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Nanotechnological Innovations Enhancing the Topical Therapeutic Efficacy of Quercetin: A Succinct Review
Abstract
Nanotechnology is currently the new hot topic in dermatology and nutraceutical/cosmeceutical delivery, owing to the advantages it provides in terms of enhancing the skin permeation of drugs, as well as increasing their therapeutic efficacy in the treatment of different dermatological diseases. There is also a great interest in the topical delivery of nutraceuticals; which are natural compounds with both therapeutic and cosmetic benefits, in order to overcome the side effects of topically applied chemical drugs. Quercetin is a key nutraceutical with topical antioxidant and anti-inflammatory properties which was reported to be effective in the treatment of different dermatological diseases, however, its topical therapeutic activity is hindered by its poor skin penetration. This review highlights the topical applications of quercetin, and summarizes the nanocarrier-based solutions to its percutaneous delivery challenges.
... [6] Recently, several researchers have focused on the beneficial effects of using active dietary ingredients, such as phytochemicals in counteracting multiple diseases related to oxidative stress. [7][8][9][10][11][12][13][14] Previous investigators demonstrated the possible antidiabetic action of Curcuma longa (turmeric) rhizome, and it was proven effective in counteracting the oxidative stress and metabolic disorders as well as hepatopathy. [15] Curcumin is the main bioactive component of turmeric rhizome and is considered a highly active phenolic compound. ...
... Counting of spermatogenic cells was performed including spermatogonia, primary and secondary spermatocytes, spermatids and spermatozoa. Finally, regarding the Modified Johnsen spermatogenesis scoring, it was conducted as follows: (1) No seminiferous epithelium, (2) No germinal cells, Sertoli cells only, (3) Spermatogonia only, (4) No spermatozoa or spermatids, few spermatocytes, (5) No spermatozoa or spermatids, many spermatocytes, (6) No spermatozoa, no late spermatids, few early spermatids, (7) No spermatozoa, no late spermatids, many early spermatids, (8) Less than five spermatozoa per tubule, few late spermatids, (9) Slightly impaired spermatogenesis, many late spermatids, disorganized epithelium, (10) Full spermatogenesis. ...
Objectives:
Curcumin is a promising nutraceutical with reported diverse therapeutic properties, but of limited oral bioavailability. The current manuscript investigates the role of encapsulation of curcumin in nanoemulsion form in counteracting the adverse effect of chronic ingestion of a high-fat high-fructose diet (HFHF) by juvenile male rats regarding testicular abnormalities and declined spermatogenesis.
Methods:
Curcumin nanoemulsion was administered orally to Wistar rats at a dose of 5 or 10 mg/kg and compared with curcumin powder, followed by a pharmacological and histological assessment.
Key findings:
Results demonstrated that curcumin nanoemulsion was superior to curcumin powder, particularly in enhancing the percentage progressive motility of spermatozoa, normalization of essential and non-essential amino acids in semen, normalization of serum leptin and testosterone levels, as well as normalization of oxidative and nitrosative parameters. It was also proven to reduce testicular DNA fragmentation, while elevating testicular cellular energy. In addition, curcumin nanoemulsion administered at a dose of 10 mg/kg induced the highest level of spermatogenesis, delineated by histological examination of the seminiferous tubules.
Conclusions:
It can be concluded that curcumin nanoemulsion administered at a dose of 10 mg/kg successfully ameliorates the adverse effects of a HFHF on spermatogenesis.
... However, one of the main challenges of phytochemicals (naturally occurring constituents from plants) is their poor penetration via the skin barrier which might prohibit their dermal administration [3]. Nanotechnology application has been investigated by many researchers to resolve the problems of topical application of natural products [6]. Nanocarriers can enhance the penetration of the entrapped drugs by improving their solubility and protecting them against instability problems [7]. ...
The foremost target of the current work was to formulate and optimize a novel bergamot essential oil (BEO) loaded nano-phytosomes (NPs) and then combine it with spironolactone (SP) in order to clinically compare the efficiency of both formulations against acne vulgaris. The BEO-loaded NPs formulations were fabricated by the thin-film hydration and optimized by 3² factorial design. NPs’ assessments were conducted by measuring entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). In addition, the selected BEO-NPs formulation was further combined with SP and then examined for morphology employing transmission electron microscopy and three months storage stability. Both BEO-loaded NPs selected formula and its combination with SP (BEO-NPs-SP) were investigated clinically for their effect against acne vulgaris after an appropriate in silico study. The optimum BEO-NPs-SP showed PS of 300.40 ± 22.56 nm, PDI of 0.571 ± 0.16, EE% of 87.89 ± 4.14%, and an acceptable ZP value of −29.7 ± 1.54 mV. Molecular modeling simulations showed the beneficial role of BEO constituents as supportive/connecting platforms for favored anchoring of SP on the Phosphatidylcholine (PC) interface. Clinical studies revealed significant improvement in the therapeutic response of BEO-loaded NPs that were combined with SP over BEO-NPs alone. In conclusion, the results proved the ability to utilize NPs as a successful nanovesicle for topical BEO delivery as well as the superior synergistic effect when combined with SP in combating acne vulgaris.
... Among advanced drug delivery systems, nanotechnology-based formulations are currently fascinating research community in administering dermatology products, nutraceuticals, cosmetics, and pharmaceuticals. Enhancement of skin permeation, ex-vivo cutaneous drug deposition and improved therapeutic efficacy of the bioactive are other merits offered by these formulations (Nasr and Al-Karaki, 2020). From the abundant current literature reports, numerous novel nano carrier systems for topical delivery have been explored by formulation scientists (Amer et al., 2020). ...
Background
Quercetin is one of the most critical endogenous anti-oxidants used widely in cosmetics, nutraceuticals, and pharmaceuticals products for skincare and therapeutics due to its protective character against oxidants and inflammation. Although low hydrophilicity and poor percutaneous absorption of quercetin make it an untrustworthy entrant for topical delivery, numerous new perspectives have been developed and proposed to overwhelm these problems. Amongst multiple outlooks, nanoparticles-based drug delivery system has gained highlighted attention and showed various advantages in topical delivering a hydrophobic drug like quercetin.
Method
The relevant literature was collected from an exhaustive search on databases like PubMed, ScienceDirect, Google Scholar, and others using various keywords, including “quercetin nanoformulations,” “dermal nanoformulations of quercetin,” “quercetin topical formulations,” and many others. Publications in the English language accessed till July 2021 were chosen, whereas non-English language papers, dissertations, unpublished data, and non-original papers were excluded from the study.
Results
The present review comprises of various quercetin nanoformulations developed last decade for topical delivery of quercetin. Until recently, numerous nanocarriers systems, including nanovesicles, nanospheres, nanocapsules, nanogels, nanofibres, nanoemulsions, micelles, gold nanoparticles, silica nanoparticles, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), have been developed for skin delivery of quercetin that not only improves the solubility and skin permeability but also augments the physicochemical stability and provides sustain and control release.
Conclusions
Nanostructured particles of herbal drugs offer several advantages over other conventional drug delivery systems. Advanced delivery formulations not only help in solving hitches such as poor solubility, bioavailability and stability of quercetin, but also, in the case of topical delivery, overcome the formidable barrier of the skin. Indeed, the application of herbal nanomedicine and herbal nano-drug delivery system is certainly the trend. However, for clinical utilization of such formulations, their investigation in humans needs to be explored. Such exploration along with in depth analysis and dose optimization can pave way for commercial success of quercetin advanced carrier systems for topical application.
... Based on these studies, it was delineated that baicalin suffers from low bioavailability of about 2.2 ± 0.2%, owing to its low aqueous solubility, permeability, distribution coefficient and stability [2]. Nanotechnology was recommended as one of the possible solutions for the pharmaceutical challenges of baicalin, since nanoparticles were previously reported to allow solubilization of nutraceuticals and increase their bioavailability, which is further reflected on their therapeutic efficacy [3][4][5][6][7]. Particularly for baicalin, several types of nanoparticles have been reported as carriers for this nutraceutical, achieving promising therapeutic results. ...
Baicalin is a natural flavonoid isolated from the roots of the medicinal plant Scutellaria baicalensis, which has been widely used in China since ancient times. It exhibits many beneficial effects on human health including antimicrobial, anti-inflammatory, anticancer and antioxidant activities. Therefore, it can be used alone or as an adjuvant with other drugs in the treatment of a variety of diseases. Despite its pharmacological merits, baicalin suffers from several pharmacokinetic limitations, including hydrolysis in the gastrointestinal tract (GIT) and first pass metabolism, in addition to its poor aqueous solubility. As an approach to overcome these challenges and increase the bioavailability of baicalin, several nanocarriers were introduced to enhance its solubilization and absorption. This review presents an overview on the pharmacological activities of baicalin, and describes in details the different nanocarriers that were reported for its delivery via different routes of administration to date.
... Despite its merits, the therapeutic potential of CUR is limited by its challenging physicochemical properties such as poor solubility, low bioavailability, and photodegradation (Cheng et al., 2013;Mohanty et al., 2012). Nanotechnology has provided a solution for the challenging delivery problems of nutraceuticals and allowed for the full exertion of their therapeutic properties (Abu-Azzam & Nasr, 2020; Amer et al., 2020;El-Gogary et al., 2019;Hatem et al., 2018, Hatem et al., 2018a, 2018bNasr & Al-Karaki, 2020;Shaaban et al., 2019). ...
Diabetes mellitus has been implicated in the exacerbation of cerebral ischemic injuries. Among the most promising therapeutic approaches is the combination of nutraceuticals and nanotechnology. Curcumin has been termed “the magic molecule”, and it was proven to exert several therapeutic actions. Therefore, the aim of the presented work was to investigate the therapeutic effects of curcumin nanoemulsion (NC) administered orally on the middle cerebral artery occlusion and reperfusion (MCAO/Re)‐induced cerebral damage in rats with streptozotocin‐induced diabetes. The cerebral injury was induced in rats by MCAO/Re 6 weeks after single intraperitoneal STZ injection (50 mg/kg; i.p.). MCAO/Re diabetic rats were then treated with NC (50 and 100 mg/kg; bw; p.o.) for two consecutive weeks. The results of the present study showed that oral treatment of MCAO/Re diabetic rats with NC was associated with a marked attenuation of the neurological deficit score as well as the brain imbalance of the redox homeostasis. NC treatment was also associated with decline in the brain expression of tumor necrosis factor, interleukin‐1β, COX‐2, cleaved caspase‐3, and nuclear factor kappa B. In addition, the expression of glucose transporter 1 proteins upon treatment was restored.
