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Stability, biocompatibility and antioxidant activity of PEG-modified liposomes containing resveratrol
Abstract
The present investigation reports the development of PEG-modified liposomes for the delivery of naturally occurring resveratrol. PEG-modified liposomes were prepared by direct sonication of the phospholipid aqueous dispersion, in the presence of two PEG-surfactants. Small, spherical, unilamellar vesicles were produced, as demonstrated by light scattering, cryo-TEM, and SAXS. The aging of the vesicles was assessed by using the Turbiscan® technology, and their physical stability was evaluated in vitro in simulated body fluids, results showing that the key features of the liposomes were preserved. The biocompatibility of the formulations was demonstrated in an ex vivo model of hemolysis in human erythrocytes. Further, the incorporation of resveratrol in PEG-modified liposomes did not affect its intrinsic antioxidant activity, as DPPH radical was almost completely inhibited, and the vesicles were also able to ensure an optimal protection against oxidative stress in an ex vivo human erythrocytes-based model. Therefore, the proposed PEG-modified liposomes, which were prepared by a simple and reliable method, represent an interesting approach to safely deliver resveratrol, ensuring the preservation of the carrier structural integrity in the biological fluids, and the antioxidant efficacy of the polyphenol to be exploited against oxidative stress associated with cancer.
... The scattering vector was calibrated by measuring the standard silver behenate. The scattering curves were recorded every 20 min up to 2 h, the appropriate background was subtracted, and the results were analyzed using a home-made fitting procedure based on a Gaussian description of the bilayers and using a Levenberg-Marquardt minimization scheme [24][25][26][27][28] that includes the pertinent smearing corrections. ...
... A deeper structural characterization was performed by means of SAXS analyses. The SAXS profiles of liposomes and PG-PEVs (Figures 3 and 4), together with the fits of the lamellar model, showed electronic density profiles typical of bilayers, as described in the literature [24,25,27,28]. The main parameters derived from the fits are reported in Table 7. sentative images of PG-PEVs are shown in Figure 2. ...
... A deeper structural characterization was performed by means of SAXS analyses. The SAXS profiles of liposomes and PG-PEVs (Figures 3 and 4), together with the fits of the lamellar model, showed electronic density profiles typical of bilayers, as described in the literature [24,25,27,28]. The main parameters derived from the fits are reported in Table 7. ...
The nanoformulation of plant extracts in phospholipid vesicles is a promising strategy to exploit the biological properties of natural bioactive substances and overcome drawbacks such as poor aqueous solubility, chemical instability, low skin permeation and retention time, which strongly limit their topical application. In this study, Prunus spinosa berries were used for the preparation of a hydro-ethanolic extract, which showed antioxidant and antibacterial properties owing to the presence of phenolic compounds. Two types of phospholipid vesicles were developed to improve the applicability as topical formulations. Liposomes and Penetration Enhancer-containing Vesicles were characterized for mean diameter, polydispersity, surface charge, shape, lamellarity, and entrapment efficiency. Additionally, their safety was assayed with different cell models, including erythrocytes and representative skin cell lines.
... [97] Furthermore, the development and optimization of liposomes modified with polyethylene glycol (PEG) and Quercetin encapsulated with chitosan or lecithin polymeric nanoparticles have resveratrol properties. [98] Another study suggested that Eudragit coated liposomes are efficient vesicle systems for quercetin integration, retention, and transport. Adding the Eudragit coating to liposomes boosted their physical stability under simulated gastrointestinal conditions (acidic pH and high ionic strength). ...
... [64] The suggested technique has the potential for therapeutic applications against oxidative stress, providing promising prospects for using resveratrol PEG-modified liposomes in vivo, with a particular emphasis on increasing the shelf life in blood circulation. [98] Although, more literature is needed to elaborate on the antioxidant potential of liposomes-based drug delivery systems in the treatment of chronic disorders. ...
The target delivery of sensitive components to get the intended benefits is a challenge for the global food industry. One of the principal strategies used to boost individualized absorptivity, nutrient stability, and enhanced food quality is the application of liposomal systems in the food industry, which allows controlled release of bioactive compounds. Lipid-oriented encapsulation strategies such as liposomes are superior for encapsulating sensitive components, increasing product solubility and bioavailability, and accurately targeting encapsulated content in food and nutraceutical production. In this review, the nature, composition, and different methodologies for the preparation of liposomes, such as the Bangham Method, ethanol injection method, microfluidic channel method, and freeze-drying method summarized. Moreover, the crucial role of liposomes in delivering sensitive bioactive compounds to cure different health maladies has been emphasized.
... Studies have shown that PEG-modified liposomes could maintain most of the dose in the blood (Panwar et al., 2010). For example, in the study of Caddeo et al. (2018), resveratrol is delivered via PEG-modified liposomes, and it was found that the stability and antioxidant effect of PEG-modified liposomes were superior to the conventional liposomes. Besides, PEG-modified liposomes can maintain structural stability and functional traits for 2 months at 4−8 • C, and it still showed the antioxidant activity of red blood cells after incubation at 37 • C for 4 h (Caddeo et al., 2018). ...
... For example, in the study of Caddeo et al. (2018), resveratrol is delivered via PEG-modified liposomes, and it was found that the stability and antioxidant effect of PEG-modified liposomes were superior to the conventional liposomes. Besides, PEG-modified liposomes can maintain structural stability and functional traits for 2 months at 4−8 • C, and it still showed the antioxidant activity of red blood cells after incubation at 37 • C for 4 h (Caddeo et al., 2018). PEG can also be combined with other trimmers to modify liposomes and give them special functions. ...
Liposomes have become a research hotspot in recent years as food delivery systems with attractive properties, including the bilayer structure assembled like the cell membrane, reducing the side‐effect and improving environmental stability of cargos, controlling release, extending duration of functional ingredients, and high biodegradable and biocompatible abilities in the body. However, the conventional liposomes lack stability during storage and are weak in targeted absorption in the gastrointestinal track. At present, surface modification has been approved to be an effective platform to shield these barricades and help liposomes deliver the agents safely and effectively to the ideal site. In this review, the gastrointestinal stability of conventional liposomes, cargo release models from liposomes, and the biological fate of the core materials after release were emphasized. Then, the strategies in both physical and chemical perspectives to improve the stability and utilization of liposomes in the gastrointestinal tract, and the emerging approaches for improving gut targeting by specifically modified liposomes and the intestinal receptors relative to liposomes/cargos absorption were highlighted. Last but not the least, the safety, challenges, and opportunities for the improvement of liposomal bioavailability were also discussed to inspire new applications of liposomes as oral carriers.
... Once verified that there is no drift in the measurements, those spectra are summed and the resultant is background subtracted (water in this case) and scaled to absolute intensity by comparison with the water intensity. SAXS patterns were analyzed using a home-made fitting procedure based on a Gaussian description of the bilayers and using a Levenberg-Marquardt minimization scheme [21][22][23][24][25][26] and using a sphere or ellipsoid core-shell description for the micellar surfactants. ...
... Polar hydrogen atoms were introduced to the constructed protein structure to correct ionization and tautomeric states of amino acid residues [35]. AutoGrid was used to prepare the geometry of the binding site by employing a grid box with 14 (20,62,24) points that enclose the original ligand (CPS), and the box spacing was 0.37 Å. All parameters were set to their default values in Autodock Tools 1.5.4 44 [32]. ...
Cationic surfactants based on phenylalanine (CnPC3NH3Cl) and tryptophan (CnTC3NH3Cl) were synthesized using renewable raw materials as starting compounds and a green synthetic procedure. The synthesis, acid-base equilibrium, aggregation properties, and antibacterial activity were investigated. Conductivity and fluorescence were used to establish critical micelle concentrations. Micellization of CnPC3NH3Cl and CnTC3NH3Cl occurred in the ranges of 0.42-16.2 mM and 0.29-4.6 mM, respectively. Since those surfactants have some acidic character, the apparent pKa was determined through titrations, observing increasing acidity with increasing chain length and being slightly more acidic with the phenylalanine than the tryptophan derivatives. Both families showed promising antibacterial efficacy against eight different bacterial strains. Molecular docking studies against the enzyme peptidoglycan glycosyltransferase (PDB ID:2OQO) were used to investigate the potential binding mechanism of target surfactant molecules. According to small angle X-ray scattering (SAXS) results, the surfactants incorporate into DPPC (Dipalmitoyl Phosphatidyl Choline) bilayers without strong perturbation up to high surfactant concentration. Some of the C12TC3NH3Cl/DPPC formulations (40%/60% and 20%/80% molar ratios) exhibited good antibacte-rial activity, while the others were not effective against the tested bacteria. The strong affinity between DPPC and surfactant molecules, as determined by the DFT (density functional theory) method, could be one of the reasons for the loss of antibacterial activity of these cationic surfactants when they are incorporated in vesicles.
... In addition, the stability of the PEG-liposomes was evaluated in a simulated biological fluid. Hanks' solution is commonly used to simulate body fluids, as it contains inorganic salts and glucose that confer a similar osmotic pressure as that of intercellular fluids [15]. PEG-liposomes remained essentially unaltered after dilution and incubation for 24 h with Hank's solu- The PEG-liposomes were monitored during storage by evaluating the mean diameter, polydispersity, and zeta potential. ...
... In addition, the stability of the PEG-liposomes was evaluated in a simulated biological fluid. Hanks' solution is commonly used to simulate body fluids, as it contains inorganic salts and glucose that confer a similar osmotic pressure as that of intercellular fluids [15]. PEG-liposomes remained essentially unaltered after dilution and incubation for 24 h with Hank's solution. ...
Liver cancer is one of the most common causes of cancer death worldwide. In recent years, substantial progress has been made in the development of systemic therapies, but there is still the need for new drugs and technologies that can increase the survival and quality of life of patients. The present investigation reports the development of a liposomal formulation of a carbamate molecule, reported as ANP0903, previously tested as an inhibitor of HIV-1 protease and now evaluated for its ability to induce cytotoxicity in hepatocellular carcinoma cell lines. PEGylated liposomes were prepared and characterized. Small, oligolamellar vesicles were produced, as demonstrated by light scattering results and TEM images. The physical stability of the vesicles in biological fluids was demonstrated in vitro, alongside the stability during storage. An enhanced cellular uptake was verified in HepG2 cells treated with liposomal ANP0903, resulting in a greater cytotoxicity. Several biological assays were performed to elucidate the molecular mechanisms explaining the proapoptotic effect of ANP0903. Our results allow us to hypothesize that the cytotoxic action in tumor cells is probably due to the inhibition of the proteasome, resulting in an increase in the amount of ubiquitinated proteins within the cells, which in turn triggers activation of autophagy and apoptosis processes, resulting in cell death. The proposed liposomal formulation represents a promising approach to deliver a novel antitumor agent to cancer cells and enhance its activity.
