Since ancient times, the use of natural compounds has been of great importance for medicine mainly in the prevention and treatment of different pathologies [1,2]. That is why they represent the main source of used compounds in the discovery and/or development of new drugs [3]. An example of natural compounds with bioactive potential is propolis, which is a resinous compound produced by bees from plants exudates. Studies both in vitro and in vivo have identified a wide variety of biological activities for propolis: antibacterial [4], antifungal [5], antioxidant [6], anti-inflammatory [7], anti-carcinogenic [8] and anti-angiogenic [9]. These activities are attributed to its polyphenols rich composition, molecules that present different biological properties: relaxing [10], antioxidant [11], antithrombotic [12], antiangiogenic [13], anti-inflammatory [14], anti-carcinogenic [15], among others. Biochemically, polyphenols are secondary metabolites exclusively synthesized by plants and their entire structure is based in one or more hydroxyl groups attached to an aromatic ring (benzene) [16]. Since the role of polyphenols in plants is related to growth, development and defense, they are found in leaves, fruits and seeds, as well as in a wide range of food of plant origin (vegetables, tea, cocoa, wine, etc.) [17]. Concerning to the presence and abundance of polyphenols in propolis, they are very variable due to their close dependence with the botanical origin of plants, climate, geographical location, year and time of collection [3,18,19]. Examples of this important dependence are the studies of three Brazilians, one Polish and one Chilean propolis. For the Brazilians propolis, Daleprane et al. [9] reported that artepellin C, pinocembrin and kampferol were the main components of green propolis; 3-hydroxy-8,9-dimethoxypterocarpane, medicarpine and daidezein were the main components of red propolis; and pinocembrin, phenyl ester of caffeic acid, quercetin and galangin were the main components of brown propolis. For the Polish propolis, Szliszka et al. [20] detected that was mainly composed by the flavonoids pinobanksin, chrysin and methoxyflavanone; and the phenolics acids coumarin, ferulic and caffeic. Finally, for the Chilean propolis with anti-atherogenic and anti-angiogenic activity [21], the main polyphenols detected in the ethanolic extract were caffeic acid (a phenolic acid) and pinocembrin (a flavonone) [22].Daily intake of polyphenols has multiple health benefits [23] because they reduce the risk of developing non-communicable diseases such as diabetes [11], cancer [24] and cardiovascular diseases [25]. In vivo studies reported that supplementation of the diet with persimmon extract rich in polyphenols maintains plasma lipid levels in hypercholesterolemic mice [26]; whereas the use of a mixture of resveratrol, CA and catechin significantly reduces the atheroma plaque in ApoE knockout mice [27]. Although the consumption of polyphenols contributes to the prevention of diseases, its oral administration without compound protection translates into a low efficiency at the action site. This is due to several factors such as concentration, binding site, chemical structure, stability in the gastrointestinal environment and aqueous solubility, which, in general, have a negative impact on absorption levels, metabolization degree, distribution throughout the body, life span and compound excretion [2,28]. Finally, the pharmacokinetics of polyphenols is also influenced by age, health status, intestinal microbiota and diet of patients, as well as by their oral antibiotic treatments [29,30]. All of the above is translated into different reports of low bioavailability of polyphenols, for example, 0.56–4.54 nmol/L for anthocyanins [31], 0.46–1.28 μmol/L for flavonones [32], and 37–60 nmol/L for phenolic acids [33].Due to the low bioavailability of polyphenols after oral intake, several strategies have been developed to improve the bioavailability and bioactivity of these compounds. One of them is the use of microparticles based on biomaterials whose main function is to protect and transport the entire biomolecule [34]. Concerning this, nanoporous silicon (nPSi), is an excellent biomaterial that has been successfully used for the controlled release of different drugs and biomolecules, due to its large surface area, porous structure, biocompatibility, biodegradability, bioresorbability and resistance to low pH [35,36,37]. Moreover, because of the versatility of its surface chemistry, different functionalization strategies routes have been explored in order to enhance the load and controlled release of drugs [38]. A refined technique is to embed polymers into their nanopores to form composites [39]. In this regard, β-cyclodextrin (βCD), which is a biocompatible and aqueous soluble molecule, has been successfully used in drug delivery applications. The wide application of βCD in this field is related to the possibility to form the “host-guest” complexation (βCD/drug) [40]; drugs are encapsulated into its lipophilic cavity structure, whereas its outer hydrophilic surface can be crosslinked with other molecules (i.e., citric acid), yielding a 3D-polymer network suitable for drug delivery applications. Therefore by combining a flexible and soft βCD polymer within the highly porous inorganic matrix of nPSi as substrate, both stability and control of drugs release can be improved, increasing their therapeutic potential by reducing their degradation before they reach the target tissues [40]. Based on this, we hypothesize that nPSi-βCD composite is a safe alternative system for oral administration of CA and Pin since it has no toxic effects on human cells. The aim of this work is to determine if nPSi-βCD microparticles are a suitable and safe material for the load and controlled release of caffeic acid (CA) and pinocembrin (Pin), two of the main components of a Chilean propolis with anti-atherogenic and anti-angiogenic activity. This study includes the synthesis and physicochemical characterizations of nPSi-βCD microparticles loaded or not with CA or Pin, their respective release profiles and the corresponding cytocompatibility tests for each polyphenol and composite.
https://www.mdpi.com/1999-4923/11/6/289/htm
Dina Guzmán-Oyarzo, Dulcineia S. P. Abdalla, Gonzalo Recio-Sánchez, Jacobo Hernández-Montelongo, Luis A. Salazar, Tanya Plaza