Practical applications
From all these results, it can be concluded that oral supplementation of curcumin nanoemulsion (NC) in diabetic rats reduced the brain injury via augmentation of the expression of glucose transporter 1, as well as its antioxidant and anti‐inflammatory properties. Therefore, NC could be delineated as a promising treatment option for cerebral ischemia in diabetic patients.
... Drug carriers achieve topical delivery by either accessing a shunt, such as hair follicle, or by preferentially accumulating in the spaces between corneocytes where they intermingle with skin lipids and positively influence drug permeation. Another alternative proposed mechanism is by disintegrating or merging/fusing on skin surface into extended lipidic structures, such as lipid multilamellae, which indirectly enhance skin permeation (Honeywell-Nguyen et al. 2002;Nasr et al. 2008aNasr et al. , 2008bAmer et al. 2019;Nasr and Al-Karaki 2020). ...
Dermatological products constitute a big segment of the pharmaceutical market. From conventional products to more advanced ones, a wide variety of dosage forms have been developed till current date. A representative of the advanced delivery means is carrier-based systems, which can load large number of drugs for treatment of dermatological diseases, or simply for cosmeceutical purposes. To make them more favorable for topical delivery, further incorporation of these carriers in a topical vehicle such as gels or creams is made. Therefore in the current review article, an overview is compiled of the most commonly encountered novel carrier based topical delivery systems; namely lipid based (nanoemulsions, microemulsions, solid lipid nanoparticles and nanostructured lipid carriers), and vesicular carriers (non deformable such as liposomes, niosomes, emulsomes and cerosomes, and deformable such as transfersomes, ethosomes, transethosomes and penetration enhancer vesicles), with special emphasis on those loaded in a secondary gel vehicle. A special focus was made on the commonly encountered dermatological diseases, such as bacterial and fungal infections, psoriasis, dermatitis, eczema, vitiligo, oxidative damage, aging, alopecia, and skin cancer.
... Penetration is the major challenge and penetration enhancers are utilized to increase the transportation of drugs in dermal layers by increasing the transfer rate through the epidermal layer and augment skin retention of active ingredient. [15,16] Therefore, it is mandatory to optimize the application of penetration enhancers to maintain the therapeutic concentration of drug at the target area by integrating several assessment techniques such as permeation kinetic, in silico docking, molecular simulation techniques, artificial neural network (ANN), and nanoscaled TDDDS. ...
Skin permeation is an integral part of penetration of topical therapeutics. Zero order in addition to Higuchi permeation kinetic is usually preferred in topical drug delivery cargo. Penetration of therapeutic entities through epidermal barrier is a major challenge for scientific fraternity. Furthermore, penetration of therapeutic entities determines the transportation and ultimately therapeutic efficacy of topical dermal dosage forms. Apart from experimentation models, mathematical equations, in silico docking, molecular dynamics (MDs), and artificial neural network (Neural) techniques are being used to assess free energies and prediction of electrostatic attractions in order to predict the permeation phenomena of therapeutic entities. Therefore, in the present review, we have summarized the significance of kinetic equations, in silico docking, MDs, and ANN in assessing and predicting the penetration behavior of topical therapeutics through dermal dosage form. In addition, the role of chitosan biomacromolecule in modulating permeation of topical therapeutics in skin has also been illustrated using computational techniques.
... Nobiletin has only been topically formulated in a hydrogel delivery system till current date 21 , thus, the encapsulation of nobiletin in nanoparticles intended to deposit in skin layers is expected to enhance its therapeutic outcome by overcoming its poor solubility and aiding its skin permeation. The use of nanotechnology has been explored by researchers to overcome the challenges of conventional topical delivery of natural molecules 22 . Nanoparticles can modify the penetration of the encapsulated substances by increasing their solubility, shielding them against instability causes, and providing their controlled release [23][24][25][26][27][28] . ...
Skin cancer is one of the most dangerous diseases, leading to massive losses and high death rates worldwide. Topical delivery of nutraceuticals is considered a suitable approach for efficient and safe treatment of skin cancer. Nobiletin; a flavone occurring in citrus fruits has been reported to inhibit proliferation of carcinogenesis since 1990s, is a promising candidate in this regard. Nobiletin was loaded in various vesicular systems to improve its cytotoxicity against skin cancer. Vesicles were prepared using the thin film hydration method, and characterized for particle size, zeta potential, entrapment efficiency, TEM, ex-vivo skin deposition and physical stability. Nobiletin-loaded composite penetration enhancer vesicles (PEVs) and composite transfersomes exhibited particle size 126.70 ± 11.80 nm, 110.10 ± 0.90 nm, zeta potential + 6.10 ± 0.40 mV, + 9.80 ± 2.60 mV, entrapment efficiency 93.50% ± 3.60, 95.60% ± 1.50 and total skin deposition 95.30% ± 3.40, 100.00% ± 2.80, respectively. These formulations were selected for cytotoxicity study on epidermoid carcinoma cell line (A431). Nobiletin-loaded composite PEVs displayed the lowest IC50 value, thus was selected for the in vivo study, where it restored skin condition in DMBA induced skin carcinogenesis mice, as delineated by histological and immuno-histochemical analysis, biochemical assessment of skin oxidative stress biomarkers, in addition to miRNA21 and miRNA29A. The outcomes confirmed that nobiletin- loaded composite PEVs is an efficient delivery system combating skin cancer.
... Pradhan et al. [36] showed that quercetin was efficient in inhibiting migration and proliferation of B16F10 cells at 50 µM concentration. Quercetin also acts as an emerging anti-melanoma agent by enhancing p53 and Nrf2 levels [37,38]. Quercetin conjugated to different nanoparticles inhibited proliferation of various cancer cell lines than quercetin alone; silver, superparamagnetic and gold nanoparticles conjugated with quercetin inhibited growth of human breast cancer cell lines than quercetin alone and a varying range of IC50 values were reported [23,39,40]. ...
Cancer has a significant impact on public health around the world. Treating cancer by chemotherapy or radiotherapy has several side effects. In combinational cancer therapy, combining nanoparticles with chemotherapeutic and/or natural agents increases the synergistic therapeutic effects by reducing undesired side effects. In the pharmaceutical field, the use of quercetin was limited due to its partial solubility in aqueous solutions. Titanium dioxide nanotubes (TNT) have a higher surface area for carrier molecules with unique physical and chemical characteristics. We investigated the effect of quercetin, TNT, or conjugated TNT with quercetin (TNT–Qu) on the B16F10 murine melanoma model and two-stage chemical carcinogenesis model using 7, 12-Dimethylbenz (a) anthracene as a tumor initiator and Phorbol 12-myristate-13 acetate as a tumor promoter. The topical application of TNT–Qu enhanced the anti-tumor activity in comparison to quercetin or TNT alone. TNT–Qu treatment to the tumor-bearing mice significantly reduced the tumor growth than quercetin or TNT alone treatment. TNT–Qu inhibited tumor growth by regulating phospho-STAT3 levels in the tumor microenvironment. In the two-stage chemical carcinogenesis model, TNT–Qu treatment has no effect on skin color and delayed the mortality rate in tumor-bearing mice. The histopathological data supports that TNT–Qu treatment exhibited reduced squamous cell carcinoma and ameliorated to a large extent with very low epidermal hyperplasia compared with quercetin or TNT alone. TNT–Qu treatment restored the γδ T cells levels to the normal skin level. Furthermore, TNT–Qu significantly inhibited the blood vessel formation in chick chorioallantoic membrane assay. TNT conjugated with quercetin could thus be a promising combinational molecule for effectively treating skin cancer.
... Overall, there are several strategies that can be adopted to increase the solubility and subsequent bioavailability of flavonoids with therapeutic potential. Although much progress has been recently made, novel drug delivery systems suitable for an optimized topical application should continue to be explored [112,[154][155][156][157]. A summary of the therapeutic application of flavonoids and the different nanocarriers used to enhance their delivery to the skin is described in Table 3. ...
Flavonoids are one of the vital classes of natural polyphenolic compounds abundantly found in plants. Due to their wide range of therapeutic properties, which include antioxidant, anti-inflammatory, photoprotective, and depigmentation effects, flavonoids have been demonstrated to be promising agents in the treatment of several skin disorders. However, their lipophilic nature and poor water solubility invariably lead to limited oral bioavailability. In addition, they are rapidly degraded and metabolized in the human body, hindering their potential contribution to the prevention and treatment of many disorders. Thus, to overcome these challenges, several cutaneous delivery systems have been extensively studied. Topical drug delivery besides offering an alternative administration route also ensures a sustained release of the active compound at the desired site of action. Incorporation into lipid or polymer-based nanoparticles appears to be a highly effective approach for cutaneous delivery of flavonoids with good encapsulation potential and reduced toxicity. This review focuses on currently available formulations used to administer either topically or systemically different classes of flavonoids in the skin, highlighting their potential application as therapeutic and preventive agents.
... Of the different modes of treatment for AGA, topical therapy is particularly favored by the patients, owing to the ease of administration of topical dosage forms, and the lesser side effects that accompany localized application [25,26]. However, the skin barrier properties present a challenge for the proper penetration of drugs [27][28][29]. A proposed solution is the use of nanoparticles for topical delivery of drugs, which has been proven successful in treatment of different dermatological diseases [30][31][32][33][34][35][36][37][38][39]39], and AGA in particular [13,14,40,41]. ...
Introduction
: Coenzyme Q10 (CoQ10) is an antioxidant molecule with anti-aging activity on human hair, and because of its pharmaceutical limitations such as large molecular weight, high lipophilicity and poor water solubility, its therapeutic effectiveness has been hampered. Therefore, different vesicular nanocarriers were developed in the current work, for enhancement of the skin penetration of CoQ10 for treatment of androgenic alopecia.
Areas covered
In order to overcome the poor skin penetration of CoQ10, it was formulated in liposomes, transfersomes, ethosomes, cerosomes and transethosomes using the thin film hydration method. Results revealed that transethosomes was the carrier of choice for CoQ10, in which it displayed a particle size of 146 nm, zeta potential -55 mV and entrapment efficiency of 97.63%. Transethosomes also achieved the highest deposition percentage for CoQ10, exceeding 95% in the different skin layers. Upon clinical examination in patients suffering from androgenic alopecia, CoQ10 transethosomes displayed better clinical response than the administration of CoQ10 solution, which was further confirmed by dermoscopic examination.
Expert opinion
: Findings of this study further prove that loading antioxidants such as CoQ10 in nanocarriers maximizes their therapeutic efficiency, and opens many opportunities for their application in treatment of several other topical diseases.