... Such a long retention of RV has never been reported for unilamellar liposomes. Usually, RV is completely released from phosphatidylcholine-based liposomes within a few hours [48][49][50][51]. This high retention of the polyphenol represents an added value for multilamellar liposomes storage as compared to unilamellar liposomes. ...
... Meng et al. designed PC-based liposomes with a RV loading of 2.5% [49], Vijayakumar added cholesterol in their composition and a RV loading of a 2.1% was obtained [50], while a value of 3.8% was found for RV-loaded ULLs containing oleic acid. Caddeo et al. prepared oligo/multilamellar liposomes from PC and claimed a RV loading of 4.9 ± 0.4% which is thus slightly higher than ours [51]. ...
Trans-Resveratrol (RV) was encapsulated in multi-lamellar liposomes (MLLs) composed of a mixture of phosphatidylcholine (P100), Tween 80 (T80) and water. The P100-to-T80 ratio as well as their water content were chosen based on a previous study to promote transdermal transport of RV. The effect of RV on the size, elasticity, and charge of MLLs was evaluated as well as the effect of encapsulation on the apparent solubility of RV. The diffusion of RV and MLLs in artificial skin, namely Strat-M™, was monitored by confocal Raman imaging, and compared with that of a RV solution and empty MLLs, while the transdermal passage rate was measured by UV–vis spectrophotometry on both artificial and excised human skin. RV was found to remain localized in the outer layer of the skin with less than 3% passing through it over a 24-h period in both skin types. Encapsulation in MLLs drastically increased its transdermal passage: 73 ± 10% after 3 h of incubation on excised human skin, and 10% on Strat-M™ after 9 h. Whereas RV in its free form underwent cis isomerization, MLLs protected it up to 9h before undergoing chemical degradation after 24h.
... Such a long retention of RV has never been reported for unilamellar liposomes. Usually, RV is completely released from phosphatidylcholine-based liposomes within a few hours [48][49][50][51]. This high retention of the polyphenol represents an added value for multilamellar liposomes storage as compared to unilamellar liposomes. ...
... Meng et al. designed PC-based liposomes with a RV loading of 2.5% [49], Vijayakumar added cholesterol in their composition and a RV loading of a 2.1% was obtained [50], while a value of 3.8% was found for RV-loaded ULLs containing oleic acid. Caddeo et al. prepared oligo/multilamellar liposomes from PC and claimed a RV loading of 4.9 ± 0.4% which is thus slightly higher than ours [51]. ...
Trans-Resveratrol (RV) was encapsulated in multi-lamellar liposomes (MLLs) composed of a mixture of phosphatidylcholine (P100), Tween 80 (T80) and water. The P100-to-T80 ratio as well as their water content were chosen based on a previous study to promote transdermal transport of RV. The effect of RV on the size, elasticity, and charge of MLLs was evaluated as well as the effect of encapsulation on the apparent solubility of RV. The diffusion of RV and MLLs in artificial skin, namely Strat-M™, was monitored by confocal Raman imaging, and compared with that of a RV solution and empty MLLs, while the transdermal passage rate was measured by UV–vis spectrophotometry on both artificial and excised human skin. RV was found to remain localized in the outer layer of the skin with less than 3% passing through it over a 24-h period in both skin types. Encapsulation in MLLs drastically increased its transdermal passage: 73 ± 10% after 3 h of incubation on excised human skin, and 10% on Strat-M™ after 9 h. Whereas RV in its free form underwent cis isomerization, MLLs protected it up to 9h before undergoing chemical degradation after 24h.
... Antioxidant activity (AA) of free C3G, C3G-NU, and GA-C3G-NU was evaluated in vitro by measuring their free radical scavenging activity using DPPH and ABTS methods, as shown in Fig. 5E and F. This assay involves the reduction in concentration of the DPPH and ABTS radicals in the presence of an antioxidant molecule that captures a hydrogen bond and absorbs the unpaired electron, this causes solution discoloration, and the degree of this color change correlates with a drop in absorbance, indicating the scavenging efficiency of the tested sample (Caddeo, et al., 2018). The obtained results reported that the antioxidant activity of free C3G, C3G-NU, and GA-C3G-NU using DPPH was 96.15, 50.33, and 43.64 μg VCE/mL, as well as ABTS was 94.17, 68.50, and 44.22 μg VCE/mL, respectively. ...
Cyanidin-3-O-glucoside (C3G) is a flavonoid with various biological properties, susceptible to degradation and instability under different external factors. Thus, this study aimed to develop novel gum Arabic (GA)-coated nano-nutriosomes (NUs) to improve the stability of C3G and facilitate its controlled delivery and cellular uptake as well as investigate the potential of GA-coated NU as a delivery system for C3G. The optimum concentration of GA to coat C3G-NU was 0.5% (w/v). The properties of NU systems were studied through DLS, HPLC, TEM, DSC, and FTIR. The results showed that C3G was successfully loaded in NUs and GA-NUs with a high encapsulation efficiency of 93.04% and 93.37%, nanosized 175.46 nm and 157.66 nm, with a PDI of 0.27 and 0.22, respectively. Besides, FTIR and DSC analysis showed a successful conjugation between GA and NUs, where GA-C3G-NU showed better physicochemical stability under thermal, pH, and ionic conditions, as well as GA can significantly control the release of C3G preserving around 90.16%. Furthermore, GA-C3G-NU showed better performance in C3G retention under different food simulants ≥ 89%. Moreover, the antioxidant activity of C3G-NU and GA-C3G-NU was DPPH (50.33 and 43.64 μg VCE/mL, respectively), and ABTS (68.50, and 44.22 μg VCE/mL, respectively). All NUs showed biocompatibility in Caco-2 cells with no cytotoxicity, with higher cellular uptake for GA-C3G-NU. Therefore, GA-NU could be a promising nanocarrier for encapsulating, controlling, and delivering functional ingredients.
... Resveratrol is a molecule with low aqueous solubility ranging from 0.05 mg/mL in water to 374 mg/mL in polyethylene glycol 400 (PEG-400), and poor stability dependent on temperature, light, and pH; it is relatively stable above pH 6 and has maximum degradation at pH 9 [16,17]. Resveratrol is a soluble molecule in polar solvents such as ethanol and DMSO; it has a high membrane permeability (estimated by its log P of 3.1) which provides a transport mechanism by transepithelial diffusion. ...
Cerebral ischemia represents a particular condition among neurological diseases due to its high frequency, high associated mortality, and the permanent disability in patients that survive it. Numerous studies in animal models have demonstrated the protective properties of resveratrol against cerebral ischemia. Resveratrol is a soluble molecule in polar solvents with high membrane permeability; however, it is rapidly metabolized at the liver and is also a substrate of the ATP binding cassette transporters located at the blood–brain barrier. These circumstances reduced bioavailability of resveratrol to the brain. In this review, we examined nasal resveratrol’s formulations including nanocarriers such as nanostructured lipid carriers, nanoemulsions, nanoparticles, bilosomes, cubosomal, and transferosomes that are directly transported to the brain. An intranasal administration route evades resveratrol transformation due to liver metabolism. Components of nanoformulations increased resveratrol absorption to the brain by enhancing permeation through specific approaches and also maintaining stability during storage. Both characteristics improved the delivery of resveratrol with conserved antioxidant capacity and protective properties for neurological models. Although demonstration that the nanoformulations prevents resveratrol’s blood–brain barrier retention is missing, properties of resveratrol’s nanoformulation encourage testing in clinical trials; however, regulatory approval for a novel nanocarrier in nasal drug delivery is complicated and needs approval.
... [22][23][24] The uncharged, synthetic polymer polyethylene glycol (PEG) can bind large amounts of water as well. 25 PEG is highly biocompatible [26][27][28] and has been reported to reduce immunoreactivity 29 , which enables a broad range of biomedical applications. For instance, PEG has been employed as a component in coatings for medical devices, and such PEG-based coatings entailed an improved tribological performance of implants. ...
Macromolecular coatings can improve the surface properties of many medical devices by enhancing their wetting behavior, tribological performance, and anti-biofouling properties – and covalent coatings produced from mucin glycoproteins have...
... However, the permeability and bioavailability aspects of EGCG encapsulated in liposomes have not been thoroughly investigated. Recent efforts have therefore focused on optimizing liposome stability and achieving high-concentration targeting enrichment by modifying targeting ligands on liposome surfaces (Caddeo et al., 2018). Glycosylation-modified liposomes have emerged as a promising strategy, as they can address the demand for glucose in the uncontrolled proliferation of diseased cells and selectively bind to cancer cell targets through ligand-specific recognition (Cvjetinovic et al., 2021), thereby enhancing the accumulation and transport efficiency of targeted drugs (Qu, Li, Guan, Li, Hai, & Wu, 2014;Toy, Peiris, Ghaghada, & Karathanasis, 2014). ...
... In another study, PEG-resveratrol liposomes were shown to be more stable than simple resveratrol liposomes. In the PEG-based liposomes, no significant physical alterations (e.g., mean particle size) and no significant vesicle migration and aggregation were observed, and there was a constancy of the PI (polydispersity index) [85]. Moreover, Manconi et al. [86] combined a grape pomace extract (4 or 5% (w/v)) in small-sized sodium alginate (SA)-or arabic gum (AG)-based liposomes with good encapsulation efficiency, potentiating its applicability in the nutraceutical industry. ...
The largest human organ, the skin, serves a variety of essential functions including protection, preservation of water and electrolytes, regulation of body temperature, and fat storage. Its maintenance and preservation are supported by cosmetic products, whose functions include cleaning, protection, and modulation. The market for these products is predicted to increase from 100.13 billion USD in 2021 to 145.82 billion USD in 2028. Recently, it has been suggested that grape by-products (totalling 14.5 million tons per year just in Europe) has a great potential to be used in the creation of new cosmetic products. In this regard, this article aims to provide a comprehensive overview of the current state of knowledge regarding the bioactive compounds in grape pomace, the advantages of applying them to the skin, and the main cosmetic products already on the market incorporating these bioactives. Most of these compounds are derived from the Vitis vinifera L. species, and exhibit several biological properties, such as antioxidant, antimicrobial, anti-inflammatory, inhibition of skin degrading enzymes, protection from UVA damage, increased cell viability, and skin whitening effect. On the other hand, nanoencapsulation techniques can provide a significant improvement in the stability of grape-derived bioactive compounds, in particular of resveratrol, and this issue is also addressed in a critical manner in this review.
... The scattering curves were recorded every 20 min up to 2 h to check for sample stability; those curves were summed up and background was subtracted. SAXS patterns were analyzed using a homemade fitting procedure based on a Gaussian description of the bilayers and using a Levenberg-Marquardt minimization scheme [21][22][23][24][25], which takes into account the instrumental convolution for detector width and beam profile. ...
