Delivery Of Natural Products Research Articles

Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies.

Viral infections affect three to five million patients annually. While commonly used antivirals often show limited efficacy and serious adverse effects, herbal extracts have been in use for medicinal purposes since ancient times and are known for their antiviral properties and more tolerable side effects. Thus, naturally based pharmacotherapy may be a proper alternative for treating viral diseases. With that in mind, various pharmaceutical formulations and delivery systems including micelles, nanoparticles, nanosuspensions, solid dispersions, microspheres and crystals, self-nanoemulsifying and self-microemulsifying drug delivery systems (SNEDDS and SMEDDS) have been developed and used for antiviral delivery of natural products. These diverse technologies offer effective and reliable delivery of medicinal phytochemicals. Given the challenges and possibilities of antiviral treatment, this review provides the verified data on the medicinal plants and related herbal substances with antiviral activity, as well as applied strategies for the delivery of these plant extracts and biologically active phytochemicals. Graphical

Nanotechnology to improve the Alzheimer's disease therapy with natural compounds.

Alzheimer's disease (AD) is a form of dementia with high impact worldwide, accounting with more than 46 million cases. It is estimated that the number of patients will be four times higher in 2050. The initial symptoms of AD are almost imperceptible and typically involve lapses of memory in recent events. However, the available medicines still focus on controlling the symptoms and do not cure the disease. Regarding the advances in the discovery of new treatments for this devastating disease, natural compounds are gaining increasing relevance in the treatment of AD. Nevertheless, they present some limiting characteristics such as the low bioavailability and the low ability to cross the blood-brain barrier (BBB) that hinder the development of effective therapies. To overcome these issues, the delivery of natural products by targeting nanocarriers has aroused a great interest, improving the therapeutic activity of these molecules. In this article, a review of the research progress on drug delivery systems (DDS) to improve the therapeutic activity of natural compounds with neuroprotective effects for AD is presented. Graphical abstract.

Nanocarriers: A Successful Tool to Increase Solubility, Stability and Optimise Bioefficacy of Natural Constituents.

Natural products are fascinating molecules in drug discovery for their exciting structure variability and also for their interaction with various targets. Drugs multi-targeting effect represents a more realistic approach to develop successful medications for many diseases. However, besides a large number of successful in vitro and in vivo studies, most of the clinical trials fail. This is generally related to the scarce water solubility, low lipophilicity and inappropriate molecular size of natural compounds, which undergo structural instability in biological milieu, rapid clearance and high metabolic rate. Additionally, some molecules are destroyed in gastric juice or suffer to a massive pre-systemic metabolism in the liver, when administered orally, limiting their clinical use. A reduced bioavailability can also be linked to drug distribution/accumulation in non-targeted tissues and organs that increase the side effects lowering the therapeutic efficacy and patient compliance. Nanomedicine represents a favourable tool to increase bioavailability and activities of natural products. Generally, nanovectors provide a large surface area and can overcome anatomic barriers. Each nanovector has its own advantages, disadvantages, and characteristics. In this review, different nanocarriers made of compounds which are Generally Recognized As Safe (GRAS) for the delivery of natural products, marketed as food supplements and medicines are reported.

Nanoparticles in the Use of Natural Products for the Treatment of Lung Cancer

Objective: Carry out a bibliographical survey about the use of nanoparticles in the delivery of natural products for the treatment of lung cancer. Methods: A bibliographic review was made using the descriptors “Nanoparticles”, “Biological Products” and “Lung Neoplasms”, through the databases ScienceDirect, PubMed and SciELO, in the period from 2009 to 2018. Results: After analyzing the articles according to the inclusion criteria, we obtained 31 articles, of which 25.81% refer to natural products in the treatment of lung cancer, 29.03% to nanoparticles in the treatment of lung cancer and 45.16 % to nanoparticles as carriers of natural products for the treatment of lung cancer. Conclusion: The use of nanoparticles allows the delivery of natural products, increasing their therapeutic properties against lung cancer cells, and decreasing the side effects of these highly toxic agents.

The application of pomelo peel as a carrier for adsorption of epigallocatechin-3-gallate.