... Pradhan et al. [36] showed that quercetin was efficient in inhibiting migration and proliferation of B16F10 cells at 50 µM concentration. Quercetin also acts as an emerging anti-melanoma agent by enhancing p53 and Nrf2 levels [37,38]. Quercetin conjugated to different nanoparticles inhibited proliferation of various cancer cell lines than quercetin alone; silver, superparamagnetic and gold nanoparticles conjugated with quercetin inhibited growth of human breast cancer cell lines than quercetin alone and a varying range of IC50 values were reported [23,39,40]. ...
Cancer is a leading cause of death throughout the world. Melanoma is a skin cancer with a significant impact on global public health. Application of nanotechnology in the field of cancer diagnosis, drug delivery, imaging and therapy, has the most attractive approach as nanoparticles reach target sites easily due to their unique properties. Previous studies have shown that titanium dioxide nanotubes (TNT) and quercetin are effective anticancer agents. However, conjugated TNT with quercetin (TNT–Qu) as a combinational treatment is unexplored yet. This study is aimed to explore the anticancer activity of TNT, quercetin, and TNT–Qu in B16F10 melanoma skin cancer cells. TNT–Qu significantly inhibited proliferation at 25 µg/mL of IC 50 lower than quercetin (34 µg/mL) and TNT alone (72 µg/mL). TNT–Qu treatment inhibited migration and significantly induced 60.29% apoptosis in melanoma cells when compared to TNT (14.14%) or quercetin (44.86%) alone treatment. Furthermore, quercetin and TNT–Qu decreased the reactive oxygen species and superoxide levels due to quercetin's antioxidant properties. TNT–Qu treatment arrested 55.5% cells in G2/M phase more than quercetin (30.7%) or pristine TNT (3.7%) treatment. The molecular mechanism of TNT–Qu on melanoma cells revealed that it enhanced the cleaved caspase-3 levels and induced more apoptosis than TNT or quercetin alone. Hence, Novel TNT–Qu exhibited enhanced anticancer properties and could be a potential therapeutic combinational molecule for the treatment of skin cancer. Schematic representation of the proposed mechanism of TNT, quercetin and TNT–Qu inducing apoptosis in B16F10 melanoma cells. TNT–Qu enhanced the cleaved caspase-3 and induced caspase-dependent apoptosis. Importantly, it down-regulates the ROS and dysfunctions mitochondria and enhances the DNA fragmentation.
... 34 Then, the use of nobiletin and quercetin can be useful in systemic or topical delivery. 26,65 Despite the therapeutical value of those compounds, their use remains restricted, because of their bioavailability and low water solubility. 26 As observed with NSAIDs, the investigations on the therapeutical properties of natural compounds, namely, curcumin, 66,67 rutin, 68 resveratrol, 69 and quercetin, 70 suggested that they can be good candidates for addressing the severe complications of COVID-19. ...
Green solvents such as ionic liquids (ILs) unlock possibilities for developing innovative biomedical and pharmaceutical solutions. ILs are the most investigated solvents for compound extractions, as reaction media and/or catalysts, and a desired eco-friendly solvent to process biomacromolecules for biomaterial production. Investigations demonstrate that the tunable nature and physicochemical features of ILs are also beneficial for building up delivery systems through their combination with bioactive compounds. Bioactive compounds from synthetic origins, like ibuprofen, ketoprofen, and natural sources such as curcumin, flavonoids, and polyphenols are essential starting points as preventive and therapeutic agents for treating diseases. Therefore, the association of those compounds with ILs opens up windows of opportunities in this research field. This Review assesses some of the main and important recent information and the current challenges concerning delivery platforms based on ILs combined with bioactive compounds of both natural and synthetic origins. Moreover, the chemistry, bioavailability, and biological functions of the main bioactive compounds used in the ILs-based delivery platforms are described. These data are presented and are discussed, together with the main delivery routes of the systems.
... The currently available topical treatments are of limited efficacy, which necessitates the development of new therapies to satisfy the unmet medical needs [11,12]. The wide-ranging therapeutic applications of polyphenols in the treatment of various diseases in addition to their safety potential and natural origin insinuate their use for the development of novel pharmaceutical products for management of different types of wounds, including burns [13,14]. Resveratrol (trans-3,5,4 ′ -trihydroxy-trans stilbene) is a natural polyphenolic compound belonging to the subgroup of stilbenes, and is found in many plants including grape skins, peanuts, and mulberries [15]. ...
Burns are complicated wounds characterized by prolonged and persistent inflammatory phase. The combination of nutraceuticals in nano-delivery systems is hypothesized to enhance therapeutic efficacy and achieve better healing outcome. In this regard, we investigated the combination of two polyphenols; curcumin and resveratrol, in a nanoemulsion based gel system (nanoemulgel). The ex-vivo skin deposition of the prepared nanoemulgels was measured, and their in-vivo burn healing potential was tested in rat-burn induced model by measurement of inflammatory markers, oxidative stress markers, amino acids and vitamin E levels, in addition to histopathological examination. The particle size of the nanoemulsions ranged from 167-180 nm with PDI less than 0.4 and negative zeta potential (-17 to -20 mV). Remarkable retention of the nutraceuticals in the skin when loaded alone or combined in nanoemulgels, reaching ≈60% of the applied dose was shown after 48 hr. In vivo results proved the better burn healing outcome of the nanoemulgel formulation combining both curcumin and resveratrol, with histopathological features similar to normal control skin. Findings delineated the augmented burn healing potential of the nutraceuticals combination, and the promising delivery traits of the nanoemulgel dosage form, which can be further exploited with other nutraceuticals combinations.
Objective:
Ferulic acid (FA) is a promising nutraceutical molecule which exhibits antioxidant and anti-inflammatory properties, but it suffers from poor solubility and bioavailability. In the presented study, FA nanoemulsions were prepared to potentiate the therapeutic efficacy of FA in prevention of gastric ulcer.
Methods:
FA nanoemulsions were prepared, pharmaceutically characterized, and the selected nanoemusion was tested for its ulcer-ameliorative properties in rats after induction of gastric ulcer using ethanol, by examination of stomach tissues, assessment of serum IL-1β and TNF-α, assessment of nitric oxide, prostaglandin E2, glutathione, catalase and thiobarbituric acid reactive substance in stomach homogenates, as well as histological and immunohistochemical evaluation.
Results:
Results revealed that the selected FA nanoemulsion showed a particle size of 90.43 nm, sustained release of FA for 8 h, and better in vitro anti-inflammatory properties than FA. Moreover, FA nanoemulsion exhibited significantly better anti-inflammatory and antioxidant properties in vivo, and the gastric tissue treated with FA nanoemulsion was comparable to the normal control upon histological and immunohistochemical evaluation.
Conclusion:
Findings suggest that the prepared ferulic acid nanoemulsion is an ideal anti-ulcer system, which is worthy of further investigations.
Objective:
Apigenin and gallic acid are natural compounds that are useful as antioxidant, anti-inflammatory and anticancer agents, especially when used together in combination. Therefore, the development and validation of a simultaneous method of analysis for both compounds in pure form and when encapsulated in an advanced delivery system such as liposomes would be useful.
Methods:
Analysis was performed using C18 column under isocratic conditions. The mobile phase was acetonitrile: water containing 0.2% orthophosphoric acid at a ratio of 67:33, flow rate 1 ml/min, and detection wavelength 334 nm for apigenin and 271 nm for gallic acid.
Results:
The assay method was linear at the concentration range (5-600 µg/mL) with R2 of 1 for both drugs. The method was also shown to be precise and robust with RSD less than 2% with LOD (0.12, 0.1 µg/mL) and LOQ (4.14, 3.58 µg/mL) for apigenin and gallic acid respectively. The method was also applicable for the determination of the entrapment efficiency of both drugs when co-loaded in a nanoliposomal formulation.
Conclusion:
The described HPLC method was shown to be suitable, sensitive, and reproducible for the simultaneous identification and quantification of apigenin and gallic acid. The analytical results were accurate and precise, with good recovery, low limit of detection, and the chromatographic assay was accomplished in less than 3 min, suggesting the suitability of the method for routine analysis of both drugs in pharmaceutical formulations.
The review focuses on the lipid based nanocarriers, with special attention paid to natural bioactive payloads. First, micelles and microemulsions are considered as very attractive colloidal nanocontainers that allow for marked improving the solubility of hydrophobic bioactives. Further, liposomal vehicles are reviewed, with both advantages and limitations discussed. Literature assay covers up-to-date information of about last three to five years, although brief background is given on the pioneer works addressing the liposomes and their evolution from bench to bedside. Final part of the review is devoted to the modern modifications of vesicular nanocarriers which can be adapted to specific administration way due to improved targeting properties, permeability, mucoadhesiveness and possibility to cross biological barriers. Therein, such kinds of nanocarriers as transfersomes, niosomes, ethosomes, chitosomes are evaluated; and separate sections focus on the natural based formulations, i.e., phytosomes and invasomes.
Vitiligo is the most common depigmenting disorder characterized by white patches in the skin. The pathogenetic origin of vitiligo revolves around autoimmune destruction of melanocytes in which, for instance, oxidative stress is responsible for melanocyte molecular, organelle dysfunction and melanocyte specific antigen exposure as well as melanocyte cell death and thus serves as an important contributor for vitiligo progression. In recent years, natural products have shown a wide range of pharmacological bioactivities against many skin diseases, and this review focuses on the effects and mechanisms of natural compounds against vitiligo models. It is showed that some natural compounds such as flavonoids, phenols, glycosides and coumarins have a protective role in melanocytes and thereby arrest the depigmentation, and, additionally, Nrf2/HO-1, MAPK, JAK/STAT, cAMP/PKA, and Wnt/β-catenin signaling pathways were reported to be implicated in these protective effects. This review discusses the great potential of plant derived natural products as anti-vitiligo agents, as well as the future directions to explore.
Introduction: Oleuropein is a promising nutraceutical found in abundance in olive leaf, with reported antioxidant and anti-inflammatory properties, and hence could be a valuable treatment for dermatological diseases such as psoriasis.
Areas covered: In order to overcome the poor skin penetration of oleuropein, it was formulated in a microemulsion nanocarrier. The selected microemulsion formulation displayed a particle size of 30.25±4.8 nm, zeta potential 0.15±0.08 mV and polydispersity index 0.3±0.08, with storage stability for 1 year in room temperature and total deposition in skin layers amounting to 95.67%. Upon clinical examination in psoriatic patients, the oleuropein microemulsion formulation was proven superior to the marketed Dermovate cream composed of clobetasol propionate, in terms of reduction of Psoriasis Area and Severity Index (PASI) scores, as well dermoscopic imaging and morphometric analysis of the psoriasis lesions, in which oleuropein microemulsion exhibited marked improvement in the clinical manifestations of psoriasis.