The formulation of plant extracts in phospholipid vesicles is a promising strategy to exploit their biological properties while solving problems related to poor solubility in water, high instability, and low skin permeation and retention time. In this study, Ceratonia siliqua ripe pods were used for the preparation of a hydro-ethanolic extract, which showed antioxidant properties owing to the presence of biologically active compounds identified by liquid chromatography–mass spectrometry (e.g., hydroxybenzoic acid and flavonoid derivatives). To improve the applicability of the extract in therapy, a topical formulation based on liposomes was explored. The vesicles were characterized by small size (around 100 nm), negative charge (−13 mV), and high entrapment efficiency (>90%). Furthermore, they displayed both spherical and elongated shapes, with oligolamellar structure. Their biocompatibility was demonstrated in cells, including erythrocytes and representative skin cell lines. The antioxidant activity of the extract was proved by the scavenging of free radicals, the reduction of ferric ions, and the protection of skin cells from oxidative damage.
... показано, что липосомы, модифицированные ПЭГ, практически не изменялись после 2 мес. хранения, тогда как обычные липосомы демонстрировали прогрессирующую агрегацию и преципитацию [53]. Однако пегилирование липосом не только повышает стабильность везикул, но также может ограничивать клеточный захват и эндосомальное высвобождение, снижая конечный терапевтический эффект [54], и вызывать нежелательные реакции различной степени тяжести, вплоть до анафилактического шока [55,56]. ...
Liposomes are one of the most well-known and promising nanoscale drug delivery systems. Liposomal medicinal products are successfully used in clinical practice for cardiovascular, oncological, dermatological, and other indications. The development of liposomes and their widespread implementation in clinical practice are relevant tasks.
The aim of the study was to summarise and analyse scientific data regarding the structure, composition, and classification of liposomes, as well as specific aspects of liposome production methods.
This review covers up-to-date information on marketed liposomal medicinal products. The authors illustrate how production methods affect the composition and structure of liposomes. The size and lamellarity are important characteristics of liposomes that determine the encapsulation efficiency and biodistribution of active pharmaceutical ingredients (APIs). The choice of excipients depends on the intended use of liposomal medicinal products. The article summarises the main liposome production methods, highlighting specific usage aspects, advantages and disadvantages. Conventional liposome production methods are easy to apply and do not require complex equipment, and their principal disadvantages include the low efficiency of API encapsulation within liposomes and the high complexity of scaling up technological processes. The authors pay special attention to microfluidic techniques for liposome preparation, which are characterised by a highly controlled technological process (in terms of size distribution and lamellarity), high reproducibility, and scalability to the level of industrial production and are applicable to encapsulating different APIs.
... 25 NCAP consists of two distinct functional domains: (i) three consecutive phenylalanine−aspartic acid−phenylalanine sequences (FDF) serve as the backbone of the NCAP peptide chain; (ii) hydrophilic polyethylene glycol (PEG) domains attached to the N-terminus of peptide chains to significantly improve the hydrophilicity and biocompatibility of nanofibers. 26 We co-assembled PCBP and NCAP in the same molar ratio to form nanofibers (PCBP-NCAP NFs). Our results demonstrate that PCBP-NCAP NFs can supramolecularly assemble into nanofibers and exhibit high biocompatibility with animal cells both in vitro and in vivo. ...
Antibiotic resistance is an escalating global health concern that could result in tens of millions of deaths annually from drug-resistant bacterial infections in the future, especially in animal husbandry. Peptide antibacterial nanomaterials offer a competitive alternative to antibiotics because of their distinct mechanism of physically penetrating pathogenic biological membranes. This study developed amphiphilic co-assembled peptide nanofibers with high biological selectivity (PCBP-NCAP NFs) to overcome the high cytotoxicity of peptide PCBP and the low antibacterial activity of peptide NCAP. PCBP-NCAP NFs exhibit broad-spectrum antibacterial activity and excellent biocompatibility, with negligible in vivo and in vitro toxicity. Additionally, PCBP-NCAP NFs possess direct antibacterial efficacy and potential immunomodulatory capabilities using a piglet systemic infection model. Its unique mechanism of membrane penetration and the ability to bind to anionic components on the surface of pathogenic bacteria make them less susceptible to drug resistance. In conclusion, these findings have significant implications for the advancement of supramolecular peptide nanomedicines for clinical application and animal husbandry.
... Moreover, the quenching of the intrinsic antioxidant activity of PTZ due to the presence of a formyl unit can be attributed to the electron-acceptor effect diminishing the ability of sulfur heteroatom to interact with radical species [57]. The significant antioxidant activity of PEGylated imine derivatives compared to TEGylated ones can be attributed to the capacity of PEG to potentiate the antioxidant activity of imine units [52,58]. All in all, the obtained results indicated that PEGylated imine derivatives have a free radical scavenging potential property that could influence tumor cells' cytotoxicity. ...
The paper aims to investigate the antitumor activity of a series of phenothiazine derivatives in order to establish a structure–antitumor activity relationship. To this end, PEGylated and TEGylated phenothiazine have been functionalized with formyl units and further with sulfonamide units via dynamic imine bonds. Their antitumor activity was monitored in vitro against seven human tumors cell lines and a mouse one compared to a human normal cell line by MTS assay. In order to find the potential influence of different building blocks on antitumor activity, the antioxidant activity, the ability to inhibit farnesyltransferase and the capacity to bind amino acids relevant for tumor cell growth were investigated as well. It was established that different building blocks conferred different functionalities, inducing specific antitumor activity against the tumor cells.
... The carbamate bond in the lipid structure was stable under neutral conditions, but acidic conditions triggered RES release, indicating that this nanoplatform can enhance RES accumulation in the acidic tumor microenvironment and improve its antitumor efficacy (Zhao et al., 2020). However, conventional liposomes are unstable during storage (Caddeo et al., 2018) and have low targeting ability (Laginha et al., 2005). Therefore, RES-loaded liposomes were modified with poly(ethylene glycol) (PEG), resulting in a nanoplatform (PEG-lip-RES) with better stability and biocompatibility; low toxicity against murine macrophage cells (RAW264.7), ...
Resveratrol is a polyphenol with diverse pharmacological activities, but its clinical efficacy is limited due to low solubility/permeability, light-induced isomerization, auto-oxidation, and rapid metabolism. Nanodelivery systems, such as liposomes, polymeric nanoparticles, lipid nanocarriers, micelles, nanocrystals, inorganic nanoparticles, nanoemulsions, protein-based nanoparticles, exosomes, macrophages, and red blood cells (RBCs) have shown great potential for improving the solubility, biocompatibility, and therapeutic efficacy of resveratrol. This review comprehensively summarizes the recent advances in resveratrol nanoencapsulation and describes potential strategies to improve the pharmacokinetics of existing nanoformulations, enhance targeting, reduce toxicity, and increase drug release and encapsulation efficiency. The article also suggests that in order to avoid potential safety issues, resveratrol nanoformulations must be tested in vivo in a wide range of diseases.
... This phenomenon is due to the capability of some encapsulated compounds, particularly EOs to induce an extraordinary cohesion and packing among the apolar chains in the membrane bilayer of NLPs (Sebaaly et al. 2021). Also, some substances like polyethylene glycol (PEG), which are used on the surface of NLPs to induce a repulsive force and prevent particles from precipitation, have the capability to decrease the size of NLPs (Caddeo et al. 2018). ...
Todays, nanoliposomes (NLPs) are considered as one of the most efficient nanocarriers to deal with bacteria, practically in food products. These nanodelivery systems are able to be loaded with different bioactive compounds. The main aim of this review is investigating recent approaches (mostly from the years of 2018 to 2022) regarding development of nanoliposomal natural antibacterial compounds. In this regard, NLPs alone, combined with films, coatings, or fibers, and in coated forms are reviewed as advanced delivery systems of antibacterial substances. Moreover, a robust and comprehensive coverage of the morphological and physical properties of formulated NLPs as well as their interactions with antibacterial substances are discussed. The importance of NLPs to encapsulate antibacterial ingredients, advantages and drawbacks, antibacterial pathways of formulated NLPs, and comparison of them with pure antibacterial bioactive compounds are also explained.
... These vesicles are useful to safely deliver resveratrol. All of these are lipid polymers modified or used as an additive for their variety of applications (Caddeo et al., 2018). ...
Shellac, also known as Laccifer lacca, lac, resinous glaze, or confectioner’s glaze, is the refined version of lac, a resin secreted by lac insects. Lac is secreted by female lac bugs, most commonly of the species Kerria lacca. Shellac is an edible resin and is used in both food and non-food end-use industries. The other main constituents of these materials are shellac wax as well as dye equally hold their position to contribute to the food industry especially postharvesting. It is most commonly used as a surface glazing agent, but has a plethora of other applications as well. Shellac is an age-old material that is of animal origin, its quality and quantity depend largely on the host–insect interaction. India is a leading producer, and processor of these materials. The shellac material is placed in the generally recognized as safe (GRAS) category which makes it suitable for the edible material as well as to be useful for the food and allied industry. The application of shellac can be categorized into two broad subheadings: (a) shelf-life enhancement as a coating agent; (b) as a smart edible sensor. The majority of the work has been done on the shelf-life enhancement and quality preservation of fruits and vegetables. However, an extension of this work also led to another area of value addition to the edible products like confectionery items and infant toys. The use of shellac for the edible smart sensor has gained its importance in the last decades where shellac has been used in association with other edible polymers to give colorimetric sensing to the fruit and vegetable spoilage with time. Apart from the above-mentioned domain, it is also a strong candidate for the substitute of single-use plastic; this makes it a desirable eco-friendly material for food packaging material. In the present chapter, this natural lipid polymer (shellac) will be presented for its versatile application in the food and allied industries as well as its future prospects as smart edible sensors.
... The stability characteristics of CNPs in various experiments is shown in Table 6. The PS, PDI, and zeta potential were all insignificantly different, ensuring the stability of stored formulations under changing pH conditions [32]. ...
The goal of this study was to optimize and formulate apigenin (APG)-loaded pegylated chitosan nanoparticles (PEGylated-CNPs) via ionic gelation techniques using the Box–Behnken design (BBD). Three individual variables, X1(chitosan: TPP concentration), X2 (PEG-400 concentration), and X3 (sonication time), were investigated for their influence on response variables (Y1—particle size (PS); Y2—drug entrapment efficiency (DEE); and Y3—zeta potential (ZP). The optimized formula of APG-PEGylated CNPs was picked from the statistical design and was then examined for physical, morphological, release characterization, anti-oxidant, and anti-tumor potential. The average PS, PDI, %DEE, and ZP were found to be 139.63 ± 5.67 nm, 0.296 ± 0.014, 79.55 ± 3.12%, and 24.68 ± 1.84 mV, respectively. The optimized APG formulation was chosen and reformulated based on the desirability function. Results of the observed and predicted values of responses through the BBD process were found to be nearly identical. The resulting APG-PEGylated CNPs were spherical and smooth, according to surface morphology studies. The release study revealed that PEGylated-CNPs exhibited biphasic release patterns distinguished by an initial burst release of APG only at early phases accompanied by a delayed release near 24 h. Furthermore, APG-PEGylated CNPs demonstrated statistically increased antioxidant activities and cytotoxicity against MCF-7 cells compared to pure APG. Based on the findings, it is possible to conclude that BBD was efficient in optimizing the PEGylated CNPs formulation and recognizing the impacts of formulation variables. In conclusion, the developed formulation has a significant potential for anticancer therapy.
