Innovative delivery and release systems for antioxidants and other active substances in the treatment of cancer

Cancer is one of the major diseases leading to death worldwide, and the fight against the disease is still challenging. Cancer diseases are usually associated with increased oxidative stress and the accumulation of reactive oxygen and nitrogen species as a result of metabolic alterations or signaling aberrations. While numerous antioxidants exhibit potential therapeutic properties, their clinical efficiency against cancer is limited and even unproven. Conventional anticancer antioxidants and drugs have, among others, the great disadvantage of low bioavailability, poor targeting efficiency, and serious side effects, constraining their use in the fight against diseases. Here, we review the rationale for and recent advances in potential delivery systems that could eventually be employed in clinical research on antioxidant therapy in cancer. We also review some of the various strategies aimed at enhancing the solubility of poorly water-soluble active drugs, including engineered delivery systems such as lipid-based, polymeric, and inorganic formulations. The use of cyclodextrins, micro- and nanoemulsions, and thermosensitive smart liposomes as useful systems for the delivery and release of poorly aqueous-soluble drugs, improving their bioactivity and stability, is also addressed. We also provide some details on their formulation processes and their use in a variety of medical applications. Finally, we briefly cover a case study specifically focused on the use of delivery systems to minimize oral cancer and associated dental problems.Xunta de Galicia | Ref. ED431E 2018/07Universidade de Vigo | Ref. C11Universidade de Vigo | Ref. ABH1-V231Xunta de Galicia | Ref. ED431D 2017/1

Biochemistry of antioxidants: mechanisms and pharmaceutical applications

Natural antioxidants from fruits and vegetables, meats, eggs and fish protect cells from the damage caused by free radicals. They are widely used to reduce food loss and waste, minimizing lipid oxidation, as well as for their effects on health through pharmaceutical preparations. In fact, the use of natural antioxidants is among the main efforts made to relieve the pressure on natural resources and to move towards more sustainable food and pharmaceutical systems. Alternative food waste management approaches include the valorization of by-products as a source of phenolic compounds for functional food formulations. In this review, we will deal with the chemistry of antioxidants, including their molecular structures and reaction mechanisms. The biochemical aspects will also be reviewed, including the effects of acidity and temperature on their partitioning in binary and multiphasic systems. The poor bioavailability of antioxidants remains a huge constraint for clinical applications, and we will briefly describe some delivery systems that provide for enhanced pharmacological action of antioxidants via drug targeting and increased bioavailability. The pharmacological activity of antioxidants can be improved by designing nanotechnology-based formulations, and recent nanoformulations include nanoparticles, polymeric micelles, liposomes/proliposomes, phytosomes and solid lipid nanoparticles, all showing promising outcomes in improving the efficiency and bioavailability of antioxidants. Finally, an overview of the pharmacological effects, therapeutic properties and future choice of antioxidants will be incorporated.Fundação para a Ciência e Tecnologia | Ref. UIDB/50006/2020Fundação para a Ciência e Tecnologia | Ref. UIDP/50006/202

Adsorption of gallic acid, propyl gallate and polyphenols from Bryophyllum extracts on activated carbon

The adsorption of gallic acid (GA) and propyl gallate (PG) on activated carbon (AC) was studied as a function of the AC mass and temperature. Clean first order behavior was obtained for at least three half-lives and the equilibrium was reached after ∼4 h contact time. An increase in the temperature (T = 20–40 °C) increases their adsorption rate constant values (k1) by 2.5 fold but has a negligible effect on the amount of antioxidant adsorbed per mass of AC at equilibrium. We also analyzed the adsorption process of polyphenols from Bryophyllum extracts and ca 100% of the total amount of the polyphenols in the extract were adsorbed when using 7 mg of AC. Results can be explained on the basis of the Freundlich isotherm but do not fit the Langmuir model. Results suggest that the combination of emerging in vitro plant culture technologies with adsorption on activated carbon can be successfully employed to remove important amounts of bioactive compounds from plant extracts by employing effective, sustainable and environmental friendly proceduresXunta de Galicia | Ref. ED431D 2017/18Xunta de Galicia | Ref. ED431E 2018/07Ministerio de Educación, Cultura y Deporte | Ref. FPU15/04849Xunta de Galicia | Ref. POS-B/2016/01

Control of antioxidant efficiency of chlorogenates in emulsions: modulation of antioxidant interfacial concentrations