Expert opinion: Findings of this study further prove the promising role of nutraceuticals, as well as nanoparticles in enhancing the therapeutic outcome of treatments, and open new era of applications in a variety of diseases.
High consumption of industrialized food with high fat content is generally associated with insulin resistance, which in turn causes memory impairment and cognitive decline. Nicotinamide and ascorbic acid are among the promising neuroprotective molecules; however, an appreciable therapeutic activity necessitates the administration of a large dose of either. Therefore, the study aimed to assess if loading them in chitosan nanoparticles in doses 5–10 times lower than the unencapsulated forms would achieve comparable therapeutic results. Animals were fed a high-fat-high-fructose (HFHF) diet for 75 days. The vitamins in their conventional form (100 mg/kg) and the nanoparticles under investigation (10 and 20 mg/kg) were given orally concomitantly with the diet in the last 15 days. The intake of HFHF diet for 75 days led to an insulin-resistant state, with memory impairment, which was verified behaviorally through the object recognition test. This was accompanied by significant reduction in brain insulin-like growth factor 1 (IGF-1), increased acetylcholine esterase activity, increase in the serotonin and dopamine turnover ratio, and increase in oxidative stress and 8-OHdG, indicating cellular DNA fragmentation. Cellular energy was also decreased, and immunohistochemical examination verified the high immunoreactivity in both the cortex and hippocampus of the brain. The administration of nanoparticulated nicotinamide or ascorbic acid with a 10 times lesser dose than the unencapsulated forms managed to reverse all aforementioned harmful effects, with an even lesser immunoreactivity score than the unencapsulated form. Therefore, it can be concluded that nicotinamide or ascorbic acid chitosan nanoparticles can be recommended as daily supplements for neuroprotection in patients suffering from insulin resistance after conduction of clinical investigations.
Ultraviolet radiation is a major risk factor for human skin damage, especially solar ultraviolet-B (UVB) which can induce inflammation, photoaging, and skin cancer. Quercetin (Qu), one of flavonoid family members, has showed protective effects against UVB radiation. However, its application for topical use is limited by low hydrophilicity and poor percutaneous absorption. Herein, we found that Qu, if entrapped into TPP-Chitosan nanoparticles (TCs), can be efficiently uptake by HaCaT cells and easily permeate through the epidermis layer, meanwhile display better stability and low cytotoxicity. We also found that Qu-loaded TCs (QTCs) could notably enhance the effect of Qu on inhibiting the NF-kB/COX-2 signaling pathway as well as ameliorating the skin edema caused by UVB radiation. Therefore, this study provided a method to get rid of Qu’s low hydrophilicity, enhance its percutaneous absorption and retention in the skin, and further improve its anti-UVB effect, and demonstrated that Qu-loaded chitosan nanoparticles can be used as the therapeutic agent for topical use against UVB radiation.
Psoriasis is a commonly encountered chronic dermatological disease, presenting with inflammatory symptoms in patients. Systemic treatment of psoriasis is associated with several adverse effects, therefore the development of a customized topical treatment modality for psoriasis would be an interesting alternative to systemic delivery. The therapeutic modality explored in this article was the comparative treatment of psoriatic patients using nanoparticulated methotrexate in the form of jojoba oil-based microemulsion with or without fractional erbium YAG laser. Assessment parameters included follow-up photography for up to 8 weeks of treatment, estimation of the psoriasis severity [TES (thickness, erythema, scales)] score, and histopathological skin evaluation. The prepared methotrexate microemulsion was clinically beneficial and safe in treatment of psoriasis vulgaris. The concomitant use of the fractional laser provided improvement in the psoriatic plaques within shorter time duration (3 weeks compared to 8 weeks of treatment), presenting an alternative topical treatment modality for psoriasis vulgaris.
The authors show a brief overview of the vitiligo’s unconventional therapies. A part for well-documented effectiveness of L-phenylalanine, PGE2 and antioxidant agents in the treatment of vitiligo, for the other therapeutical approaches more investigations are needed.
Quercetin has been widely used to treat many diseases because of its high antioxidant activity. However, it has low oral bioavailability and penetration through the skin. The aim of this research was to enhance penetration and bioavailability of quercetin using transdermal ethosomal gel. Three ethosomal formulae, E1 (1%), E2 (1.5%) and E3 (2%) with different concentration of quercetin were prepared using thin-film hydration method. Their physical properties were characterized, and then a selected ethosomal formula was incorporated into a gel dosage form. Two gels, one ethosomal and the other non-ethosomal were prepared. In vitro penetration using Franz diffusion cells and bioavailability study in Sprague Dawley male rats were carried out. Results showed that E2 was the chosen formula to be incorporated into the gel dosage form. According to the in vitro penetration study, the diffusion flux of quercetin from the ethosomal and non-ethosomal gels were 343.35±17.69 ng/cm2/h and 120.68±11.92 ng/cm2/h, respectively (P<0.05). In the bioavailability study, ethosomal gel showed higher maximum concentration (Cmax) and area under curve (AUC0-t) when compared to non-ethosomal gel and oral suspension. Cmax from the ethosomal gel, non-ethosomal gel, and oral suspension were 413.49±28.64 ng/ml, 189.46±49.68 ng/ml, and 61.92±14.31 ng/ml, respectively (P<0.05). AUC0-t from the ethosomal gel, non-ethosomal gel, and oral suspension were 4035.15±560.60, 584.87±265.46, and 431.21±239.85, respectively (P<0.05). In conclusion, ethosomal gel could increase penetration and bioavailability of quercetin compared to non-ethosomal gel.
Infections caused by Candida albicans , often refractory and with high morbidity and mortality, cause a heavy burden on the public health while the current antifungal drugs are limited and are associated with toxicity and resistance. Many plant-derived molecules including compounds isolated from traditional Chinese medicine (TCM) are reported to have antifungal activity through different targets such as cell membrane, cell wall, mitochondria, and virulence factors. Here, we review the recent progress in the anti- Candida compounds from TCM, as well as their antifungal mechanisms. Considering the diverse targets and structures, compounds from TCM might be a potential library for antifungal drug development.
In this study, we investigated the potential of intradermal delivery of nanoparticulate vaccines to modulate the immune response of protein antigen using hollow microneedles. Four types of nanoparticles covering a broad range of physiochemical parameters, namely poly (lactic-co-glycolic) (PLGA) nanoparticles, liposomes, mesoporous silica nanoparticles (MSNs) and gelatin nanoparticles (GNPs) were compared. The developed nanoparticles were loaded with a model antigen (ovalbumin (OVA)) with and without an adjuvant (poly(I:C)), followed by the characterization of size, zeta potential, morphology, and loading and release of antigen and adjuvant. An in-house developed hollow-microneedle applicator was used to inject nanoparticle suspensions precisely into murine skin at a depth of about 120μm. OVA/poly(I:C)-loaded nanoparticles and OVA/poly(I:C) solution elicited similarly strong total IgG and IgG1 responses. However, the co-encapsulation of OVA and poly(I:C) in nanoparticles significantly increased the IgG2a response compared to OVA/poly(I:C) solution. PLGA nanoparticles and liposomes induced stronger IgG2a responses than MSNs and GNPs, correlating with sustained release of the antigen and adjuvant and a smaller nanoparticle size. When examining cellular responses, the highest CD8(+) and CD4(+) T cell responses were induced by OVA/poly(I:C)-loaded liposomes. In conclusion, the applicator controlled hollow microneedle delivery is an excellent method for intradermal injection of nanoparticle vaccines, allowing selection of optimal nanoparticle formulations for humoral and cellular immune responses.
Abstract Background Malnutrition resulting from protein and calorie deficiency continues to be a major concern worldwide especially in developing countries. Specific deficiencies in the protein intake can adversely influence reproductive performance. The present study aimed to evaluate the effects of curcumin and curcumin nano-emulsion on protein deficient diet (PDD)-induced testicular atrophy, troubled spermatogenesis and decreased reproductive performance in male rats. Methods Juvenile rats were fed the protein deficient diet (PDD) for 75 days. Starting from day 60 the rats were divided into 4 groups and given the corresponding treatments for the last 15 days orally and daily as follows: 1st group; curcumin group (C) received 50 mg/kg curcumin p.o. 2ndgroup; curcumin nano-form low dose group (NCL) received 2.5 mg/kg nano-curcumin. 3rd group; curcumin nano-form high dose group (NCH) received 5 mg/kg nano-curcumin. 4th group served as malnutrition group (PDD group) receiving the protein deficient diet daily for 75 days and received distilled water ingestions (5 ml/kg p.o) daily for the last 15 days of the experiment. A normal control group was kept under the same conditions for the whole experiment and received normal diet according to nutrition requirement center daily for 75 days and received distilled water ingestions (5 ml/kg p.o) daily for the last 15 days of the experiment. Results PDD induced significant (P
The aim of the current manuscript was to test the applicability of a nanocomposite system of penetration enhancer vesicles (PEVs) within polymeric in situ forming gel network composed of poloxamer and hyaluronic acid for the intranasal delivery of the antiemetic dimenhydrinate (DMH). PEVs were prepared using phospholipids and labrasol/transcutol/PEG 400 as penetration enhancers, and characterized for entrapment efficiency (EE%), particle size, zeta potential and morphology. The nanocomposite in situ forming gel system was characterized for its sol-gel temperature, viscosity and mucoadhesiveness, and was pharmacodynamically tested on a cisplatin induced emesis model in rats in terms of food, water, kaolin intake and stomach weight content. The selected PEVs formula displayed EE% of 83% for DMH, particle size of 121 nm and a surface charge of 0.83 mV. The selected nanocomposite in situ gelling formula showed a viscosity of 2.13 Pa.S, mucoadhesive force of 0.62 N and DMH controlled release over 6 hours. The pharmacodynamic study showed the superiority of the nanocomposite in situ gelling formula; being administered at a lower dose than the oral marketed formula. The described nanocomposite system proved to be successful for the intranasal delivery of DMH, thus presenting a promising delivery modality for similar antiemetics.
Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.