Pomelo (Citrus grandis) is the largest citrus fruit, the peel of which is a well-known agricultural wastes. Disposal of pomelo peel after consumption is a serious environment problem. As a natural, versatile bio-absorbent, pomelo peel has shown excellent adsorption capacity for several pollutants, attributed to its micro-pores; however, there is no relevant report on its adsorption capacity for natural products or food ingredients. The ability of pomelo peel to adsorb epigallocatechin-3-gallate (EGCG) was examined in this study. The physicochemical characterizations of pomelo peel were determined by Fourier transform infrared spectroscopy, scanning electron microscopy and high-performance liquid chromatography. The adsorption process of EGCG onto pomelo peel from aqueous solution was carried out at a range of concentrations (50-800 mg L-1 ) and temperatures (25, 40 and 55 °C). The main components of pomelo peel are composed of dietary fiber, which provide sufficient adsorption sites during the adsorption process. The adsorption of EGCG onto pomelo peel showed excellent fitness with a pseudo-second-order model. Both Langmuir and Freundlich models were able to describe the isothermal adsorption of EGCG onto pomelo peel. The results of thermodynamic analysis suggested that adsorption is spontaneous and endothermic in nature, and that the process is likely to be dominated by a physisorption mechanism. The results of this study indicate that pomelo peel has potential adsorption capacity for EGCG, which can be used as an effective, low-cost carrier for delivery of natural products in functional food and dietary supplement applications. © 2018 Society of Chemical Industry.

Nanoscale Delivery Systems: Actual and Potential Applications in the Natural Products Industry.

Compounds and extracts derived from natural sources continue to stand in the spotlight of drug design owing to their versatile interaction with enzymes, receptors and metabolic pathways. Nanomedicine offers an operative tool for the efficient delivery of natural products, in terms of increased bioavailability, targeting, and controlled release while protecting active constituents against physico-chemical alterations. The interest of the scientific community in the field of nanosized delivery of natural compounds is demonstrated by the exponential growth of the publications in this field. Beyond the presentation of successful examples of nanoscale delivery systems containing natural products, the scope of this review is to point out the yet underexplored capacities of this field with relevance for the pharmaceutical and nutraceutical market. Departing from a short presentation of plant-derived natural products and strategies to obtain nanoformulations, the current work discusses nanoparticulate drug delivery systems targeting diseases of various organs and systems: skin, central nervous system, skeletal tissue, cardiovascular apparatus, and diabetes. While notable progress has been achieved in the preparation of nanomedicines containing selected dietary polyphenols, works dealing with crude extracts or standardized fractions are much less frequent. In fact, most of the plants with solidly documented therapeutic properties and registered in pharmacopoeias still wait to benefit from advances in the field of nanotechnology. At least for some of them, adequate nanoformulation shall contribute to their removal from the group of dietary supplements and pharmaceutical preparations with suboptimal bioavailability and efficacy.

Impact of nanotechnology on the delivery of natural products for cancer prevention and therapy

Chemoprevention of human cancer by dietary products is a practical approach of cancer control, especially when chemoprevention is involved during the early stages of the carcinogenesis process. Research over the last few decades has clearly demonstrated the efficacy of dietary products for chemoprevention in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated to bedside for clinical use. Among many reasons, inefficient systemic delivery and bioavailability of promising chemopreventive agents are considered to significantly contribute to such a disconnection. Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and therapy of the disease. In a similar trait, we introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention (Cancer Res. 2009; 69:1712-1716). This idea, which we termed as 'nanochemoprevention', was exploited by several laboratories and has now become an advancing field in chemoprevention research. This review summarizes some of these applications of nanotechnology in medicine, particularly focused on controlled and sustained release of bioactive compounds with emphasis on current and future utilization of nanochemoprevention for prevention and therapy of cancer.

Opinion Paper: Nanotechnology: A Successful Approach to Improve Oral Bioavailability of Phytochemicals.