... As expected, both plain and RES liposomes exhibited a close to neutral zeta potential with −0.96 ± 1.26 mV and −5.65 ± 1.82 mV, respectively. The entrapment efficiency was found to be high with 89% of RES in liposomes; this is in agreement with our earlier findings [7,12,33] and literature [6,[34][35][36]. In previous studies, the RES release from the delivery system was thoroughly evaluated confirming a sustained RES release from both liposomal and liposomes-in-hydrogel formulations compared to the respective controls [12,33]. ...
The natural polyphenol resveratrol (RES) has shown great potential as an antimicrobial, including against microbes associated with vaginal infections. To fully exploit the activities of RES, an all-natural ingredients formulation for RES delivery at vaginal site has been developed, namely liposomes loaded with RES, incorporated into a chitosan hydrogel as secondary vehicle. Although considered non-toxic and safe on their own, the compatibility of the final formulation must be evaluated for its biocompatibility and non-irritancy to the vaginal mucosa. As a preclinical safety assessment, the impact of RES formulation on the tissue viability, the effect on barrier function and cell monolayer integrity, and cytotoxicity were evaluated using the cell-based vaginal tissue model, the EpiVaginal™ tissue. RES liposomes-in-hydrogel formulations neither affected the mitochondrial activity, nor the integrity of the cell monolayer in RES concentration up to 60 µg/mL. Moreover, the barrier function was maintained to a greater extent by RES in formulation, emphasizing the benefits of the delivery system. Additionally, none of the tested formulations expressed an increase in lactate dehydrogenase activity compared to the non-treated tissues. The evaluation of the RES delivery system suggests that it is non-irritant and biocompatible with vaginal tissue in vitro in the RES concentrations considered as therapeutic.
Advancements in nanotechnology were vastly applied in medicine and pharmacy, especially in the field of nano-delivery systems. It took a long time for these systems to ensure precise delivery of very delicate molecules, such as RNA, to cells at concentrations that yield remarkable efficiency, with success rates reaching 95.0% and 94.5%. These days, there are several advantages of using nanotechnological solutions in the prevention and treatment of cancer and viral infections. Its interventions improve treatment outcomes both due to increased effectiveness of the drug at target location and by reducing adverse reactions, thereby increasing patient adherence to the therapy. Based on the current knowledge an updated review was made, and perspective, opportunities and challenges in nanomedicine were discussed. The methods employed include comprehensive examination of existing literature and studies on nanoparticles and nano-delivery systems including both in vitro tests performed on cell cultures and in vivo assessments carried out on appropriate animal models, with a specific emphasis on their applications in oncology and virology. This brings together various aspects including both structure and formation as well as its association with characteristic behaviour in organisms, providing a novel perspective. Furthermore, the practical application of these systems in medicine and pharmacy with a focus on viral diseases and malignancies was explored. This review can serve as a valuable guide for fellow researchers, helping them navigate the abundance of findings in this field. The results indicate that applications of nanotechnological solutions for the delivery of medicinal products improving therapeutic outcomes will continue to expand.
The use of liposomes as an effective delivery system has been well documented. This system offers protection to functional components from various environmental factors such as light, oxygen, temperature and pH. However, liposomes also present certain limitations, including poor targeting, instability, short in vivo circulation time and low utilisation of encapsulated substances. These drawbacks can be addressed through the modification of liposomes. This review article examines the preparation of modified liposomes using methods such as the thin‐film method, reverse evaporation method and injection method. The purpose of liposome modification and its application in food are discussed, with a focus on enhancing targeting, prolonging in vivo circulation time, improving stability and ensuring the stability of encapsulated substances during storage. Additionally, the article explores modification methods such as polyethylene glycol modification, peptide and protein modification and polysaccharide modification. This comprehensive review aims to contribute to a better understanding of liposome modification and provide valuable references for the development of novel modified liposomes.
The green preparation of highly dispersed carbon nanotube (CNT) conductive inks remains a critical challenge in the field of flexible electronics. Herein, a waterborne CNT dispersion approach mediated by carboxylated cellulose nanofibers (C-CNFs) was proposed. CNFs, special biomass materials with excellent nanostructures and abundant active surface groups, are used as green dispersants. During the dispersion process, benefiting from chemical charge and dimensional matching, C-CNF/CNT wicking-driven stable composite structures (CCNTs) were co-assembled via hydrogen bonding, electrostatic stabilization and π–π stacking between the interfaces, generating controlled orientational structures and promoting stable dispersion and conductivity of CNTs, which were demonstrated via molecular dynamics simulations combined with a variety of physicochemical characterization methods. The dispersion concentration of CNTs in a CCNT slurry can reach 80 wt%, and the obtained CCNT slurry has a low zeta potential (less than − 60 mV) and good stability. Due to the film-forming properties of CNFs and in-plane oriented self-assembly of CCNT, the composite self-supporting films were fabricated with high electrical conductivity (67 S cm−1) and mechanical performance (tensile strength of 153 MPa). In addition, the resulting biobased CCNT ink is compatible with a variety of printing processes and adaptable to various substrates. Moreover, this ink can be used to construct multifunctional advanced sensors with electrochemical, electrothermal, and deformation/piezoresistive responses, which demonstrate excellent performance in monitoring human health.
Poly(N-vinylcaprolactam-co-hydroxyethyl acrylate-co-phenyl vinyl sulfide) (poly(VC-co-HEA-co-PVS)) and poly(N-vinylcaprolactam-co-N-vinylpyrrolidone-co-phenyl vinyl sulfide) (poly(VC-co-VP-co-PVS)) were synthesized as thermos-sensitive oxidizable terpolymers. The copolymerization was confirmed by the 1H-NMR and FT-IR spectroscopy. VC homopolymer exhibited its lower critical solution temperature (LCST) around 32 ℃. The copolymerization of HEA with VC and of VP with VC decreased and increased the LCST of VC homopolymer, respectively. The inclusion of PVS (an oxidizable monomer) in the copolymers decreased the LCST. The PVS of the copolymers could be oxidized by H2O2, solution (0.1%), evidenced by 1H-NMR spectroscopy. Upon the oxidation, the LCST of poly(VC-co-PVS) and poly(VC-co-HEA-co-PVS) increased markedly possibly due to an increase in the hydrophilicity of PVS. However, the LCST of poly(VC-co-VP-co-PVS) was not markedly affected by the oxidation. The interface activity of poly(VC-co-PVS) and poly(VC-co-HEA-co-PVS) slightly decreased but that of poly(VC-co-VP-co-PVS) markedly increased by the oxidation. The critical micelle concentration of the copolymers was determined by a fluorescence method, and it was 0.087 to 0.105 mg/mL. The micelles of the copolymers were found as circular objects on a transmission electron microscope. The mean hydrodynamic diameters of micelles were 107.4 to 471.6 nm, depending on the polymer composition. The PVS-containing copolymers formed larger micelles than VC homopolymer, possibly because the monomer could enhance an intermolecular hydrophobic interaction due to its phenyl group.
Cancer therapy-induced heart injury is a significant concern for cancer patients undergoing chemotherapy, radiotherapy, immunotherapy, and also targeted molecular therapy. The use of these treatments can lead to oxidative stress and cardiomyocyte damage in the heart, which can result in heart failure and other cardiac complications. Experimental studies have revealed that chemotherapy drugs such as doxorubicin and cyclophosphamide can cause severe side effects such as cardiac fibrosis, electrophysiological remodeling, chronic oxidative stress and inflammation, etc., which may increase risk of cardiac disorders and attacks for patients that underwent chemotherapy. Similar consequences may also be observed for patients that undergo radiotherapy for left breast or lung malignancies. Polyphenols, a group of natural compounds with antioxidant and anti-inflammatory properties, have shown the potential in protecting against cancer therapy-induced heart injury. These compounds have been found to reduce oxidative stress, necrosis and apoptosis in the heart, thereby preserving cardiac function. In recent years, nanoparticles loaded with polyphenols have also provided for the delivery of these compounds and increasing their efficacy in different organs. These nanoparticles can improve the bioavailability and efficacy of polyphenols while minimizing their toxicity. This review article summarizes the current understanding of the protective effects of polyphenols and nanoparticles loaded with polyphenols against cancer therapy-induced heart injury. The article discusses the mechanisms by which polyphenols protect the heart, including antioxidant and anti-inflammation abilities. The article also highlights the potential benefits of using nanoparticles for the delivery of polyphenols.
A biocatalytic system that could produce bioactive resveratrol poly-glucosides, using sucrose as a low-cost source of UDP-glucose donors and amylosucrase DgAS from Deinococcus geothermalis, was developed in this study. This system boasts several advantages, including the rapid and direct conversion of substrates to products, thermostability, regio-stereospecificity, and effectiveness, both in vitro and in vivo, at 40 °C. The results showed that the optimal reaction condition of the production of resveratrol glucosides was obtained by 2.0 µg/mL DgAS and 100 mM sucrose at pH 7.0, incubated at 40 °C for 5 h. With a success rate of around 97.0% in vitro and 95.0% in vivo in a short period of time, resveratrol-O-glucosides showed exciting outcomes in cosmetic applications, including antioxidant, anti-inflammatory, anti-aging, and whitening effects when tested with Raw 264.7, B16, and HS68 cell lines. DgAS is recognized as an important biocatalyst due to its high thermostability, effectiveness, and specificity among all known amylosucrases (ASases) in the production of poly-glucosides in a chain of polyphenols, such as resveratrol, making it an ideal candidate for industrial use in the cost-effective production of cosmetic items.
Cancer is currently one of the most intractable diseases causing human death. Although the prognosis of tumor patients has been improved to a certain extent through various modern treatment methods, multidrug resistance (MDR) of tumor cells is still a major problem leading to clinical treatment failure. Chemotherapy resistance refers to the resistance of tumor cells and/or tissues to a drug, usually inherent or developed during treatment. Therefore, an urgent need to research the ideal drug delivery system to overcome the shortcoming of traditional chemotherapy. The rapid development of nanotechnology has brought us new enlightenments to solve this problem. The novel nanocarrier provides a considerably effective treatment to overcome the limitations of chemotherapy or other drugs resulting from systemic side effects such as resistance, high toxicity, lack of targeting, and off-target. Herein, we introduce several tumor MDR mechanisms and discuss novel nanoparticle technology applied to surmount cancer drug resistance. Nanomaterials contain liposomes, polymer conjugates, micelles, dendrimers, carbon-based, metal nanoparticles, and nucleotides which can be used to deliver chemotherapeutic drugs, photosensitizers, and small interfering RNA (siRNA). This review aims to elucidate the advantages of nanomedicine in overcoming cancer drug resistance and discuss the latest developments.