The novelties encountered in the field of formulation have provided promising solutions for the problematic vaccine development of hapten molecules. In the current study, the novel preparation of a cationic nanoliposomal immunogen of the heat stable enterotoxin (STa) was reported. STa was produced from clinically ETEC isolate of diarrheic neonatal calves and purified using RP-HPLC. STa was loaded into the cationic vesicles which were characterized for their particle size, surface charge, morphology, STa loading, and stability. The STa loaded cationic nanoliposome was used for mice immunization and the generation of STa antibody was monitored using ELISA. Results displayed the spherical nature of the STa loaded vesicles, their suitable size and homogeneity represented by a particle size of 228.1 nm and a PDI of 0.202. The surface charge of the STa nanoliposomes was +29.9, demonstrating sufficient stability during refrigeration storage. The STa loaded cationic nanoliposome was able to elicit specific STa antibody response, and to confer effective protection against STa challenge in mice. The STa antibody binding titer and neutralization capacity were 105 and 104 mouse units/ml serum, respectively. The developed system is a one-step procedure, which overcomes the disadvantage of the complexity of generation of the hapten-carrier conjugate. In conclusion, the developed STa-cationic nanoliposomal immunogen is feasible and has the potential to improve effectiveness against ETEC, suggesting its applicability in preventing the harmful effects of ETEC infection in neonatal calves.
Background:
Vulvovaginal candidiasis (VVC) is a common gynecological disease. Candida albicans is believed to be mainly implicated in VVC occurrence, the biofilm of which is one of the virulence factors responsible for resistance to traditional antifungal agents especially to fluconazole (FCZ). Quercetin (QCT) is a dietary flavonoid and has been demonstrated to be antifungal against C. albicans biofilm.
Methods:
17 C. albicans isolates including 15 clinical ones isolated from VVC patients were employed to investigate the effects of QCT and/or FCZ on the inhibition of C. albicans biofilm.
Results:
We observed that 64 µg/mL QCT and/or 128 µg/mL FCZ could (i) be synergistic against 10 FCZ-resistant planktonic and 17 biofilm cells of C. albicans, (ii) inhibit fungal adherence, cell surface hydrophobicity (CSH), flocculation, yeast-to-hypha transition, metabolism, thickness and dispersion of biofilms; (iii) down-regulate the expressions of ALS1, ALS3, HWP1, SUN41, UME6 and ECE1 and up-regulate the expressions of PDE2, NRG1 and HSP90, and we also found that (iv) the fungal burden was reduced in vaginal mucosa and the symptoms were alleviated in a murine VVC model after the treatments of 5 mg/kg QCT and/or 20 mg/kg FCZ.
Conclusion:
Together with these results, it could be demonstrated that QCT could be a favorable antifungal agent and a promising synergist with FCZ in the clinical management of VVC caused by C. albicans biofilm.
Antioxidants are substances that may protect cells from the damage caused by unstable molecules such as free radicals. Flavonoids are phenolic substances widely found in fruits and vegetables. The previous studies showed that the ingestion of flavonoids reduces the risk of cardiovascular diseases, metabolic disorders, and certain types of cancer. These effects are due to the physiological activity of flavonoids in the reduction of oxidative stress, inhibiting low-density lipoproteins oxidation and platelet aggregation, and acting as vasodilators in blood vessels. Free radicals are constantly generated resulting in extensive damage to tissues leading to various disease conditions such as cancer, Alzheimer's, renal diseases, cardiac abnormalities, etc., Medicinal plants with antioxidant properties play a vital functions in exhibiting beneficial effects and employed as an alternative source of medicine to mitigate the disease associated with oxidative stress. Flavonoids have existed over one billion years and possess wide spectrum of biological activities that might be able to influence processes which are dysregulated in a disease. Quercetin, a plant pigment is a potent antioxidant flavonoid and more specifically a flavonol, found mostly in onions, grapes, berries, cherries, broccoli, and citrus fruits. It is a versatile antioxidant known to possess protective abilities against tissue injury induced by various drug toxicities.
Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase – a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables, and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated antiproliferative and proapoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anticancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review, we explore the potential of quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a “four-focus area strategy” to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to (i) modulate cellular bioreduction potential and associated signaling cascades, (ii) affect transcription of relevant genes, (iii) regulate epigenetic processes, and (iv) develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects.
Whitening cosmetics with anti-melanogenesis activity are very popular worldwide. Many companies have tried to identify novel ingredients that show anti-melanogenesis effects for new product development. Among many plant-derived compounds, polyphenols are thought to be one of the most promising anti-melanogenesis ingredients. In order to prepare effective whitening polyphenols, 3,3,4,5,7-pentahydrosyflavone (quercetin) has been widely researched and applied to commercial products because it is present in high levels in many edible plants. Quercetin is thus a representative polyphenol and has recently gained attention in the cosmetics field. There are many controversies, however, regarding the effect of quercetin, based on in vitro studies, cell line experiments, and human trials. In this review, toxicity and efficacy data for quercetin and its derivatives in various experimental conditions (i.e., various cell lines, concentration ranges, and other parameters) were examined. Based on this analysis, quercetin itself is shown to be ineffective for hypopigmentation of human skin. However, a few types of quercetin derivatives (such as glycosides) show some activity in a concentration-dependent manner. This review provides clarity in the debate regarding the effects of quercetin.
Amphotericin B is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting as cryptococcosis the immunocompromised patients. However, severe side effects have limited the utility of this drug. The aim of this study was to evaluate the antifungal effect of the combination of amphotericin B with quercetin or rutin and as a protective of citotoxic effect. The antifungal activity to amphotericin B, quercetin and rutin alone and in combination was determined in Candida sp and Cryptococcus neoformans strains. Cytotoxicity test on erythrocytes was performed by spectrophotometric absorbance of hemoglobin. The amphotericin B MIC was reduced when used in combination with quercetin or rutin to C. neoformans ATCC strain and reduced when combined with rutin to a clinical isolate of C. neoformans. In addition, the combination of quercetin with amphotericin B may reduce the toxicity of amphotericin B to red blood cells. Our results suggest that quercetin and rutin are potential agents to combine with amphotericin B in order to reduce the amphotericin dose to lessen side effects and improve antifungal efficacy.
In vitro and some animal models have shown that quercetin, a polyphenol derived from plants, has a wide range of biological actions including anti-carcinogenic, anti-inflammatory and antiviral activities; as well as attenuating lipid peroxidation, platelet aggregation and capillary permeability. This review focuses on the physicochemical properties, dietary sources, absorption, bioavailability and metabolism of quercetin, especially main effects of quercetin on inflammation and immune function. According to the results obtained both in vitro and in vivo, good perspectives have been opened for quercetin. Nevertheless, further studies are needed to better characterize the mechanisms of action underlying the beneficial effects of quercetin on inflammation and immunity.
Context: The systemic treatment of onychomycosis has been hampered by the reported side effects of antifungals in addition to the limited blood circulation to the affected nails. Topical ungual treatment would circumvent the limitations of systemic onychomycosis treatment.
Objective: Preparation and characterization of nail penetration enhancer containing nanovesicles (nPEVs) loaded with sertaconazole for topical treatment of onychomycosis.
Materials and methods: nPEVs were prepared using different nail penetration enhancers (N-acetyl-L-cysteine, thioglycolic acid, thiourea and ethanol) by the thin film hydration method, and characterized for their particle size, zeta potential, entrapment efficiency (EE%), elasticity, viscosity, physical stability and morphology. The selected nPEVs formula and the marketed Dermofix® cream were compared in terms of nail hydration, transungual drug uptake and antifungal activity against Trichophyton rubrum.
Results: N-acetyl-l-cysteine was the optimum nail penetration enhancer for incorporation within vesicles. nPEVs showed high EE% of sertaconazole ranging from 77 to 95%, a size ranging from 38–538 nm and a zeta potential ranging from +48 to +72 mV. The selected nPEVs formula displayed spherical morphology and good storage stability. Compared to the conventional marketed cream, the selected nPEVs formula showed 1.4-folds higher hydration and drug uptake enhancement into nail clippings. Furthermore, it showed significantly higher zone of inhibition for Trichophyton rubrum (20.9 ± 0.25 mm) than the marketed cream (11.6 ± 0.44 mm).
Conclusion: Nail penetration enhancer containing nanovesicles (nPEVs) present a very promising option, worthy of clinical experimentation on onychomycotic patients.
Topical drug delivery across the skin can offer many advantages, such as confer sustained drug release, lower fluctuations in plasma drug levels, circumvent first-pass metabolism, improve patient compliance, and provide local (dermal), or systemic (transdermal) effects (Schafer-Korting et al., 2007; El Maghraby et al., 2008). However, the barrier function of the skin, exerted by the horny layer of the stratum corneum, impairs the penetration and absorption of drugs (Bouwstra and Ponec, 2006). This layer prevents the penetration of hydrophilic compounds much more efficiently as compared to lipophilic compounds (Bouwstra et al., 2003; Bouwstra and Ponec, 2006). Therefore, there has been wide interest in exploring new techniques to increase drug absorption through the skin. Novel topical drug delivery systems, with the use of nanotechnology in dosage form design, have been used to facilitate overcoming the skin barrier. This article will summarize recent findings of lipid-based nano-delivery systems for skin delivery of drugs and bioactives agents.
There is a strong current trend for using complementary and alternative medications to treat atopic dermatitis. Atopic dermatitis is a common, chronic, pruritic, and inflammatory skin disease. It can have a profound, negative effect on patients' quality of life. Mild cases of atopic dermatitis can be controlled by the application of moisturizers and topical corticosteroids. However, in severe cases, application of immunosuppressive medication is unavoidable but it can have adverse effects. In traditional Persian medicine, diseases similar to resistant atopic dermatitis are treated with whey in combination with decoction of field dodder. Both whey and field dodder have anti-inflammatory properties. Consumption of whey can also aid skin repair, mitigate pruritus, and help combat the high level of stress experienced by patients. Therefore, it is hypothesized that consumption of traditional medicinal treatment of whey with decoction of field dodder can be applied as a complementary treatment for atopic dermatitis.
© The Author(s) 2015.
Among the common myths in the cosmetics industry is the perception that acne only happens to teenagers, and specifically to females. However, acne is not limited to a specific age, neither to a certain gender, and it creates a stressful problem for many people. Many chemical treatments for acne were proven to be successful, but when administered as such they showed many adverse effects, starting from itching to skin dryness and inflammation. Natural remedies have also been explored for acne treatment, and despite their safety, they suffered many stability problems attributed to their physicochemical properties, creating an obstacle for their topical delivery. Therefore, many nanocarriers were used to deliver those chemical and natural remedies topically to maximize their therapeutic potential in acne treatment. The present review discusses the different nanocarriers which were proven successful in improving the acne lesions, focusing on vesicular, lipidic, and polymeric systems.