Abstract Phytochemicals have gained significant recognition for their potential therapeutic uses against a variety of human diseases. However, the poor water solubility, limited intestinal absorption and low water stability of phytochemicals generally prevent from achieving a high oral bioavailability and even detectable plasma levels of the parent compound. Dose escalation is not always a solution to address limited oral bioavailability, and may increase the risk of adverse events, most frequently in the gastrointestinal system [1]. Low water solubility is a common reason for the limited bioavailability of drug candidates because passing through the unstirred aqueous layer on the surface of the intestinal epithelium is a pre-requisite for the intestinal absorption of compounds. It has been estimated that over 40 % of the drugs being identified through combinatorial screening programs are poorly soluble in water [2]. Therefore, formulation improvement into highly stable, water-soluble and orally bioavailable forms is regarded as a prerequisite for the clinical application of phytochemicals. Nanotechnology has emerged as an efficient tool to address the problems regarding solubility, stability and oral bioavailability of phytochemicals [3]. Several nano-sized delivery systems have been utilized to enhance the physicochemical properties of phytochemicals. Characteristics of the most common biocompatible and biodegradable nanoparticulate systems used for the delivery of natural products are summarized in Table 1. Nanoparticulate delivery systems confer a number of advantages, including facilitated transport of incorporated phytochemicals across the biological barriers, enhanced bioavailability of poorly water-soluble phytochemicals, targeted delivery of phytochemicals, protection of sensitive compounds from biological and environmental degradation, and controlled release [4]. Some famous examples of nanoformulated phytochemicals are shown in Table 2 [5-7]. Furthermore, many nanomaterials are being studied in clinical trials or have been approved by the Food and Drug Administration to be used in humans. Liposomal daunorubicin (Daunoxome®; described in patents EP0004467 and US20070286897) and albumin-bound paclitaxel (Abraxane®, described in patents WO2014105644 and WO2008057562) are two breakthrough examples of successful formulation of natural products using nanotechnology-based approaches. Table 2 summarizes some pharmacologically important phytochemicals with optimized nanoformulations [8, 9]. Curcumin is another important anti-cancer and cardioprotective phytopharmaceutical [10-12] for which various nanoformulations have been developed [12], as described in patents WO2013108270 and EP2349237. While nanotechnology offers promising solutions for the formulation of phytochemicals, some challenges still remain to be overcome before developing any nanoparticulate system to be used in clinical practice. These considerations include potential long-term toxicity of nanoparticles, non-specific uptake into cells, off-target biodistribution and tissue accumulation, and costly and complicated manufacturing process of some nanocomposites particularly in the targeted forms [8]. In spite of these challenges, biocompatible and biodegradable nanocarriers are increasingly finding applications in pharmaceutical and nutraceutical industries. Future investigations should address long-term safety issues of nanomaterials particularly when used repeatedly for chronic diseases.

Nanotherapeutics for anti-inflammatory delivery

The science innovations improved the patient quality of life and perspectives. In particular, the revolutionary turmoil of the second half of twentieth century in the Science Academia poses the milestone to develop innovative supramolecular nanotherapeutics and enforce nanotechnology and drug delivery. The driving force of this revolution was the synthesis of novel, safe and biocompatible nanomaterials, which can be easily combined to design new supramolecular nanotherapeutics. Additionally, these innovative nanomaterials can, per se or as supramolecular nanocarriers, deliver bioactive compounds, which show different physical-chemical features, and treat different diseases. Recently, pharmaceutical industry and academia show a specific interest for natural products, which emerge as potential new drug candidates for the therapeutic treatment of inflammatory pathologies. In fact, the delivery of natural products by using supramolecular nanotherapeutics can represent a great opportunity in nanomedicine and an alternative therapeutic option to conventional medicine for treating inflammatory diseases. In this review, we will discuss the recent innovation of supramolecular nanotherapeutics delivering natural anti-inflammatory compounds and provide an overview of their application in nanomedicine.

Vesicles and micelles: Two versatile vectors for the delivery of natural products

Natural plant-based extracts and isolated constituents have been widely used around the world since ancient times for both treatment and prevention of human diseases. Currently, the importance of natural products in clinical practice is highlighted by the number of herbal medicinal products on the market. However, formulation development of many active constituents of plant extracts is often hampered by their limited bioavailability due to several issues among which low water solubility, poor absorption and degradation are the most frequent. To overcome these issues, several research studies proposed to combine herbal medicinal products with nanocarriers widely used as drug delivery systems. The nanotechnology approach is especially attractive because colloidal carriers can modify the payload pharmacokinetic and biodistribution, as well as increase solubility, stability, and efficacy. Moreover, nanoencapsulation may decrease toxicity and modulate drug release.In recent years, delivery systems such as micelles and vesicles, obtained by the self-assembly of biocompatible surfactants, have attracted increasing attention as carriers for various herbal products. Thus, the aim of this paper is to review the main investigations developed by Italian research groups on formulations of natural products, including isolated compounds, extracts and essential oils, using micelles and vesicles as carriers.

Natural product-based nanomedicine: recent advances and issues.