A biocatalytic system that could produce bioactive resveratrol poly-glucosides using sucrose as a low-cost source of UDP-glucose donors and amylosucrase DgAS from Deinococcus geothermalis was developed in this study. This system boasts several advantages, including fast and direct conversion of substrates to products, thermostable, and regio-stereospecific, and effectiveness in vitro and in vivo at 40°C. With a success rate of around 97.0% in a short period in vitro and 95.0% in vivo, resveratrol-O-glucosides showed exciting outcomes in cosmetic activities, such as antioxidant, anti-inflammatory, anti-aging, and whitening effects when tested with Raw 264.7, B16, and HS68 cell lines. DgAS is recognized as an important biocatalyst due to its higher thermostability, effectiveness, and specificity among all known amylosucrases (ASases) in the production of poly-glucosides in a chain of polyphenols, like resveratrol, making it an ideal candidate for industrial use to cost-effective production of cosmetic items.
The surfactant rhamnolipid (RL) was used to modify the liposomes. β‐carotene (βC) and rutinoside (Rts) were utilized to generate co‐encapsulated liposomes through an ethanol injection method that used both hydrophilic and hydrophobic cavities to fabricate a novel cholesterol‐free composite delivery system. The RL complex‐liposomes loaded with βC and Rts (RL–βC–Rts) showed higher loading efficiency and good physicochemical properties (size = 167.48 nm, zeta‐potential = −5.71 mV, and polydispersity index = 0.23). Compared with other samples, the RL–βC–Rts showed better antioxidant activities and antibacterial ability. Moreover, dependable stability was uncovered in RL–βC–Rts with still 85.2% of βC storage from nanoliposome after 30 days at 4°C. Furthermore, in simulated gastrointestinal digestion, βC exhibited good release kinetic properties. The present study demonstrated that liposomes constructed from RLs offer a promising avenue for the design of multicomponent nutrient delivery systems using both hydrophilic.
OSA-starch stabilized EPA nanoliposomes (OSA-EPA-NLs) were prepared by thin film rehydration/dispersion method. The physical properties and morphology of OSA-EPA-NLs were characterized. The best formulated sample was used to measure the storage stability and oxidative properties of EPA under different environmental stresses and to determine release and absorption of OSA-EPA-NLs in vitro and in vivo. The results showed that the encapsulation efficiency of OSA-EPA-NLs was 84.61%. All samples were relatively stable under different environmental stresses, and the release rate of EPA in simulated intestine stage (89.87%) was higher than that in the simulated gastric stage (5.86%). The areas under the EPA concentration-time curve of OSA-EPA-NLs group and EPA-NLs group through in vivo study were 0.42 and 0.32, respectively, which indicated that OSA-starch could improve the stability of EPA nanoliposomes and enhance EPA bioavailability in the form of ethyl esters.
The application of plant essential oil liposomes to prevent and control food safety risks caused by Campylobacter jejuni (C. jejuni) still faces challenges such as lack of targeting and low release rate. Here, a bacteria-targeted and protease-activated antibacterial liposome (ACCLPs) was successfully synthesized through encapsulation of clove essential oil (CEO) by film dispersion method, embedding of casein by freeze-thaw method, and conjugation of C. jejuni antibody on the liposome membrane by post-insertion method. The average particle size, the essential oil encapsulation rate, the casein mosaic rate, and the antibody coupling efficiency of ACCLPs were determined as185.87 nm,16.9%,70.1% and 87.5%, respectively. The modification with C. jejuni antibody could significantly improve the targeting of ACCLPs to C. jejuni. Controlled release experiments showed that the exocrine protease from C. jejuni could hydrolyze the embedded casein and perforation on the ACCLPs, thus leading to a bacteria-dependent CEO release and significant prolonging the antibacterial effects of ACCLPs. Application results of ACCLPs on C. jejuni-contaminated foods showed that ACCLPs could effectively inhibit C. jejuni in a variety of meat products, fruits and vegetables and extend their shelf life without significantly affecting food quality. The results above in this work would provide a new view for the development of high efficient liposome-based antibacterial system of plant essential oil.
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, paclitaxel (PTX) represents the first-line therapy for TNBC; however it presents a hydrophobic behavior and produces severe adverse effects. The aim of this work is to improve the therapeutic index of PTX through the design and characterization of novel nanomicellar polymeric formulations composed of a biocompatible copolymer Soluplus® (S), surface-decorated with glucose (GS), and co-loaded either with histamine (HA, 5 mg/mL) and/or PTX (4 mg/mL). Their micellar size, evaluated by dynamic light scattering, showed a hydrodynamic diameter between 70 and 90 nm for loaded nanoformulations with a unimodal size distribution. Cytotoxicity and apoptosis assays were performed to assess their efficacy in vitro in human MDA-MB-231 and murine 4T1 TNBC cells rendering optimal antitumor efficacy in both cell lines for the nanoformulations with both drugs. In a model of TNBC developed in BALB/c mice with 4T1 cells, we found that all loaded micellar systems reduced tumor volume and that both HA and HA-PTX-loaded SG micelles reduced tumor weight and neovascularization compared with the empty micelles. We conclude that HA-PTX co-loaded micelles in addition to HA-loaded formulations present promising potential as nano-drug delivery systems for cancer chemotherapy.
Monascus red pigments (MRPs), which are a kind of natural colorant produced by Monascus spp., are widely used in the food and health supplements industry but are not very stable during processing and storage. Thus, MRPs were embedded into liposome membranes using a thin-film ultrasonic method to improve stability in this study. Monascus red pigments liposomes (MRPL) exhibited spherical unilamellar vesicles (UV) with particle size, polydispersity indexes (PDI), and zeta potential of 20–200 nm, 0.362 ± 0.023, and −42.37 ± 0.21 mV, respectively. pH, thermal, light, metal ion, storage, and in vitro simulated gastrointestinal digestion stability revealed that, compared with free MRPs, liposomes embedding significantly enhanced the stability of MRPs when exposed to adverse environmental conditions. Furthermore, anticancer assay suggested that MRPL exhibited a stronger inhibitory effect on MKN-28 cells by damaging the integrity of cells, with the IC50 value at 0.57 mg/mL. Overall, MRPLs possess stronger stability in external environment and in vitro simulated digestion with greater anticancer activity, indicating that MRPLs have the potential for promising application in the functional foods and pharmaceutical industries.
As a result of their unique physical properties, biological membrane mimetics such as biopolymers are used in a broad range of scientific and technological applications. This comprehensive book covers new applications of biopolymers in the research and development of industrial scale nutraceutical and functional food grade products. All the major food biopolymers are included, from plant, animal and marine sources. Coverage also includes biopolymer-based drug delivery mechanisms intended for biological applications such as bio-detection of pathogens, fluorescent biological labels, and drug and gene delivery.
This is the first interdisciplinary book to address this area specifically and is essential reading for those who produce the functional biopolymer materials as well as those who seek to incorporate them into appropriate nutraceutical, food and drug delivery products.
Functional foods are increasingly preferred by consumers because in addition to nutritional intake, they provide remarkable health benefits. One of the strategies for food functionalization is the incorporation of bioactive compounds encapsulated in different colloidal delivery systems (CDSs) in food matrices. This chapter provides an overview of the principles and factors involved in the design of CDSs for food ingredients and nutraceuticals in order to increase the quality and health benefits of food. The correlation between the nutritional and sensory attributes of functional foods and the physicochemical and biological characteristics of bioactive compounds and encapsulating materials is based on the principles of the design concepts; Quality by Design (QbD) and Reverse Engineering Design (RED). The physicochemical characteristics of micro/nanoparticles and their influence on the functionality of biocomponents incorporated into food matrices and their impact on digestion, absorption and metabolism are also discussed. In addition, the main CDSs are described, such as lipid-based CDSs and polymeric CDSs used in food fortification.
The stabilization of liposomes is an important aspect for maintaining the integrity of liposome structure. The stability of liposomes reduces in terms of uncontrollable fusion, undesirable payload loss, short shelf life, and unexpected mixing. Additionally, liposomes undergo physical as well as chemical degradation, causing low efficiency and quality of the formulation, and also the possibility of product degradation with undesirable side effects. Various factors influence the stability of liposomes, such as temperature, pH, surface charge, and lipid composition. To overcome this, various approaches have been implemented to stabilize them. This chapter describes various methods of liposome stabilization, such as surface modification, stabilizing membrane, changing lipid composition, and the addition of surfactants and nanoparticles. Furthermore, drying techniques such as freeze drying, spray drying, spray-freeze drying, electrohydrodynamic, and supercritical methods are also discussed for the preservation of liposomes.
Nanoliposomes are ideal nanocarriers for encapsulated active compounds used in the food industry as they provide stability and controlled release. However, cholesterol may pose risks in large intake, which is the commonly-used nanoliposome stabilizers. In this study, resveratrol was used instead of cholesterol as a novel nanoliposome stabilizer to construct a resveratrol blank liposome (RBL) system. The RBL system was used to protect the bacteriocin CAMT6 to create bacteriocin-loaded nanoliposomes (BLLs). The RBLs and BLLs had favourable particle sizes (172.71 nm and 150.47 nm), polydispersity index (PDI) values (0.150 and 0.120) and zeta potentials (−41.54 mV and −43.53 mV, respectively). According to Differential scanning colourimetry (DSC) and X-ray diffraction (XRD) analyses, resveratrol altered the structure of the phospholipid layer. The phospholipid layers of the RBLs and BLLs had higher mobility when resveratrol was used as a stabilizer instead of cholesterol. Structurally, resveratrol was inserted egg yolk lecithin to constitute an RBL. CAMT6 was loaded in BLLs with spherical and shell-core structures. The BLL encapsulation efficiency was 97.32% and exhibited three release phases, with the release rates reaching 62%. In experiments with milk, the BLLs effectively protected the anti-Listeria activity of CAMT6. In summary, resveratrol is a suitable nanoliposome stabilizer and the proposed RBL system is an excellent way to improve the stability of water-soluble preservatives, such as bacteriocins, in complex food environments.
Polyphenols are secondary metabolites, naturally found in plants. They are typically known for their antioxidant activity and beneficial impact on health. Extraction of polyphenols from biological matrices is the first step toward their valorization. Many methods of separation (chromatography) are used to separate the polyphenols from the undesirable fraction of the extract. Moreover, the increasing interest in the isolation (e.g., ultrafiltration, nanofiltration) techniques for the purification of polyphenols is mainly due to their potential applications as natural antioxidants in food, pharmaceutical, and cosmetic industries. Many preservation methods (e.g., drying, encapsulation) are required to maintain their biological activities throughout the process. Finally, and after the recovery of polyphenols and their purification, colorimetric, chromatographic and spectrometric methods (LC-MS, GC-MS-MS) are used to identify and characterize polyphenols. This chapter discusses the methodologies used for separation, purification, analysis, and preservation of polyphenols.