Background: The present work aims to formulate nanostructured lipid carriers (NLCs) exhibiting high skin deposition and high inherent antioxidant potential to repurpose the use of melatonin hormone and some antioxidant oils in the treatment of androgenic alopecia (AGA).
Research design and methods: NLCs were characterized for their size, charge, drug entrapment, anti-oxidant potential, physical stability, in vitro release, surface morphology, and ex-vivo skin deposition. Their merits were clinically tested on patients suffering from AGA by calculating the degree of improvement, conduction of hair pull test, histometric assessment and dermoscopic evaluation.
Results: Results revealed that melatonin NLCs showed nanometer size, negatively charged surface, high entrapment efficiency and high anti-oxidant potential, in addition to sustained release for 6 hours. Furthermore, NLCs displayed good storage stability and they were able to increase the skin deposition of melatonin 4.5 folds in stratum corneum, 7 folds in epidermis, and 6.8 folds in the dermis compared to melatonin solution. Melatonin NLCs displayed more clinically desirable results compared to the melatonin solution in AGA patients, manifested by increased hair density and thickness and decreased hair loss.
Conclusions: The aforementioned system was shown to be a very promising treatment modality for AGA, which is worthy of futuristic experimentation.
Nanotechnology has provided several advantages for the treatment of cancer. Polymeric nanocapsules (PNCs) were proven promising in the treatment of different cancer types, such as hepatic cancer. Meanwhile, the exploration of novel indications of old molecules with the purpose of cancer treatment has been widely reported. Among the promising therapeutic moieties, rosuvastatin (RV) was delineated as a potential anticancer drug. Hence, the target of the presented manuscript was to develop PNCs loaded with RV to overcome its delivery challenges and augment its anticancer activity. RV PNCs were fabricated by the nanoprecipitation method using poly-lactide-co-glycolide PLGA polymer, and were characterized for the size, polydispersity index (PDI), charge, entrapment efficiency EE%, in-vitro release, stability, and morphology. Furthermore, their anticancer activity was tested on HepG2 cells using MTT assay, followed by elucidating the cytotoxic activity using flow cytometry. Results showed that RV PNCs displayed particle size ranging from 186-239 nm, average PDI, and negative zeta potential with sufficient stability for 3 months. PNCs were able to load RV at high EE% reaching 82.6% and sustain its release for 8 hours. RV PNCs were superior in their anticancer activity on HepG2 cells, as delineated from the viability study and further elucidated by enhanced apoptosis in addition to cell cycle arrest at G2/M phase, suggesting their promise in treatment of hepatic cancer.
Curcumin is a natural pigment that generates singlet oxygen upon light excitation, hence it can be used as a photosensitizer in photodynamic therapy. The extremely low water solubility and poor systemic bioavailability make curcumin a challenging molecule to be used clinically. In the current manuscript, two nanocarrier systems for curcumin were prepared and characterized; nanoliposomes and PVP capped gold nanoparticles. The dark and photocytotoxicity were investigated as a function of light fluence rate (100 and 200 mW/cm²) on HepG2 cancer cells. In vivo Erlich tumor model was developed and comparison of the tumor volume, survival rate and histopathological alterations was made for the two nanocarriers. Results showed that both curcumin nanocarriers were successfully prepared and characterized. Light irradiation was able to augment the cytotoxicity of both curcumin liposomes and gold nanoparticles, with the former being superior in cytotoxicity compared to the latter. The tumor size was almost diminished one month post photodynamic treatment for both systems with regression in the number of tumor cells upon histopathological evaluation, with curcumin liposomes producing better tumor regression than gold nanoparticles with comparable survival rate. Liposomes were confirmed to be superior to gold nanoparticles as a photodynamic treatment modality for cancer.
Objectives: For topical application of quercetin it is necessary to improve the low efficiency of its intradermal delivery as well as its low solubility in aqueous and organic vesicles. The aim of this study was to determine the usefulness of a microemulsion for that purpose. Methods: A microemulsion consisting of isopropyl myristate, 150 mM NaCl solution, Tween 80 and ethanol was prepared. The skin delivery of quercetin by microemulsion using excised guinea-pig and Yucatan micropig skin in Franz diffusion cells was examined. Lipid peroxidation in skin was also tested using iron(II) and citrate. Key findings: Using a w/o microemulsion as a vehicle, intradermal delivery of quercetin was significantly increased, as was its solubility. Quercetin penetrated deep into the skin, but no transfer was observed into the receptor compartment. It was confirmed that quercetin retained in the skin dose-dependently inhibited lipid peroxidation. Conclusions: The findings indicate the potential use of microemulsions for the skin delivery of quercetin, where it exerts antioxidative effects.
The aim of the study is to explore the effect of quercetin-loaded solid lipid nanoparticles on trauma therapy and scar inhibition and its related mechanism. Brain external skin of SD rats was removed. Masson staining, Sirius Red staining and scanning electron microscopy was used for the evaluation of the effect of quercetin solid lipid nanoparticle on traumatic repair and scar inhibition. The astrocyte migration model was used to investigate the effect of quercetin. Western blotting was applied to determine the expression of TGF-β1, TGF-βRI, TGF-βRII, Smad2, Smad3, Smad4 and Smad7 in traumatic skin and astrocytes. The repair rate of traumatic skin in groups QL and QS was significantly higher than that in groups C and CS (P<0.05) after 7 days, 14 days and 21 days of administration. Quercetin solid lipid nanoparticles significantly inhibited the proliferation and migration of astrocytes (P<0.05). Compared with C group, the relative expression of TGF-β1, TGF-βRI, TGF-βRII, Smad2, Smad3, Smad4 and Smad7 did not significantly in astrocytes and skin tissue of CS (P>0.05). Compared with groups C and CS, the relative expression of TGF-β1, TGF-βRI, TGF-βRII, Smad2, Smad3 and Smad4 in astrocytes and skin tissue of QL and QS were significantly decreased and the relative expression of Smad7 was significantly increased (P<0.05). Quercetin solid lipid nanoparticles can inhibit the activation of TGF-β/Smad pathway, accelerating the wound repair and inhibiting the formation of scar.
The ischemia–reperfusion (I/R) induced skin lesion has been identified as primary cause of pressure ulcers. To date, attempts to prevent pressure ulcers have not produced a significant improvement. Quercetin, one of the most widely distributed flavonoids in fruits and vegetables, exhibits its antioxidant and anti‐inflammatory properties against many diseases, including ischemic heart disease, atherosclerosis, and renal injury. In vitro wound scratch assay was first used to assess the function of quercetin in wounding cell model. Next, animal pressure ulcers model was established with two cycles of I/R. The impact of quercetin in the wound recovery, immune cell infiltration and pro‐inflammatory cytokines production was investigated in this model. Mechanistic regulation of quercetin at the wound site was also studied. Quercetin accelerated wound closure in cell scratch assay. Dose response study suggested 1 μM quercetin for in vivo study. In I/R injury model, quercetin treatment significantly accelerated wound closure, reduced immune cell infiltration and pro‐inflammatory cytokines production. Signaling study showed quercetin treatment inhibited MAPK but not NFĸB activation. Quercetin treatment improved the wound healing process in I/R lesions by suppressing MAPK pathway. Our results supported that quercetin could be a potential therapeutic agent for pressure ulcers.
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Antioxidants are among the most important cosmeceuticals, with proven ability of inhibiting cellular damage. The topical skin administration of antioxidants is essential for minimizing skin aging and achieving better skin protection against harmful free radicals. However, their unfavorable physiochemical properties such as chemical instability, excessive hydrophilicity or lipophilicity and others could be a great obstacle against their skin promising effects as well as their delivery to deeper skin layers. These problems could all be remedied through the use of delivery carriers. The present review discusses the various delivery carriers which were proven successful in improving the beneficial effects of antioxidants against skin aging, namely different vesicular systems, lipidic systems, polymeric systems and carbon nanotubes, and their applications in topical antioxidant delivery.
Background:
Liposomes are promising systems for the delivery of macromolecules and poorly absorbed drugs, owing to their ability to compartmentalize drugs, their biodegradability and biocompatibility.
Objective:
The aim of the present study was to formulate and evaluate conventional and modified glucosamine sulphate (GluS) and chondroitin sulphate (CS) liposomal formulations, to enhance their oral permeation for the treatment of osteoarthritis (OA).
Method:
Liposomal formulations were prepared by the thin-film hydration method using two types of phospholipids; Epikuron 200© and Epikuron 200© SH, and three permeation enhancers; poloxamer 407, cetylpyridinium chloride, and sodium deoxycholate. In-vitro characterization of liposomal formulations was conducted in terms of entrapment efficiency, particle size, zeta potential, viscosity, physical stability and mucoadhesive strength. Surface morphology and vesicle shape, ex-vivo intestinal permeation, and histopathological studies were further carried out on the selected formulation.
Results:
Results showed that the liposomal formulation containing sodium deoxycholate was the most optimum formula, showing high entrapment efficiency (60.11% for GluS and 64.10% for CS) with a particle size of 4.40 µm, zeta potential of -17.2 mV and viscosity of 2.50 cP.
Conclusion:
The aforementioned formula displayed the highest cumulative % permeated of GluS and CS through rabbit intestinal mucosa compared to the solution of drugs and other liposomal formulations (64.20% for GluS and 78.21% for CS) after 2 hours. There were no histopathological alterations in the intestinal tissue, suggesting the safety of the utilized liposomal formulation. In light of the above, liposomes can be considered promising oral permeation-enhancer system for GluS and CS, which is worthy of future bioavailability experimentation.
The ultimate goal of this research was to overcome the low immunogenicity of the biological macromolecule (heat stable enterotoxin STa) via its conjugation to biodegradable PLGA nanoparticles (NP). STa was first isolated from Enterotoxigenic Escherichia coli (ETEC), purified and identified using reported HPLC procedures. Optimized homogenous PLGA NP, prepared using the nanoprecipitation technique were used for conjugating STa using the carbodiimide synthesis. Covalent binding of STa to PLGA NP was confirmed via FTIR and (1)HNMR analysis. Safety and tolerability of the developed nanoparticulated STa-PLGA conjugate were confirmed by MTT assay on A549 lung cancer cells. After subcutaneous immunization, STA-PLGA NP conjugate induced a significant immune response in mice showing a strong binding and neutralizing antibody titer. The developed novel STa-PLGA NP conjugate is expected to provide promising protection against enterotoxigenic Escherichia coli (ETEC).