BACKGROUND Controlling the interfacial concentrations of antioxidants (AOs) in oil-in-water emulsions can be regarded as a unique approach for increasing the efficiency of AOs in inhibiting the oxidation of lipids. Classical methods to determine the AO distribution in binary systems cannot be employed and their distribution needs to be assessed in the intact emulsion. RESULTS We have employed a well-established kinetic method to determine the distribution of a homologous series of AOs derived of chlorogenic acid in olive oil-in-water emulsions and analyse the effects of AO hydrophobicity on their distributions and their efficiencies. Results indicate that variations in the efficiency of chlorogenates in emulsions are due to differences in their interfacial concentrations. Their interfacial concentrations AO(I) were much higher (20- to 150-fold) than their stoichiometric concentrations. On the other hand, their concentrations in the oil region were 1.5- to 0.1-fold. Results also show the complex effect of the oil-to-water ratio employed in the preparation of the emulsions on the (AO(I)) values. CONCLUSION Results highlight the key role of the interfacial region and of its composition (interfacial AO molarity, emulsifier concentration, oil-to-water ratio) in interpreting the efficiency of AOs in inhibiting lipid oxidation in emulsions. Thus, a careful modulation of these parameters is necessary to ensure optimum AO efficiency. (c) 2019 Society of Chemical IndustryFinancial support of the following institutions is acknowledged: FEDER (COMPETE) and FCT - Fundação para a Ciência e a Tecnologia (UID/QUI/50006/2013 - POCI-01-0145-FEDER-007265 and UID/QUI/00686/2016), Xunta de Galicia (10TAL314003PR and Programa de axudas a etapa posdoutoral), Ministerio de Educacion y Ciencia (CTQ2006-13969-BQU) and the Universities of Vigo and Porto. SL-B thanks Xunta de Galicia for a postdoctoral grant (POS-B/2016/012) and MC thanks FCT for the doctoral grant (SFRH/BD/100889/2014)

Effects of the reactive moiety of phenolipids on their antioxidant efficiency in model emulsified systems

Our previous research was focused on the effects of hydrophobicity on the antioxidant (AO) efficiency of series of homologous antioxidants with the same reactive moieties. In this work we evaluate the antioxidant efficiency of hydrophobic phenolipids in 4:6 olive oil-in-water emulsions, with different phenolic moieties (derived from caffeic, 4-hydroxycinnamic, dihydrocaffeic acids, tyrosol and hydroxytyrosol), with alkyl chains of 8 and 16 carbons, and compare the antioxidant efficiency with that of the parent compounds. All catecholic phenolipids, in particular the C8 derivatives, have proven to be better antioxidants for the oxidative protection of emulsions than their parental compounds with octyl dihydrocafffeate being the most efficient (16-fold increase in relation to the control). To understand the importance of some factors on the antioxidant efficiency of compounds in emulsions, Pearson’s correlation analysis was carried out between antioxidant activity and the first anodic potential (Epa), reducing capacity (FRAP value), DPPH radical scavenging activity (EC50) and the concentration of antioxidants in each region of the emulsified system. Results confirm the importance of the effective concentration of AOs in the interfacial region (AOI) (ρ = 0.820) and of the Epa (ρ = −0.677) in predicting their antioxidant efficiency in olive oil-in-water emulsions.Research was funded by FCT/MCTES (UIDB/QUI/50006/2020; PTDC/OCE-ETA/32492/ 2017–POCI-01-0145-FEDER-032492; doctoral grant SFRH/BD/100889/2014), FCT and REQUIMTELAQV for a post-doc fellowship (PTDC/OCE- ETA/32492/2017), Xunta de Galicia (10TAL314003PR), the University of Vigo (postdoctoral grant-Talent Recruitment Program 2018) and the IACOBUS 2019 program. The manuscript was prepared during a sabbatical leave of C. B.-D., supported by the University of Vigo

Distributions of α- and δ-TOCopherol in Intact Olive and Soybean Oil-in-Water Emulsions at Various Acidities: A Test of the Sensitivity of the Pseudophase Kinetic Model

