulness of these molecules, thus opening the possibility of their clinical application. However, polyphenol limitations (e.g., unfavourable physicochemical properties and susceptibility to degradation) have emerged. Consequently, the interest of the scientific community should be focused on developing innovative delivery systems able to stabilize polyphenols, thus facilitating topical administration and maximizing their efficacy.

Multicomponent Antibiofilm Lipid Nanoparticles as Novel Platform to Ameliorate Resveratrol Properties: Preliminary Outcomes on Fibroblast Proliferation and Migration.

The well-being of skin and mucous membranes is fundamental for the homeostasis of the body and thus it is imperative to treat any lesion quickly and correctly. In this view, polyphenols might assist and enhance a successful wound healing process by reducing the inflammatory cascade and the production of free radicals. However, they suffer from disadvantageous physico-chemical properties, leading to restricted clinical use. In this work, a complex mixture of PEGylated lipid, Glyceryl monoester, 18-ß-Glycyrrhetinic Acid and Menthol was designed to entrap Resveratrol (RSV) as the active ingredient and further produce lipid nanoparticles (LNPs) by homogenization followed by high-frequency sonication. The nanosystem was properly characterized in terms of particle size (DLS, SEM), zeta potential, drug loading, antioxidant power (DPPH), release behaviour, cytocompatibility, wound healing and antibiofilm properties. The optimized lipid mixture was homogeneous, melted at 57-61 °C and encapsulated amorphous RSV (4.56 ± 0.04% w/w). The RSV-loaded LNPs were almost monodispersed (PDI: 0.267 ± 0.010), with nanometric size (162.86 ± 3.12 nm), scavenger properties and suitable DR% and LE% values (96.82 ± 1.34% and 95.17 ± 0.25%, respectively). The release studies were performed to simulate the wound conditions: 1-octanol to mimic the lipophilic domains of biological tissues (where the First Order kinetic was observed) and citrate buffer pH 5.5 according to the inflammatory wound exudate (where the Korsmeyer-Peppas kinetic was followed). The biological and microbiological evaluations highlighted fibroblast proliferation and migration effects as well as antibiofilm properties at extremely low doses (LNPs: 22 µg/mL, corresponding to RSV 5 µM). Thus, the proposed multicomponent LNPs could represent a valuable RSV delivery platform for wound healing purposes.

Chemopreventive and Anticancer Role of Resveratrol against Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most prevailing and aggressive head and neck cancers, featuring high morbidity and mortality. The available conventional treatments suffer from several adverse effects and are often inefficient in terms of their survival rates. Thus, seeking novel therapeutic agents and adjuvants is of the utmost importance for modern society. Natural polyphenolic compounds have recently emerged as promising chemopreventive and anticancer agents. Specifically, the natural compound resveratrol (RSV) has recently gained momentum for this purpose. RSV is useful for treating OSCC due to its antiproliferative, antimetastatic, and proapoptotic effects. Additionally, RSV acts against tumor cells while synergically cooperating with chemotherapeutics, overcoming drug resistance phenomena. Despite these wide-spectrum effects, there are few specific investigations regarding RSV's effects against OSCC animal models that consider different routes and vehicles for the administration of RSV. Interestingly, an injectable RSV-loaded liposome-based formulation was proven to be effective against both in vitro and in vivo OSCC models, demonstrating that the development of RSV-loaded drug delivery systems for systemic and/or loco-regional applications may be the turning point in oral cancer treatment, leading to benefits from both RSV's properties as well as from targeted delivery. Given these premises, this review offers a comprehensive overview of the in vitro and in vivo effects of RSV and its main derivative, polydatin (PD), against OSCC-related cell lines and animal models, aiming to guide the scientific community in regard to RSV and PD use in the treatment of oral precancerous and cancerous lesions.

Green Extraction of Polyphenols from Waste Bentonite to Produce Functional Antioxidant Excipients for Cosmetic and Pharmaceutical Purposes: A Waste-to-Market Approach.

In an ever-growing perspective of circular economy, the development of conscious, sustainable and environmental-friendly strategies to recycle the waste products is the key point. The scope of this work was to validate the waste bentonite from the grape processing industries as a precious matrix to extract polyphenols by applying a waste-to-market approach aimed at producing novel functional excipients. The waste bentonite was recovered after the fining process and opportunely pre-treated. Subsequently, both the freeze dried and the so-called "wet" bentonites were subjected to maceration. PEG200 and Propylene Glycol were selected as solvents due to their ability to dissolve polyphenols and their wide use in the cosmetic/pharmaceutical field. The extracts were evaluated in terms of yield, density, pH after water-dilution, total phenolic (Folin-Ciocalteu) and protein (Bradford) contents, antioxidant power (DPPH), amount of some representative polyphenols (HPLC-DAD), cytocompatibility and stability. Both solvents validated the bentonite as a valuable source of polyphenols and led to colored fluids characterized by an acidic pH after water-dilution. The best extract was obtained from the wet bentonite with PEG200 and highlighted the highest phenolic content and consequently the strongest antioxidant activity. Additionally, it displayed proliferative properties and resulted almost stable over time. Hence, it might be directly used as polyphenols-enriched functional novel raw material for cosmetic and pharmaceutics purposes.