Due to their poor solubility in hydrophilic matrices and chemical instability, the applications of quercetin and linseed oil in functional foods are limited. In this work we have encapsulated quercetin and linseed oil into NLC by high pressure homogenization technique. Quercetin and linseed oil co-loaded nanoparticles were less than 100 nm in diameter and spherical in shape. Nano-encapsulated quercetin was found to be presented in NLC with less ordered lipid cores as an encapsulated amorphous form. And the solubility of quercetin in hydrophilic matrices consisted of linseed oil and surfactants was improved by at least 1300 folds. The addition of linseed oil improved the in vitro antioxidant activities of quercetin loaded NLCs. Besides, the in vitro release of quercetin from NLC exhibited a sustained pattern. Lower lipid oxidation was found in quercetin and linseed oil co-loaded NLC compared with conventional linseed oil emulsion. Finally, storage study indicated that the fabricated NLCs were stable for more than 3 months at 25 oC. In conclusion, NLC could be a promising vehicle for delivery of hydrophobic bioactive compounds and ω-3 unsaturated fatty acids in food industry.
Psoriasis is a non-infectious, dry, inflammatory (autoimmune) skin disorder. Treatment approaches include phototherapy, topical, oral and other systemic drug delivery. However, owing to the side effects and incomplete cure accompanying the oral administration as well as phototherapy, the topical route seemed to be more satisfactory for the medical team. Dermal treatment ensuring percutaneous penetration is now highly recommended in topical indications for psoriatic patients, which can be achieved using pharmaceutical carriers. Several carrier systems loaded with antipsoriatic drugs have demonstrated promising results, with some of them strictly being confined to the skin and others allowing for systemic involvement also. The evolution in this area will present a more useful and safer therapy by minimizing the drugs' degradation and loss, and increasing their bioavailability and effectiveness. Since patients require at least three topical applications for almost a 1-year period to gain health benefit, a reduction in the cost of the treatment will be of real value. A distinction of these carriers is made in the current review, to allow the choice of the most suitable pharmaceutical carrier for psoriatic patients requiring either local and/or systemic involvement.
Quercetin (QC) is a dietary flavonoid abundant in many natural plants. A series of studies have shown that it has been shown to exhibit several biological properties, including anti-inflammatory, anti-oxidant, cardio-protective, vasodilatory, liver-protective and anti-cancer activities. However, so far the possible therapeutic effect of QC on psoriasis has not been reported. The present study was undertaken to evaluate the potential beneficial effect of QC in psoriasis using a generated imiquimod (IMQ)-induced psoriasis-like mouse model, and to further elucidate its underlying mechanisms of action. Effects of QC on PASI scores, back temperature, histopathological changes, oxidative/anti-oxidative indexes, pro-inflammatory cytokines and NF-κB pathway in IMQ-induced mice were investigated. Our results showed that QC could significantly reduce the PASI scores, decrease the temperature of the psoriasis-like lesions, and ameliorate the deteriorating histopathology in IMQ-induced mice. Moreover, QC effectively attenuated levels of TNF-α, IL-6 and IL-17 in serum, increased activities of GSH, CAT and SOD, and decreased the accumulation of MDA in skin tissue induced by IMQ in mice. The mechanism may be associated with the down-regulation of NF-κB, IKKα, NIK and RelB expression and up-regulation of TRAF3, which were critically involved in the non-canonical NF-κB pathway. In conclusion, our present study demonstrated that QC had appreciable anti-psoriasis effects in IMQ-induced mice, and the underlying mechanism may involve the improvement of antioxidant and anti-inflammatory status and inhibition on the activation of the NF-κB signaling. Hence, QC, a naturally occurring flavone with potent anti-psoriatic effects, has the potential for further development as a candidate for psoriasis treatment.
Nanotechnology and material surface modification have provided a functional platform for the advancement of several medical fields such as dermatology. Furthermore, the smart choice of preparation material was proven to confer unique properties to the developed nanosystems. In this context, we focused on the sphingolipid “ceramide”, whose deficiency was found to negatively affect psoriasis.
Ceramide was doped into surfactant based vesicular phospholipid systems to create tubulated vesicles “cerosomes” loaded with a model anti-psoriatic drug “tazarotene”, and their properties were tested as compared to ceramide free vesicles. Cerosomes were characterized for their drug entrapment, viscosity, in vitro drug release, morphology, ex vivo drug skin deposition, thermal behavior, and were clinically tested on psoriatic patients. The factorial design study revealed that the surfactant type, the ceramide: surfactant ratio, and the presence of ethanol in the hydration buffer affected the entrapment efficiency and the viscosity of the vesicles. Ceramide increased the entrapment of tazarotene, decreased its release while enhancing its deposition within the skin, correlating with better clinical therapeutic outcome compared to the topical marketed product. Ceramide was also able to cause significant membrane tubulation in the vesicles, causing them to deviate from the conventional spherical morphology. As a conclusion, cerosomes present a new functional treatment modality for psoriasis which is worthy of future experimentation.
Quercetin is a plant flavonoid with strong antioxidant and antiinflammatory properties interesting for skin protection. However, its poor water solubility limits its penetration and so its efficiency on skin. For this purpose, quercetin lipid nanocapsules were formulated implementing phase inversion technique wherein several modifications were introduced to enhance quercetin loading. Quercetin lipid nanocapsules were formulated with two particle size range, (50 nm and 20 nm) allowing a drug loading of 18.6 and 32 mM respectively. The successful encapsulation of quercetin within lipid nanocapsules increased its apparent water solubility by more than 5,000 fold (from 0.5 μg/ml to about 5 mg/ml). The physicochemical properties of these formulations such as surface charge, stability and morphology were characterized. Lipid nanocapsules had spherical shape and were stable for 28 days at 25 °C. Quercetin release from lipid nanocapsules was studied and revealed a prolonged release kinetics during 24 h. Using DPPH assay, we demonstrated that the formulation process of lipid nanocapsules did not modify the antioxidant activity of quercetin in vitro (92.3%). With the goal of a future dermal application, quercetin lipid nanocapsules were applied to THP-1 monocytes and proved the cellular safety of the formulation up to 2 μg/ml of quercetin. Finally, formulated quercetin was as efficient as the crude form in the protection of THP-1 cells from oxidative stress by exogenous hydrogen peroxide. With its lipophilic nature and occlusive effect on skin, lipid nanocapsules present a promising strategy to deliver quercetin to skin tissue and can be of value for other poorly water soluble drug candidates.
The aim of this study was to develop a new microemulsion formulation for topical application of poorly soluble drug named quercetin. In order to design suitable microemulsion system, the pseudo-ternary phase diagrams of microemulsion systems were constructed at different surfactant/co-surfactant ratios using tween 80 as surfactant, transcutol® P as co-surfactant and oleic acid as oil phase. Some physicochemical properties such as droplet size, density, refractive index, electrical conductivity, pH, surface tension and viscosity of the microemulsion systems were measured at 298.15 K. The average hydrodynamic droplet size of the optimized microemulsions was obtained by dynamic light scattering method. Morphology assessment of the optimized quercetin-loaded microemulsion by transmission electron microscopy analysis indicated that the particles have the size of about 25 nm and spherical with narrow size distribution. Equilibrium solubility, in-vitro drug release at a 24 h time period, release kinetic evaluation as well as ex-vivo permeation and retention of quercetin-loaded microemulsions through rat skin has been investigated. The obtained results showed a slow release behavior without any transdermal delivery. Most of the formulations fitted best with zero-order kinetic model with a non-Fickian mechanisms. This study illustrated that the proposed QU-microemulsion has a good potential for use in sunscreen formulations.
The creation of composite systems has become an emerging field in drug delivery. Chitosan has demonstrated several pharmaceutical advantages, especially in intranasal delivery. In this manuscript, a comparative study was conducted between regular vesicles (transfersomes and penetration enhancer vesicles) and composite vesicles (chitosan containing transfersomes and penetration enhancer vesicles) loaded with a model antihypertensive drug; verapamil hydrochloride VRP. Composite vesicles displayed larger particle size than regular vesicles owing to the coating potential of chitosan on the vesicular bilayer as displayed by transmission electron microscopy, with an increased viscosity of composite vesicles and a shift in the zeta potential values from negative to positive. The entrapment efficiency of VRP in the vesicles ranged from 24 to 64%, with best physical stability displayed with transfersomal vesicles prepared using sodium deoxycholate. Chitosan slowed the in vitro release of VRP from the selected formulation but managed to achieve high penetrability across sheep nasal mucosa as displayed by confocal laser microscopy. The chitosan composite transfersomal formulation exhibited absolute bioavailability of 81.83% compared to the oral solution which displayed only 13.04%. Findings of this manuscript highly recommend chitosan as a promising functional additive in vesicular formulations to improve the intranasal delivery of drugs with low oral bioavailability.
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.
Skin is a multifunctional organ with activities in protection, metabolism and regulation. Skin is in a continuous exposure to oxidizing agents and inflammogens from the sun and from the contact with the environment. These agents may overload the skin auto-defense capacity. To strengthen skin defense mechanisms against oxidation and inflammation, supplementation of exogenous antioxidants is a promising strategy. Quercetin is a flavonoid with very pronounced effective antioxidant and antiinflammatory activities, and thus a candidate of first choice for such skin supplementation. Quercetin showed interesting actions in cellular and animal based models, ranging from protecting cells from UV irradiation to support skin regeneration in wound healing. However, due to its poor solubility, quercetin has limited skin penetration ability, and various formulation approaches were taken to increase its dermal penetration. In this article, the quercetin antioxidant and antiinflammatory activities in wound healing and supporting skin against aging are discussed in detail. In addition, quercetin topical formulations from conventional emulsions to novel nanoformulations in terms of skin penetration enhancement are also presented. This article gives a comprehensive review of quercetin for topical application from biological effects to pharmaceutical formulation design for the last 25 years of research.
Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number of cytotoxic chemotherapeutics are highly hydrophobic, which limits their utility in cancer therapy. Finally, many chemotherapeutic agents exhibit short halflives that curtail their efficacy. As a result of these deficiencies, many current treatments lead to side effects, noncompliance, and patient inconvenience due to difficulties in administration. However, the application of nanotechnology has led to the development of effective nanosized drug delivery systems known commonly as nanoparticles. Among these delivery systems, lipid-based nanoparticles, particularly liposomes, have shown to be quite effective at exhibiting the ability to: 1) improve the selectivity of cancer chemotherapeutic agents; 2) lower the cytotoxicity of anticancer drugs to normal tissues, and thus, reduce their toxic side effects; 3) increase the solubility of hydrophobic drugs; and 4) offer a prolonged and controlled release of agents. This review will discuss the current state of lipid-based nanoparticle research, including the development of liposomes for cancer therapy, different strategies for tumor targeting, liposomal formulation of various anticancer drugs that are commercially available, recent progress in liposome technology for the treatment of cancer, and the next generation of lipidbased nanoparticles. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Background:
Nanotechnology has provided substantial benefits in drug delivery, especially in the treatment of dermatological diseases. Psoriasis is a chronic inflammatory skin disease in which topical delivery of antipsoriatic agents is considered the first line treatment.
Objective:
To investigate whether the encapsulation of the synthetic retinoid tazarotene in a nanocarrier based on jojoba oil would decrease its irritation potential and clinically improve its therapeutic outcome in psoriatic patients.
Method:
A microemulsion system based on jojoba wax and labrasol/plurol isostearique was prepared and characterized.
Results:
The selected formula displayed spherical morphology, particle size of 15.49 ±2.41 nm, polydispersity index of 0.20 ±0.08, negative charge and low viscosity. The microemulsion provided two folds increase in skin deposition of tazarotene, correlating with higher reduction in psoriatic patients PASI scores after treatment (68% reduction in PASI scores versus 8.96% reduction with the marketed gel). No irritation was encountered in patients using microemulsion, with redness and inflammation reported with the marketed gel-treated patients.
Conclusion:
Jojoba oil microemulsion proved to be advantageous in reducing the irritancy of tazarotene, enhancing its skin deposition and achieving better therapeutic outcome in psoriatic patients.
A challenging disease such as lung cancer requires the combination of different modalities to achieve beneficial therapeutic outcomes. In this work, PLGA nanoparticles were chosen as colloidal carrier for two drugs with reported anti-lung cancer activity: naringin and celecoxib. PLGA nanoparticles were prepared and characterized for their particle size, zeta potential, entrapment efficiency, in vitro release, stability, morphology, cytotoxicity, as well as aerosolization and nebulization behaviors. Their biodistribution pattern upon pulmonary aerosolization, and safety on healthy lung tissues were determined as well. Results showed that the described system displayed a particle size <260 nm with unimodal distribution, entrapment efficiency for celecoxib and naringin reaching 96% and 62% respectively and a controlled release profile for the two drugs. The selected formula displayed favorable nebulization properties with high drug deposition percentages in lower impinger and impactor stages. It also exhibited higher cytotoxic activity on A549 lung cancer cell lines compared to the free drugs combination, while displaying considerable safety on healthy lung tissues. Biodistribution studies delineated the lung deposition potential of the nanoparticles accompanied with high distribution to the bones, brain and liver which are common metastatic sites of lung cancer, proving their promising nature in the treatment of lung cancer.
Quercetin (3,3',4',5,7-penthydroxyflavone)-induced biological effects have been beneficial in various disease conditions. In this study, wound healing potential of quercetin was evaluated in a time-dependent manner in open excision wounds in adult Wistar rats. Experimentally-wounded rats were divided into two groups namely, control and quercetintreated. Wounds were photographed and the area was measured on the day of wounding and on days 3, 7, 11 and 14 postwounding. The granulation/healing tissue was collected on days 3, 7, 11 and 14 post-wounding for cytokine/growth factor measurements and histology/immunohistochemistry studies. There was significant time-dependent increase in wound closure in quercetin-treated rats. Vascular endothelial growth factor and transforming growth factor- β1 expressions were significantly upregulated in quercetin-treated rats, whereas tumor necrosis factor-_ level was markedly reduced. Interleukin- 10 levels and CD31 stained vessels were markedly higher on day 3 and on day 7, respectively, in quercetin-treated rats. In H & E stained sections, quercetin-treated group showed less inflammatory cells, more fibroblast proliferation, increased microvessel density, better reepithelialization and more regular collagen deposition, as compared to control. The results suggest that topical application of quercetin promotes wound healing by effectively modulating the cytokines, growth factors and cells involved in inflammatory and proliferative phases of healing. © 2016, National Institute of Science Communication. All Rights reserved.
Atopic dermatitis (AD) is an inflammatory skin disease. Over the past few decades, AD has become more prevalent worldwide. Quercetin, a naturally occurring polyphenol, shows antioxidant, anti-inflammatory, and antiallergic activities. Several recent clinical and preclinical findings suggest quercetin as a promising natural treatment for inflammatory skin diseases. Significant progress in elucidating the molecular mechanisms underlying the anti-AD properties of quercetin has been achieved in the recent years. Here, we discuss the use of quercetin as treatment for AD, with a particular focus on the molecular basis of its effect. We also briefly discuss the approaches to improve the bioavailability of quercetin.
Indocyanine green (ICG) is a near-IR fluorescent dye with a great potential for application as photosensitizer in topical photodynamic therapy (PDT) of skin diseases. Despite its merits, its use has been hampered by its high degradation rate. Therefore, in the current article, ICG was encapsulated in a vesicular colloidal nanocarrier (transfersomes), with the aim of enhancing its therapeutic efficacy. Transfersomes were characterized for their entrapment efficiency, particle size, zeta potential, morphology, in vitro release and histopathological effect on mice skin. A pilot clinical study was conducted to test its therapeutic potential for PDT of basal cell carcinoma (BCC). Transfersomal ICG displayed particle size (∼125 nm) and a negative zeta potential (∼-31 mV). Transfersomes were also able to sustain the release of ICG >2 h. Upon incorporation of transfersomal ICG in gel form, it was found to maintain the normal histology of mice skin post-irradiation with diode laser 820 nm. Moreover, ICG transfersomal PDT achieved 80% clearance rate for BCC patients with minimal pain reported during treatment. The previous findings suggest that transfersomal nanoencapsulated ICG is a promising treatment modality for BCC.
In this study, a chemometrics approach has been used to optimize the particle size of quercetin-containing nanoemulsions prepared with spontaneous emulsification method. The experiments were performed according to the Box – Behnken experimental design, one of the most suitable experimental designs for modeling studies. The effect of three experimental parameters on the droplet size was studied using multivariate analysis. The factors studied (and their variation levels) were the concentration of lecithin in aqueous phase (0.7 – 2% w/w), the concentration of tween-80 in aqueous phase (2 – 8% w/w), and sonication time (10 – 60 minutes). In each step of experimental design, the aqueous phase was added to the organic phase including lecithin, tween-80, and quercetin in ethanol solvent. Then, the mixture was treated in ultrasonic bath for 15 min and organic solvent was removed by rotary evaporator. The droplet size was measured by a Zetasizer instrument. After determining the average particle size for each experimental run according to experimental design, modeling of this parameter was conducted in terms of experimental factors by using multiple linear regressions with SPSS software. The obtained regression model was characterized by both its descriptive and predictive ability (R2 = 0.999, standard error SE = 4.205, and F = 245.698) and allowed the preparation of quercetin nanoemulsions in a desired range.
The development of mucoadhesive lipidic nanoemulsion based on hyaluronic acid, co-encapsulating two polyphenols (resveratrol and curcumin) for the transnasal treatment of neurodegenerative diseases was attempted in the current manuscript. Nanoemulsions were prepared by the spontaneous emulsification method, and were characterized for their particle size, zeta potential, mucoadhesive strength and morphology. The selected formula was tested for its antioxidant potential, in vitro and ex vivo release of the two polyphenols, safety on nasal mucosa and in vivo quantification of the two drugs in rat brains. Its stability was tested by monitoring the change in particle size, zeta potential, drugs' content and antioxidant potential upon storage for 3 months. The optimized hyaluronic acid based nanoemulsion formula displayed a particle size of 115.2 ± 0.15 and a zeta potential of -23.9 ± 1.7. The formula displayed a spherical morphology and significantly higher mucoadhesive strength compared to its non mucoadhesive counterpart. In addition, the nanoemulsion was able to preserve the antioxidant ability of the two polyphenols and protect them from degradation. Diffusion controlled release of the two drugs was achievable till 6 hours, with an ex vivo flux across sheep nasal mucosa of 2.86 and 2.09 µg/cm(2)hr for resveratrol and curcumin, respectively. Moreover, the mucoadhesive nanoemulsion was safe on nasal mucosa and managed to increase the amounts of the two polypehnols in the brain (about 7 and 9 folds increase in AUC0-7 h for resveratrol and curcumin, respectively). Hyaluronic acid based lipidic nanoemulsion proved itself as a successful carrier enhancing the solubility, stability and brain targetability of polyphenols.
Great interest is currently centered on the biologic activities of quercetin a polyphenol belonging to the class of flavonoids, natural products well known for their beneficial effects on health, long before their biochemical characterization. In particular, quercetin is categorized as a flavonol, one of the five subclasses of flavonoid compounds. Although flavonoids occur as either glycosides (with attached glycosyl groups) or as aglycones, most altogether of the dietary intake concerning quercetin is in the glycoside form. Following chewing, digestion, and absorption sugar moieties can be released from quercetin glycosides. Several organs contribute to quercetin metabolism, including the small intestine, the kidneys, the large intestine, and the liver, giving rise to glucuronidated, methylated, and sulfated forms of quercetin; moreover, free quercetin (such as aglycone) is also found in plasma. Quercetin is now largely utilized as a nutritional supplement and as a phytochemical remedy for a variety of diseases like diabetes/obesity and circulatory dysfunction, including inflammation as well as mood disorders. Owing to its basic chemical structure the most obvious feature of quercetin is its strong antioxidant activity which potentially enables it to quench free radicals from forming resonance-stabilized phenoxyl radicals. In this review the molecular, cellular, and functional bases of therapy will be emphasized taking strictly into account data appearing in the peer-reviewed literature and summarizing the main therapeutic applications of quercetin; furthermore, the drug metabolism and the main drug interaction as well as the potential toxicity will be also spotlighted.
Fungal infections are amongst the most commonly encountered diseases affecting the skin. Treatment approaches include both topical and oral antifungal agents. The topical route is generally preferred due to the possible side effects of oral medication. Advances in the field of formulation may soon render outdated conventional products such as creams, ointments and gels. Several carrier systems loaded with antifungal drugs have demonstrated promising results in the treatment of skin fungal infections. Examples of these newer carriers include micelles, lipidic systems such as solid lipid nanoparticles and nanostructured lipid carriers, microemulsions and vesicular systems such as liposomes, niosomes, transfersomes, ethosomes, and penetration enhancer vesicles.