Natural products have been used in medicine for many years. Many top-selling pharmaceuticals are natural compounds or their derivatives. These plant- or microorganism-derived compounds have shown potential as therapeutic agents against cancer, microbial infection, inflammation, and other disease conditions. However, their success in clinical trials has been less impressive, partly due to the compounds’ low bioavailability. The incorporation of nanoparticles into a delivery system for natural products would be a major advance in the efforts to increase their therapeutic effects. Recently, advances have been made showing that nanoparticles can significantly increase the bioavailability of natural products both in vitro and in vivo. Nanotechnology has demonstrated its capability to manipulate particles in order to target specific areas of the body and control the release of drugs. Although there are many benefits to applying nanotechnology for better delivery of natural products, it is not without issues. Drug targeting remains a challenge and potential nanoparticle toxicity needs to be further investigated, especially if these systems are to be used to treat chronic human diseases. This review aims to summarize recent progress in several key areas relevant to natural products in nanoparticle delivery systems for biomedical applications.

Epigenetic mechanisms in cancer: push and pull between kneaded erasers and fate writers.

Research concerning the epigenome over the years has systematically and sequentially shown substantial development and we have moved from global inhibition of modifications of the epigenome toward identification and targeted therapy against tumor-specific epigenetic mechanisms. In accordance with this approach, several drugs with epigenetically modulating activity have received considerable attention and appreciation, and recently emerging scientific evidence is uncovering details of their mode of action. High-throughput technologies have considerably improved our existing understanding of tumor suppressors, oncogenes, and signaling pathways that are key drivers of cancer. In this review, we summarize the general epigenetic mechanisms in cancer, including: the post-translational modification of DNA methyltransferase and its mediated inactivation of Ras association domain family 1 isoform A, Sonic hedgehog signaling, Wnt signaling, Notch signaling, transforming growth factor signaling, and natural products with epigenetic modification ability. Moreover, we introduce the importance of nanomedicine for delivery of natural products with modulating ability to epigenetic machinery in cancer cells. Such in-depth and comprehensive knowledge regarding epigenetic dysregulation will be helpful in the upcoming era of molecular genomic pathology for both detection and treatment of cancer. Epigenetic information will also be helpful when nanotherapy is used for epigenetic modification.

Aloin delivery on buccal mucosa: ex vivo studies and design of a new locoregional dosing system

Context: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose.Objective: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system.Materials and methods: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudragit® RS 100 as, biocompatible, low permeable, pH-independent, and non-swelling polymer. The prepared tablets were evaluated for drug–polymer compatibility, weight variation, drug uniformity content, diameter, thickness, hardness, friability, swelling, mucoadhesive strength, and drug release.Results: Aloin has low tendency to cross buccal mucosa, permeation is marginal, and high drug amounts remain entrapped into the epithelium. Matrix tablets characteristics were in agreement with pharmacopoeial requirements. Drug release showed highly reproducible Higuchian profile. Delivery through matrix tablets promoted drug accumulation in the mucosal tissue.Discussion and conclusion: Following application of matrix tablets on porcine buccal mucosa, the amount of discharged drug recovered in the tissue should be sufficient to produce the desired effects, providing therapeutic drug levels directly at the site of action. Aloin-loaded tablets are valid candidates for prevention/treatment of potentially malignant disorders and oral cancer and could potentially lead to clinically relevant drug delivery system as coadjuvant of conventional chemotherapy/radiation therapy.

Improving on nature:The role of nanomedicine in the development of clinical natural drugs

It is astonishing to observe that in spite of the technical hitches encountered in natural product research, more than 50% of drug substances are natural products or inspired by natural compounds, covering a variety of therapeutic indications with a great range of chemical structures. Several latest reviews have tinted the tangible importance of natural products to the drug discovery process, being over a hundred natural product-derived compounds which are currently undergoing clinical trials [1]. Although these natural products represent a large source of potential drugs, mostly of them have limited clinical use due to chemical instability, low absorption and biodistribution, first pass metabolism, little accumulation in the organs of the body, inadequate efficacy or safety profiles [2,3]. These characteristics strongly influence the delivery of natural products using conventional dosage forms. Different strategies have been adopted to overcome these limitations, such as development of semisynthetic compounds or synthetic analogues, or the production of prodrugs but in mostly of the cases have not been satisfactory.

Nanoparticle Delivery of Natural Products in the Prevention and Treatment of Cancers: Current Status and Future Prospects

The advent of nanotechnology has had a revolutionary impact on many aspects of 21st century life. Nanotechnology has provided an opportunity to explore new avenues that conventional technologies have been unable to make an impact on for diagnosis, prevention, and therapy of different diseases, and of cancer in particular. Entities in nanometer sizes are excellent platforms to incorporate various drugs or active materials that can be delivered effectively to the desired action site without compromising the activity of the incorporated drug or material. In particular, nanotechnology entities can be used to deliver conventional natural products that have poor solubility or a short half life. Conventional natural products used with entities in nanometer sizes enable us to solve many of the inherent problems (stability, solubility, toxicity) associated with natural products, and also provide a platform for targeted delivery to tumor sites. We recently introduced the novel concept of using nanotechnology for enhancing the outcome of chemoprevention, which we called ‘nanochemoprevention’. This idea was subsequently exploited by several laboratories worldwide and has now become an advancing field in chemoprevention research. This review examines some of the applications of nanotechnology for cancer prevention and therapy using natural products.