Phenolics are among the most studied compounds due to their beneficial implications in human health. The conventional methods applied in the extraction of these compounds include maceration, distillation, Soxhlet, among others, and the extraction capacity depends on several factors, such as the extraction solvent and respective concentration, time, and temperature. The incorporation of green chemistry in the development of more sustainable products and processes has promoted the use of new solvents that would replace conventional ones and the application of more eco-sustainable technologies (e.g., supercritical fluids, pulsed electric fields, and ultrasounds). Green solvents, coupled with conventional extraction methods, present excellent stability for food, pharmaceutical, and cosmetic industries because they are non-toxic, non-volatile, recyclable, biodegradable, and imply lower energy cost of synthesis. In this chapter, traditional and eco-sustainable methods based on solid–liquid extraction will be revised, as well as safety issues, life-cycle assessment, and economic aspects.
Since the revolutionary discovery that phospholipids can form closed bilayered structures in aqueous systems, the study of liposomes has become a very interesting area of research. The versatility and amazing biocompatibility of liposomes has resulted in their wide-spread use in many scientific fields, and many of their applications, especially in medicine, have yielded breakthroughs in recent decades. Specifically, their easy preparation and various structural aspects have given rise to broadly usable methodologies to internalize different compounds, with either lipophilic or hydrophilic properties. The study of compounds with potential biotechnological application(s) is generally related to evaluation and risk assessment of the possible cytotoxic or therapeutic effects of the compound under study. In most cases, undesirable side-effects are associated with an interaction of the liposome with the cell membrane and/or its absorption and subsequent interaction with a cellular biomolecule. Liposomal carrier systems have an unprecedented potential for delivering bioactive substances to specific molecular targets due to their biocompatibility, biodegradability and low toxicity. Liposomes are therefore considered to be an invaluable asset in applied biotechnology studies due to their potential for interaction with both hydrophilic and lipophilic compounds. © 2015, International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag Berlin Heidelberg.
The mucosa is the primary point of entry for pathogens making it an important vaccination site to produce a protective mucosal immune response. While the sublingual (SL) mucosa presents several barriers to vaccine penetration, its unique anatomy and physiology makes it one of the best options for mucosal vaccination. Efficient and directed delivery of adjuvants and antigens to appropriate immune mediators in the SL tissue will aid in development of effective SL vaccines against infectious diseases. Herein we demonstrate a robust immune response against influenza antigens co-delivered sublingually with engineered liposomes carrying the synthetic Toll-like receptor-4 agonist, CRX-601. Liposome modification with PEG copolymers (Pluronics), phospholipid-PEG conjugates and chitosan were evaluated for their ability to generate an immune response in a SL murine influenza vaccine model. Phospholipid-PEG conjugates were more effective than Pluronic copolymers in generating stable, surface neutral liposomes. SL vaccination with surface modified liposomes carrying CRX-601 adjuvant generated significant improvements in flu-specific responses compared with unmodified liposomes. Furthermore, the coating of modified liposomes with methylglycol chitosan produced the most effective flu-specific immune response. These results demonstrate efficient SL vaccine delivery utilizing a combination of a muco-adhesive and surface neutral liposomes to achieve a robust mucosal and systemic immune response.
ABSTRACT Objective
Quercetin, resveratrol and curcumin are plant derived natural products that are rapidly gaining popularity as supplements for a wide assortment of conditions including cardiovascular disease, cancer, asthma, diabetes, neurodegeneration,
aging and stress. Unfortunately the therapeutic potential of these compounds is limited by their poor intestinal and intracellular bioavailability. Therefore this study sought to examine how combinations of quercetin, resveratrol, and curcumin, with and without piperine, 200 nM, affected an
In Vitro permeability model using apical-to-basal permeability across intact caco-2 monolayers. Quercetin, resveratrol and curcumin were applied apically alone or in combination at 50 μM and measured in the basal chamber at 30 min. Results
Resveratrol received the greatest enhancement in permeability when combined with other agents: quercetin (310%), curcumin (300%), quercetin and curcumin (323%, 350% with piperine). Curcumin also demonstrated increased permeability when combined with quercetin alone (147%) and both quercetin
and resveratrol (188%), addition of piperine resulted in a 229% increase in permeability. Quercetin permeability was not significantly affected using any combination, but showed maximal permeability when combined with resveratrol and the lowest permeability when combined with resveratrol,
curcumin and piperine together. Conclusion
Combination of quercetin, resveratrol and curcumin may improve intestinal absorption of resveratrol and curcumin without affecting quercetin absorption. These data highlight the need for further research
and suggest that developing combination therapies may improve intestinal absorption of these constituents. Our study also demonstrates that the apical-to-basal permeability across intact caco-2 monolayer model is a viable model to investigate absorption of natural compounds.
Abstract Context: Resveratrol, a natural compound found in grapes, has potential chemotherapy effects but very low oral bioavailability in humans. Objective: To evaluate the solubility, pH stability profile, plasma protein binding (PPB) and stability in plasma for resveratrol. Methods: Solubility of resveratrol was measured in 10 common solvents at 25 °C using HPLC. The solution state pH stability of resveratrol was assessed in various United States Pharmacopeia buffers ranging from pH 2 to 10 for 24 h at 37 °C. Samples were analyzed up to 24 h. Human PPB was determined using ultracentrifugation technique. Standard solutions of drug were spiked to blank human plasma to yield final concentrations of 5, 12.5 or 25 μg/mL for determination. Finally, stability of resveratrol in human and rat plasma was also assessed at 37 °C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50 μg/mL. Samples were analyzed for resveratrol concentration up to 96 h. Results: Resveratrol has wide solubility ranging from 0.05 mg/mL in water to 374 mg/mL in polyethylene glycol 400 (PEG-400). Resveratrol is relatively stable above pH 6 and has maximum degradation at pH 9. The mean PPB of resveratrol is 98.3%. Resveratrol degrades in human and rat plasma in a first-order process with mean half lives of 54 and 25 h, respectively. Conclusion: Resveratrol is more soluble in alcohol and PEG-400 and stable in acidic pH. It binds highly to plasma proteins and degrades slower in human then rat plasma.
Relatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic
acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized
to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This
study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identified and
cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were
collected from 153 tuberculosis (TB) patients, and the results were evaluated to confirm whether a correlation existed between
PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that coadministration of amidase inhibitor (bis-p-nitrophenyl phosphate [BNPP]) decreases or prevents PZA- and PZA metabolite-induced hepatotoxicity in rats. PA and 5-OH-PA
are more toxic than PZA. Electron microscopy showed that PZA and PA treatment of rats significantly increases aspartate transaminase
(AST) and alanine aminotransferase (ALT) activity and galactose single-point (GSP) levels (P < 0.005). PA and 5-OH-PA levels are also significantly correlated with hepatotoxicity in the urine of TB patients (P < 0.005). Amidase inhibitor, BNPP, decreases PZA-induced, but not PA-induced, hepatotoxicity. This is the first report of
a cell line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA-induced hepatotoxicity.
Based on the fact that quercetin (QUE) and resveratrol (RES) induce a synergic inhibition of the adipogenesis and increase apoptosis in adipocytes, and that sodium deoxycholate (SDC) has necrotic effects, the nanoencapsulation of QUE and RES into SDC-elastic liposomes is proposed as a new approach for dissolving the subcutaneous fat. The concentration of constituents and the effect of the drug incorporation into cyclodextrin inclusion complexes on the stability of QUE/RES-loaded liposomes were studied. The best liposomal formulation reduced the use of phosphatidylcholine and cholesterol in 17.7% and 68.4%, respectively. Liposomes presented a mean diameter of 149nm with a polydispesion index of 0.3. The zeta potential of liposomes was slightly negative (-13.3mV) due to the presence of SDC in the phospholipid bilayer. Encapsulation efficiency of QUE and RES into liposomes was almost 97%. To summarize, QUE/RES-loaded elastic liposomes are stable and suitable for subcutaneous injection, thereby providing a new strategy for reducing subcutaneous fat.
Pharmacokinetics of trans-resveratrol in its aglycone (RES(AGL)) and glucuronide (RES(GLU)) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of beta-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES(AGL) and RES(GLU) was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RES(AGL) and RES(GLU) were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RES(AGL) declined with a rapid elimination half-life (T(1/2), 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES(AGL) (T(1/2TER), 1.31 h). RES(AGL) and RES(GLU) also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T(1/2TER) of 1.48 and 1.58 h, respectively. RES(AGL) bioavailability was 38% and its exposure was approximately 46-fold lower than that of RES(GLU) (AUC(inf), 7.1 versus 324.7 micromol.h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES(AGL) and RES(GLU) were observed in bile-recipient rats at 4 to 8 h. The percentages of the exposures of RES(AGL) and RES(GLU) that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RES(AGL) is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RES(AGL) and RES(GLU) in rats.
In the present work, quercetin and resveratrol, natural polyphenols with strong antioxidant and anti-inflammatory properties, were co-loaded in polymer-associated liposomes conceived for oral delivery, by exploiting the potential of pH-sensitive succinyl-chitosan. Chitosan was succinylated, characterized by Nuclear Magnetic Resonance spectroscopy and Gel Permeation Chromatography, and used to form a protective shell on the surface of liposomes. The physico-chemical properties of the succinyl-chitosan liposomes were assessed by light scattering, zeta potential, cryogenic transmission electron microscopy, and small angle X-ray scattering. Small, spherical, uni- and bilamellar vesicles were produced. The succinyl-chitosan shell increased not only the physical stability of the vesicular system, as demonstrated by accelerated stability tests, but also the release of the polyphenols to a greater extent at pH 7.0, mimicking the intestinal environment.
The present investigation reports the development of liposomes for the co-delivery of naturally occurring polyphenols, namely quercetin and resveratrol. Small, spherical, uni/bilamellar vesicles were produced, as demonstrated by light scattering, cryo-TEM, SAXS. The incorporation of quercetin and resveratrol in liposomes did not affect their intrinsic antioxidant activity, as DPPH radical was almost completely inhibited. The cellular uptake of the polyphenols was higher when they were formulated in liposomes, and especially when co-loaded rather than as single agents, which resulted in a superior ability to scavenge ROS in fibroblasts. The in vivo efficacy of the polyphenols in liposomes was assessed in a mouse model of skin lesion. The topical administration of liposomes led to a remarkable amelioration of the tissue damage, with a significant reduction of oedema and leukocyte infiltration. Therefore, the proposed approach based on polyphenol vesicular formulation may be of value in the treatment of inflammation/oxidative stress associated with pre-cancerous/cancerous skin lesions.