During the last years, the formalism of the pseudophase kinetic model (PKM) has been successfully applied to determine the distributions of antioxidants and their effective interfacial concentrations, and to assess the relative importance of emulsion and antioxidant properties (oil and surfactant nature, temperature, acidity, chemical structure, hydrophilic-liphophilic balance (HLB), etc.) on their efficiency in intact lipid-based emulsions. The PKM permits separating the contributions of the medium and of the concentration to the overall rate of the reaction. In this paper, we report the results of a specifically designed experiment to further test the suitability of the PKM to evaluate the distributions of antioxidants among the various regions of intact lipid-based emulsions and provide insights into their chemical reactivity in multiphasic systems. For this purpose, we employed the antioxidants α- and δ-TOCopherol (α- and δ-TOC, respectively) and determined, at different acidities well below their pKa, the interfacial rate constants kI for the reaction between 16-ArN2+ and α- and δ-TOC, and the antioxidant distributions in intact emulsions prepared with olive and soybean oils. Results show that the effective interfacial concentration of δ-TOC is higher than that of α-TOC in 1:9 (v/v) soybean and 1:9 olive oil emulsions. The effective interfacial concentrations of tocopherols are much higher (15-96-fold) than the stoichiometric concentrations, as the effective interfacial concentrations of both δ-TOC and α-TOC in soybean oil emulsions are higher (2-fold) than those in olive oil emulsions. Overall, the results demonstrate that the PKM grants an effective separation of the medium and concentration effects, demonstrating that the PKM constitutes a powerful non-destructive tool to determine antioxidant concentrations in intact emulsions and to assess the effects of various factors affecting them.Universidade de Vigo | Ref. C11Ministério da Ciência, Tecnologia e Ensino Superior | Ref. UIDB/50006/2020Ministério da Ciência, Tecnologia e Ensino Superior | Ref. UIDP/50006/202

Polyphenols as antioxidants for extending food shelf-life and in the prevention of health diseases: encapsulation and interfacial phenomena

Toxicity caused by the exposure to human-made chemicals and environmental conditions has become a major health concern because they may significantly increase the formation of reactive oxygen species (ROS), negatively affecting the endogenous antioxidant defense. Living systems have evolved complex antioxidant mechanisms to protect cells from oxidative conditions. Although oxidative stress contributes to various pathologies, the intake of molecules such as polyphenols, obtained from natural sources, may limit their effects because of their antioxidant and antimicrobial properties against lipid peroxidation and against a broad range of foodborne pathogens. Ingestion of polyphenol-rich foods, such as fruits and vegetables, help to reduce the harmful effects of ROS, but the use of supramolecular and nanomaterials as delivery systems has emerged as an efficient method to improve their pharmacological and therapeutic effects. Suitable exogenous polyphenolic antioxidants should be readily absorbed and delivered to sites where pathological oxidative damage may take place, for instance, intracellular locations. Many potential antioxidants have a poor bioavailability, but they can be encapsulated to improve their ideal solubility and permeability profile. Development of effective antioxidant strategies requires the creation of new nanoscale drug delivery systems to significantly reduce oxidative stress. In this review we provide an overview of the oxidative stress process, highlight some properties of ROS, and discuss the role of natural polyphenols as bioactives in controlling the overproduction of ROS and bacterial and fungal growth, paying special attention to their encapsulation in suitable delivery systems and to their location in colloidal systems where interfaces play a crucial role.Fundação para a Ciência e a Tecnologia | Ref. UID / QUI / 50006/2019Fundação para a Ciência e a Tecnologia | Ref. POCI-01-0145-FEDER-032492Fundação para a Ciência e a Tecnologia | Ref. SFRH / BD / 100889/2014Xunta de Galicia | Ref. 10TAL314003P

Plant Antioxidants in Food Emulsions

Addition of free radical scavenging antioxidants (AOs) is one of practical strategies controlling the oxidative stability in food emulsions. Attention has been directed toward AOs derived from natural plant extracts with the capacity to improve health and well-being due to lack of consumers’ trust toward synthetic antioxidant in food. Nevertheless, antioxidant efficiency varies widely from one compound to another and the most abundant AOs in our diet are not necessarily those that have the best availability profile at the reaction place with free radicals. In this book chapter, we will provide a state-of-the-art summary of the uses of plant AOs in colloidal systems, ranging from their main structural features to their benefits for the human health and their antioxidant role in controlling the oxidative stress and, particularly, the oxidation of lipid-based food emulsions

Plant antioxidants in food emulsions

Addition of free radical scavenging antioxidants (AOs) is one of practical strategies controlling the oxidative stability in food emulsions. Attention has been directed toward AOs derived from natural plant extracts with the capacity to improve health and well-being due to lack of consumers’ trust toward synthetic antioxidant in food. Nevertheless, antioxidant efficiency varies widely from one compound to another and the most abundant AOs in our diet are not necessarily those that have the best availability profile at the reaction place with free radicals. In this book chapter, we will provide a state-of-the-art summary of the uses of plant AOs in colloidal systems, ranging from their main structural features to their benefits for the human health and their antioxidant role in controlling the oxidative stress and, particularly, the oxidation of lipid-based food emulsions.Xunta de Galicia | Ref. ED431D-2017/18Ministerio de Educación y Ciencia | Ref. CTQ2006-13969-BQUMinisterio de Educación, Cultura y Deporte | Ref. FPU15/04849Xunta de Galicia | Ref. POS-B/2016/01