Novel thermosensitive poly (N-isopropylacrylamide-co-vinylpyrrolidone-co-methacrylic acid) nanosystems for delivery of natural products.

The purpose of this research was to synthesize polymer based smart nanosystems for delivery of important bioactive natural products such as sesquiterpene coumarin derivatives of ferula szowitsiana, farnesiferol C as a potent anticancer. To this aim, polymeric micelles were prepared using Nisopropylacrylamide (NIPAAM), vinyl pyrrolidone (VP) and methacrylate (MAA) as monomers which were cross-linked with N, N-methylene bisacrylamide (MBA). The molar ratio of the PNIPAAm: VP: MAA group was 75.7:9.5:14.8. These micelles were further characterized upon their physicochemical properties using particle size analyzer, FT-IR, H-/C-NMR, HPLC. Particle size analyzer resulted in ~500 nm micelles with ~95% drug entrapments. Drug release from the polymeric micelles after 300 hours at 37°C and 40°C were 60 and 98 %, respectively. Upon these findings, it is proposed that the P (N-isopropylacrylamide-co-Methacrylic acid-coVinylpyrrolidone) micelles may be considered as thermosensitive delivery nanosystem.

Nanochemoprevention: Sustained Release of Bioactive Food Components for Cancer Prevention

Chemoprevention, especially through the use of naturally occurring phytochemicals capable of impeding the process of carcinogenesis at one or more steps, is an ideal approach for cancer management. Despite accomplished outcomes in preclinical settings, its applicability to humans has met with limited success for many reasons including inefficient systemic delivery and bioavailability of promising chemopreventive agents. We have recently introduced a novel concept of “nanochemoprevention” that utilizes nanotechnology for enhancing the outcome of chemoprevention (Cancer Res 69, 1712–1716, 2009). To establish the usefulness of nanochemoprevention in cancer management, we studied the efficacy of a well identified chemopreventive agent epigallocatechin-3-gallate (EGCG) encapsulated in polylactic acid (PLA) and polyethylene glycol (PEG) nanoparticles (hereafter referred to as nano-EGCG) in preclinical settings. Nano-EGCG was found to retain its biological effectiveness, with over 10-fold dose advantage compared to nonencapsulated EGCG for exerting its cell growth inhibition, proapoptotic, and angiogenic inhibitory effects. Nano-EGCG was also observed to be effective in inhibiting tumor cell growth in athymic nude mice, with over 10-fold dose advantage compared to nonencapsulated EGCG. The rate of degradation of nonencapsulated EGCG was rapid, with a complete degradation within 4 h, whereas nano-EGCG had a significantly longer half-life. This study provides a foundation for the use of nanoparticle-mediated delivery of natural products to enhance the bioavailability of active agents for their enhanced effective and chemopreventive potential. In doing this, it is hoped that perceived toxicity concerns associated with prolonged use of agents could also be minimized. Oral consumption is the most desirable and acceptable form of delivery of chemopreventive agents. One disadvantage of using PLA-PEG nanoparticles is its unstable nature in acidic environment; and therefore, it is not recommended for oral consumption. To overcome this obstacle, it will be important to develop nanoparticles encapsulating phytochemicals that are suitable for oral consumption.

Ein Auszug aus einem spätdemotischen Kassenbuch (P. Vindob. D 6141)

The present paper is devoted to the study of a late demotic document of papyrus from the Erzherzog Rainer Collection in Vienna. The document belongs to that kind of text of listed accounts, hitherto published only in a few pieces. The text in discussion provides us with about 600 numbers, as well as fractional numbers and at least 20 proper names which are characteristic for Soknopaiou Nesos. Working on the contents, a part of the accounting procedures leads us to a new understanding: revenues and expenditures are added or substracted continuously to the current total. This document, therefore, is not as usual dealing with a tax-list or a delivery of natural products or objects, but consists apparently of a register or blotter for a temple or a state administration being concerned with financial dealings. The payments are not made in natural procedure, but in money. The rather difficult understandable relationships of aforementioned persons, furthermore, are described on a trial basis.