Trans resveratrol (RSV), a natural molecule isolated from red wine, is widely known for several therapeutic potentials. RSV is proved for cardioprotective effects, vasodilation, anti-inflammatory, anticancer effects. Recently, anti cancer potential against glioma cells has also been reported. However, the clinical application of RSV in glioma treatment is largely limited because of its rapid metabolism and elimination from systemic circulation thereby exhibiting low biological half life and poor brain distribution as well. Therefore, the main objective of this study was to enhance the circulation time, biological half life and passive brain targeting of RSV using D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) coated solid lipid nanoparticles (RSV-TPGS-SLN). RSV-TPGS-SLN formulations were prepared by solvent emulsification evaporation method and evaluated for several nanoparticulate characterizations. In vitro anti cancer potential and cellular internalization of nanoparticles were also carried out in C6 glioma cell lines. Pharmacokinetics and biodistribution studies were carried out following intravenous administration in healthy Charles Foster rats. RSV-TPGS-SLN showed significantly higher in vitro cytotoxicity against and excellent cellular internalization. RSV-TPGS-SLN showed 11.12 and 9.37 times higher area under the curve and plasma half life than RSV solution, respectively. Moreover, brain distribution of RSV-TPGS-SLN was found to be 9.23 times higher in comparison to that of RSV alone. Thus, we anticipate that the RSV-TPGS-SLN formulation can be applied as a potential tool for improving circulation time, biological half life and passive brain targeting of RSV, thereby immensely useful in the treatment of glioma.
In vitro degradation behavior of squeeze cast (CAST) and equal channel angular pressed (ECAP) ZM21 magnesium alloy (2.0 wt% Zn-0.98 wt% Mn) was studied using immersion tests up to 4 w in three different biological environments. Hanks' Balanced Salt Solution (Hanks), Earle's Balanced Salt Solution (Earle) and Eagle minimum essential medium supplemented with 10% (v/v) fetal bovine serum (E-MEM + 10% FBS) were used to investigate the effect of carbonate buffer system, organic compounds and material processing on the degradation behavior of the ZM21 alloy samples. Corrosion rate of the samples was evaluated by their Mg2 + ion release, weight loss and volume loss. In the first 24 h, the corrosion rate sequence of the CAST samples was as following: Hanks > E-MEM + 10% FBS > Earle. However, in longer immersion periods, the corrosion rate sequence was Earle > E-MEM + 10% FBS ≥ Hanks. Strong buffering effect provided by carbonate buffer system helped to maintain the pH avoiding drastic increase of the corrosion rate of ZM21 in the initial stage of immersion. Organic compounds also contributed to maintain the pH of the fluid. Moreover, they adsorbed on the sample surface and formed an additional barrier on the insoluble salt layer, which was effective to retard the corrosion of CAST samples. In case of ECAP, however, this effect was overcome by the occurrence of strong localized corrosion due to the lower pH of the medium. Corrosion of ECAP samples was much greater than that of CAST, especially in Hanks, due to higher sensitivity of ECAP to localized corrosion and the presence of Cl−.
The present work demonstrates the importance of using an appropriate solution for a reliable estimation of the degradation rate of Mg-base degradable implants in biological environments, and concludes that the most appropriate solution for this purpose is E-MEM + 10% FBS, which has the closest chemical composition to human blood plasma.
Polymeric and hybrid aqueous-core nanocapsules were prepared using a low energy organic-solvent free procedure as innovative nanodevices for the ophthalmic delivery of melatonin. In order to evaluate how different cationic lipids could affect the main properties of the nanodevices, we focused our attention on mean particles size, surface charge, shape and stability (the “4S”). The results of our study confirmed the hypothesis that the coating material differently affects the overall nanoparticles properties, above all in terms of morphology: in particular, the cationic lipid dimethyldioctadecylammonium bromide allows the formation of very stable well-defined nanocapsules with non-spherical shape with sustained and prolonged drug release, thus representing a great advantage in ophthalmic application.
Recently trans-resveratrol (trans-RSV) has received great attention due to its prophylactic and therapeutic properties. Its limited bioavailability provides compelling evidence of the need for more suitable formulations in order to attain better clinical effectiveness. Some physicochemical properties of trans-RSV are still unknown or research findings are contradictory. Therefore, this paper presents newly determined trans-RSV solubility and stability at various pH and temperatures, and the importance of such data for the studies of novel trans-RSV-loaded nanofibers. In acidic pH trans-RSV was stable, whereas its degradation started to increase exponentially above pH 6.8. Consequently, it is worthwhile to note that special consideration has to be dedicated to long dissolution testing or biological assays on cell lines in order to obtain relevant data. Measurements were done by validated UV/VIS spectroscopy, HPLC, and newly developed UPLC methods. Specificity was confirmed for HPLC and UPLC method, whereas UV/VIS spectroscopy resulted in false higher trans-RSV concentrations in conditions under which it was not stable (alkaline pH, light, increased temperature). The study is of interest because it draws attention to the importance of careful selected experimental conditions, their influence on the trans-RSV stability and the implications this has for formulation development, storage, and maintenance of therapeutic doses.
Copyright © 2015. Published by Elsevier B.V.
Legumes and particularly beans are a key food of Mediterranean diet representing an important source of proteins, fiber, some minerals and vitamins and bioactive compounds. We evaluated the antioxidant and anti-mutagenic effects of a new fermented powder of a selected lectin-free and phaseolamin-enriched variety of common bean (Phaseolus vulgaris L.), named Lady Joy. Lady Joy lysate (Lys LJ) was studied in human erythrocytes and in Saccharomyces cerevisiae yeast cells. The antioxidant and anti-hemolytic properties of Lys LJ, studied in an ex vivo erythrocytes system using the cellular antioxidant assay (CAA-RBC) and the hemolysis test, evidenced a dose-dependent antioxidant activity as well as a significant hemolysis inhibition. Besides, results evidenced that Lys LJ treatment significantly decreased the intracellular ROS concentration and mutagenesis induced by hydrogen peroxide in S. cerevisiae D7 strain. In conclusion, Lys LJ showed both an antimutagenic effect in yeast and a strong scavenging activity in yeast and human cells.
Exploiting the experimental factorial design and the potentiality of Turbiscan AG Station, we developed and characterized unmodified and DDAB-coated NLC prepared by a low energy organic solvent free phase inversion temperature technique. A 22 full factorial experimental design was developed in order to study the effects of two independent variables (DDAB and ferulic acid) and their interaction on mean particle size and zeta potential values. The factorial planning was validated by ANOVA analysis; the correspondence between the predicted values of size and zeta and those measured experimentally confirmed the validity of the design and the equation applied for its resolution. The DDAB-coated NLC were significantly affected in their physico-chemical properties by the presence of DDAB, as showed by the results of the experimental design. The coated NLC showed higher physical stability with no particles aggregation compared to the unmodified NLC, as demonstrated by Turbiscan(®) AGS measurements. X-ray diffraction, Raman spectroscopy and Cryo-TEM images allowed us to assert that DDAB plays a critical role in increasing the lipids structural order with a consequent enhancement of the NLC physical stability. Furthermore, the results of the in vitro biological studies allow the revisiting of the role of DDAB to the benefit of glioblastoma treatment, due to its efficacy in increasing the NLC uptake and reducing the viability of human glioblastoma cancer cells (U87MG).
This mini-review highlights the latest advances in the chemistry and biology of Pluronic[registered sign] triblock copolymers. We focus on their applications in medicine, as drug delivery carriers, biological response modifiers, and pharmaceutical ingredients. Examples of drug delivery systems and formulations currently in clinical use, clinical trials or preclinical development are highlighted. We also discuss the role that Pluronic[registered sign] copolymers may play in the innovative design of new nanomedicines in the near future.
Pluronic copolymer L61 was found to possess a stealth function for liposomal drug delivery, comparing favorably to PEG. The liposomes modified with 0.1% L61 (w/w) were long-circulating, and preferentially accumulated in the tumor site. The paclitaxel-loaded L61-liposomes with a single injection dose could successfully arrest the tumor growth, lasting for five days, and displayed better treatment outcomes compared to the non-modified liposomes and even the PEGylated liposomes.
There has been interest in the use of trans-resveratrol as a natural preventative agent for improving health and alleviating a range of diseases. However, resveratrol has low bioavailability, and this has been associated with its poor water solubility, its low stability against environmental stress, and its inability to reach a target site in the body to exert the desired health effect. Encapsulation offers a potential approach for enhancing the solubility of resveratrol, stabilizing it against trans-to-cis isomerization, and improving its bioavailability. A range of encapsulant materials, formulations, and technologies have been examined for enhancing the delivery of resveratrol. Research on the efficacy of encapsulated resveratrol formulations and relevant doses for specific applications is required before recommendations may be made for the use of these formulations for human health outcomes.
d-α-Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) is formed by the esterification of Vitamin E succinate with polyethylene glycol 1000. As novel nonionic surfactant, it exhibits amphipathic properties and can form stable micelles in aqueous vehicles at concentration as low as 0.02wt%. It has been widely investigated for its emulsifying, dispersing, gelling, and solubilizing effects on poorly water-soluble drugs. It can also act as a P-glycoprotein (P-gp) inhibitor and has been served as an excipient for overcoming multidrug resistance (MDR) and for increasing the oral bioavailability of many anticancer drugs. Since TPGS has been approved by FDA as a safe pharmaceutic adjuvant, many TPGS-based drug delivery systems (DDS) have been developed. In this review, we discuss TPGS properties as a P-gp inhibitor, solubilizer/absorption and permeation enhancer in drug delivery and TPGS-related formulations such as nanocrystals, nanosuspensions, tablets/solid dispersions, adjuvant in vaccine systems, nutrition supplement, plasticizer of film, anticancer reagent and so on. This review will greatly impact and bring out new insights in the use of TPGS in DDS.
The physical conjugation of (tri-) block copolymer molecules to phospholipid vesicle bilayers in order to construct sterically stabilized vesicles can be carried out in two different ways: by allowing the copolymer molecules to freely participate in the small unilamellar vesicle (SUV) formation process along with the lipids or by adding the copolymer molecules to pre-formed small unilamellar liposomes. Structurally and morphologically different copolymer coated vesicle systems occur. The effect on the mean vesicle diameter and the vesicle surface characteristics is monitored by dynamic light scattering and laser Doppler electrophoresis techniques for a wide variety of block copolymer molecules of the PEO−PPO−PEO type (PEO is poly(ethylene oxide); PPO poly(propylene oxide)). Systematic investigations as a function of copolymer added concentration and molecular structure were undertaken throughout. The results indicate a dramatic increase in mean vesicle diameter when the polymer molecules are present during vesiculation, while in the case of copolymer addition to already formed liposomes the mean vesicle size follows a classic Langmuirian-type adsorption curve as a function of copolymer concentration. The ζ-potential values obtained decrease in a very similar pattern irrespective of the way of addition for the large PF127 (PEO99−PPO65−PEO99) molecule, illustrating the presence of polymer chains at the vesicle surface. For the small, more hydrophobic L61 (PEO10−PPO16−PEO10) molecule, the reduced ζ-potential value is maintained only when the copolymer molecules participate in bilayer formation, indicating absence of interaction between the polymer and the lipids when added to preformed liposomes, due to the preferred copolymer tendency to aggregate into micelles separate from the lipid bilayer particles (that eventually leads to phase separation). According to the molecular models proposed to describe the occurring lipid−copolymer interactions, addition of copolymer molecules after liposomes have been formed leads to their adsorption onto the outer liposome surface, its effectiveness being dependent on the influence that the hydrophilic (PEO) and hydrophobic (PPO) blocks exert on the copolymer molecular behaviour. Copolymer−lipid coparticipation toward bilayer formation, at low added polymer concentrations, leads to PPO block protection by arranging along with the lipids as integral parts of the vesicle bilayer, hence anchoring the PEO chains that dangle in the aqueous solution onto the vesicles. Simple geometrical considerations are also included, reinforcing the theoretical feasibility of the described models. The latter type of physically conjugating polymer chains onto vesicle surfaces is proposed as an improved alternative to the weak adsorption of amphiphilic molecules and the cumbersome chemical modification of the lipid polar headgroups to confer steric protection to liposomal surfaces.