Buccal Thin Films as Potent Permeation Enhancers for Cytisine Transbuccal Delivery.

Cytisine (CYT) is a powerful anti-smoking compound which could greatly benefit from transbuccal delivery because of both its unfavorable pharmacokinetics after oral administration and its intrinsic ability to permeate the buccal mucosa. This work aims to design CYT-loaded buccal thin films suitable for transbuccal drug delivery due to its capability of promoting the interaction between CYT and the buccal membrane. The solvent casting method was employed to prepare several thin films combining various excipients such as matrixing polymers, mucoadhesion agents, plasticizers and other compounds as humectants and sweeteners, component ratios and solvents. A total of 36 compositions was prepared and four of them emerged as the most promising in terms of aspect and flexibility. They all demonstrated homogeneity, thinness, low swelling degree, and controlled drug release according to the Power Law and Peppas-Sahlin mathematical models. Mainly, they proved able to interact with the ex vivo porcine buccal mucosa producing mucoadhesive effects, and act as potent permeation enhancers. In particular, Film B emerged as suitable as it produced a 10.6-fold Kp enhancement and a great Js value (52.33 µg/cm2·h-1), even when compared to highly concentrated CYT solutions.

Spray-Dried Cytisine-Loaded Matrices: Development of Transbuccal Sustained-Release Tablets as a Promising Tool in Smoking Cessation Therapy.

Cytisine (CYT) has emerged as a promising molecule to treat nicotine addiction, since it acts as a partial agonist of nicotinic acetylcholine receptors. However, its unfavorable pharmacokinetic properties lead to multiple administrations per day, reducing the patient's compliance and increasing the side effects. To overcome these drawbacks, CYT buccal administration is here proposed. Firstly, CYT stability in the buccal environment was assessed and its intrinsic ability to permeate/penetrate the tissue was determined by applying CYT solutions at increasing concentrations. Furthermore, a spray-drying method was selected and optimized as it is an eco-friendly, easily scalable and effective technique to obtain uniform and reproducible CYT-loaded (5% w/w) pharmaceutical powders, which were directly compressed, thus obtaining different buccal delivery systems (BDSs). The obtained BDSs were homogeneous and reproducible and embedded CYT in its amorphous form. The mechanism of CYT release was evaluated in vitro and found to be mainly driven by a Fickian diffusion phenomenon. Predominantly, the ex vivo permeation assays highlighted the ability of the BDSs to enhance CYT permeation, also producing high drug fluxes through the mucosa. Speculative mathematical evaluations based on the already-known CYT pharmacokinetic parameters showed that CYT-loaded BDSs could potentially be sufficient to obtain a therapeutic effect, thus making the reported formulations suitable candidates for further in vivo trials.

Improvement of Resveratrol Permeation through Sublingual Mucosa: Chemical Permeation Enhancers versus Spray Drying Technique to Obtain Fast-Disintegrating Sublingual Mini-Tablets.

Resveratrol (RSV) is a natural polyphenol with several interesting broad-spectrum pharmacological properties. However, it is characterized by poor oral bioavailability, extensive first-pass effect metabolism and low stability. Indeed, RSV could benefit from the advantage of the sublingual route of administration. In this view, RSV attitudes to crossing the porcine sublingual mucosa were evaluated and promoted both by six different chemical permeation enhancers (CPEs) as well as by preparing four innovative fast-disintegrating sublingual mini-tablets by spray drying followed by direct compression. Since RSV by itself exhibits a low permeation aptitude, this could be significantly enhanced by the use of CPEs as well as by embedding RSV in a spray-dried powder to be compressed in order to prepare fast-disintegrating mini-tablets. The most promising observed CPEs (menthol, lysine and urea) were then inserted into the most promising spray-dried excipients' compositions (RSV-B and RSV-C), thus preparing CPE-loaded mini-tablets. However, this procedure leads to unsatisfactory results which preclude the possibility of merging the two proposed approaches. Finally, the best spray-dried composition (RSV-B) was further evaluated by SEM, FTIR, XRD and disintegration as well as dissolution behavior to prove its effectiveness as a sublingual fast-disintegrating formulation.

Antibacterial PEGylated Solid Lipid Microparticles for Cosmeceutical Purpose: Formulation, Characterization, and Efficacy Evaluation.

The development of efficacious means of delivering antioxidant polyphenols from natural sources for the treatment of skin diseases is of great interest for many cosmetic and pharmaceutical companies. Resveratrol (RSV) and Limonene (LIM) have been shown to possess good anti-inflammatory and antibacterial properties against Staphylococcus aureus infections responsible for many skin disorders, such as acne vulgaris. In this study, solid lipid microparticles are designed as composite vehicles capable of encapsulating a high amount of trans-RSV and enhancing its absorption through the stratum corneum. A microparticulate system based on mixture of PEGylate lipids, long-chain alcohols and LIM is able to entrap RSV in an amorphous state, increasing its half-life and avoiding inactivation due to isomerization phenomena, which represents the main drawback in topical formulations. Particles have been characterized in term of shape, size distribution and drug loading. Antimicrobial tests against S. aureus have highlighted that empty microspheres possess per se antimicrobial activity, which is enhanced by the presence of LIM, demonstrating that they can represent an interesting bactericide vehicle for RSV administration on the skin.