We studied mixtures of emulsion droplets and solid particles in order to determine the possibility of specific interaction between both types of systems. The solid particles were polystyrene with grafted methylpoly(ethylene oxide) of average 2000 molecular weight. This latex form stable suspensions. This latex was prepared by dispersion polymerization and produced particles with a radius of 315 nm and low polydispersity. The emulsion was prepared by shearing a mixture of hexadecane and water and using a polymeric surfactant. Synperonic L92, as emulsifier. The Z-average droplet radius was 280 nm. Latex and emulsion were mixed by using low shear rates, and the theological properties of the mixtures were measured, as well as theological properties of the pure systems. The oscillatory behaviors of the emulsion and the suspension are similar at low volume fractions, where the emulsion droplets seem to behave as hard spheres. No specific interaction could be detected, meaning that latex-latex, emulsion-emulsion, and latex-emulsion interactions are of the same type. In steady state measurements some dependence of phi(max) (maximum volume of packing) with volume fraction and shear rate was detected for the emulsion systems. This dependence shows the influence of the deformability of the droplets. At high volume fractions, the theological behaviors of the emulsion and the suspension are very different, in both steady state and dynamic measurements. The elastic modulus in the linear region depends on the volume fraction in an exponential fashion for solid particles while the dependence is linear for the deformable particles. The mixtures show intermediate behavior, and their elasticity is well represented by a simple model in which the emulsion and the suspension elastic modulus are used in series with the appropriate weights. A dependence of the critical strain (the strain above which the theological parameters start to depend on the strain) with volume fraction has been found. The critical strain decreases with volume fraction and goes to a minimum around phi(max).
In this work, resveratrol (Res) was incorporated into chitosan microspheres for controlled release and stabilisation. The microspheres were prepared by emulsion chemical cross-linking method, and vanillin was used as the novel cross-linker. The microspheres showed a smooth surface with irregular small particles and internal voids with a size distribution between 53 and 311 μm. Interpenetrating network cross-linking mechanisms might account for the Schiff base reaction between chitosan and vanillin. The encapsulation efficiency of Res within microspheres was up to 93.68%. Res contained within microspheres was protected from light and heat compared with the free Res. In addition, release behaviours were governed by two distinct stages and dependent on pH of release media. Diffusion, swelling and erosion mechanisms might coexist for the full controlled release and Higuchi was the most suitable model for the whole release procedure. Thus, controlled release and stabilization of Res were achieved through incorporation of Res into cross-linked chitosan microspheres by vanillin.
D-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG). As such, it has advantages of PEG and Vitamin E in application of various nanocarriers for drug delivery, including extending the half-life of the drug in plasma and enhancing the cellular uptake of the drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with a hydrophile/lipophile balance (HLB) value of 13.2 and a relatively low critical micelle concentration (CMC) of 0.02% w/w, which make it to be an ideal molecular biomaterial in developing various drug delivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able to realize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance (MDR) and to promote oral drug delivery as an inhibitor of P-glycoprotein (P-gp). In this review, we briefly discuss its physicochemical and pharmaceutical properties and its wide applications in composition of the various nanocarriers for drug delivery, which we call TPGS-based drug delivery systems.
Lanthanum (La), a rare earth element with anticoagulative and antiphlogistic function, was added into the medical grade 316L stainless steel in order to improve its biocompatibility. The corrosion resistance of the La added 316L steel in two different simulated body fluids, simulated blood plasma and Hank's solution, was evaluated. The result showed that the addition of La in the steel could largely affect the corrosion behavior of the steel. The steel with 0.01% La showed the widest passive region and the best resistance to pitting attack, within the addition range of La from 0.01% to 0.08%. The corrosion resistance improvement of La added 316L stainless steel is probably due to the effect of La on the purification of the steel, the modification of inclusions, and the passive film formation in the simulated body fluids.
This study aimed at the investigation of the impact of aqueous solubility and dose manipulation on the pharmacokinetics of resveratrol.
Water soluble intravenous and oral formulations of resveratrol were prepared with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and randomly methylated-beta-cyclodextrin (RM-beta-CD), respectively. Sodium salt and suspension of resveratrol in carboxymethyl cellulose (CMC) were used as the reference intravenous and oral formulations, respectively. The pharmacokinetics of resveratrol was assessed in Sprague-Dawley rats. Plasma resveratrol concentrations were measured by high performance liquid chromatography (HPLC).
Both HP-beta-CD and RM-beta-CD enhanced the aqueous solubility of resveratrol. After intravenous administration, rapid elimination of resveratrol was observed at all tested doses (5, 10, and 25 mg kg(-1)) regardless of formulation types; with non-linear elimination occurring at the dose of 25 mg kg(-1). RM-beta-CD significantly increased the maximal plasma concentration of orally administered resveratrol, but, it did not increase the oral bioavailability in comparison with the CMC suspension. Furthermore, the oral bioavailability remained unchanged among all tested doses (15, 25, and 50 mg kg(-1)).
Aqueous solubility barrier might affect the speed but not the extent of resveratrol absorption. Further, dose manipulation (up to 50 mg kg(-1)) did not have a significant impact on the oral bioavailability of resveratrol.
To develop a population pharmacokinetic (PK) model which allowed the simultaneous modeling of trans-resveratrol and its glucuronide and sulfate conjugates.
Male Sprague-Dawley rats were administered i.v. and p.o. with 2, 10 and 20 mg·kg(-1) of trans-resveratrol. Blood was collected at different times during 24 h. An integrated PK model was developed using a sequential analysis, with non-linear mixed effect modeling (NONMEM). A prediction-corrected visual predictive check (pcVPC) was used to assess model performance. The model predictive capability was also evaluated with simulations after the i.v. administration of 15 mg·kg(-1) that were compared with an external data set.
Disposition PK of trans-resveratrol and its metabolites was best described by a three-linked two-compartment model. Clearance of trans-resveratrol by conversion to its conjugates occurred by a first-order process, whereas both metabolites were eliminated by parallel first-order and Michaelis-Menten kinetics. The pcVPC confirmed the model stability and precision. The final model was successfully applied to the external data set showing its robustness.
A robust population PK model has been built for trans-resveratrol and its glucuronide and sulfate conjugates that adequately predict plasmatic concentrations.
Natural bioactive compounds have been studied for a long time for their chemopreventive and therapeutic potential in several chronic inflammatory diseases, including cancer. However, their physicochemical properties generally result in poor chemical stability and lack of in vivo bioavailability. Very few human clinical trials have addressed absorption, distribution, metabolism, and excretion of these compounds in relation to efficacy. This limits the use of these valuable natural compounds in the clinic.
The morphology and stability of small unilamellar egg yolk phosphatidylcholine (EggPC) liposomes modified with the Pluronic copolymer (poly (oxyethylene)-poly (oxypropylene)-poly (oxyethylene) (PEO-PPO-PEO)) with different compositions on mica surface have been investigated using atomic force microscopy. Morphology studies reveal significant morphological changes of liposomes upon incorporating the Pluronic copolymer. Bilayers are observed for Pluronic with small hydrophilic (PEO) chain lengths such as L81 [(PEO)2(PPO)40(PEO)2] and L121 [(PEO)4(PPO)60(PEO)4]; bilayer and vesicle coexistence is observed for P85 [(PEO)26(PPO)39.5(PEO)26] and F87 [(PEO)61.1(PPO)39.7(PEO)61.1]; and stable vesicles are observed for F88 [(PEO)103.5(PPO)39.2(PEO)103.5], F127 [(PEO)100(PPO)65(PEO)100], and F108 [(PEO)132.6(PPO)50.3(PEO)132.6]. The micromechanical properties of Pluronic-modified EggPC vesicles were studied by analyzing AFM approaching force curve. The bending modulus (k(c)) of the Pluronic-modified EggPC vesicles increased several-fold compared with that of the pure EggPC vesicles. The significant difference is due to the enhanced rigidity of the EggPC vesicles as a result of the incorporation of PPO molecules and PEO chains. Based on the analysis of onset point by AFM and diameters of vesicles by light scattering, it was concluded that the favorable model to describe the polymer-bilayer interaction is the membrane-spanning model.
A cellular antioxidant activity (CAA) assay for quantifying the antioxidant activity of phytochemicals, food extracts, and dietary supplements has been developed. Dichlorofluorescin is a probe that is trapped within cells and is easily oxidized to fluorescent dichlorofluorescein (DCF). The method measures the ability of compounds to prevent the formation of DCF by 2,2'-azobis(2-amidinopropane) dihydrochloride (ABAP)-generated peroxyl radicals in human hepatocarcinoma HepG2 cells. The decrease in cellular fluorescence when compared to the control cells indicates the antioxidant capacity of the compounds. The antioxidant activities of selected phytochemicals and fruit extracts were evaluated using the CAA assay, and the results were expressed in micromoles of quercetin equivalents per 100 micromol of phytochemical or micromoles of quercetin equivalents per 100 g of fresh fruit. Quercetin had the highest CAA value, followed by kaempferol, epigallocatechin gallate (EGCG), myricetin, and luteolin among the pure compounds tested. Among the selected fruits tested, blueberry had the highest CAA value, followed by cranberry > apple = red grape > green grape. The CAA assay is a more biologically relevant method than the popular chemistry antioxidant activity assays because it accounts for some aspects of uptake, metabolism, and location of antioxidant compounds within cells.
We and a Dutch group reported that "empty" PEGylated liposomes (approximately 100 nm) lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). Very recently, we showed that anti-PEG IgM, induced by the first dose of "empty" PEGylated liposomes, is responsible for inducing the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no or lower immunogenicity. However, the results indicated evidence that unexpected immune responses occur even to such polymer-coated liposomes. Such immunogenicity of "empty" liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. In addition, through series of our studies, it was demonstrated that the magnitude of the ABC phenomenon depends on the physicochemical property of injected liposomes as a first dose, time interval between injection, lipid dose and drug-encapsulation.
- C Caddeo
C. Caddeo et al.
International Journal of Pharmaceutics 538 (2018) 40-47