text:
Solid Lipid Nanoparticles in Cancer Treatment
Info: 10719 words (43 pages) Dissertation
Published: 24th Feb 2022
Tagged: CancerBiomedical Science
The focus of drug discovery has switched from the concept of the 'magic bullet' drugs which target specific cells to the concept of 'magic wands' which refers to the mode of drug delivery. Drug delivery systems offer an opportunity of enhanced therapeutic effect of anticancer agents by either increasing drug concentration to tumour sites and/or reducing exposure to normal tissues. Among the variety of delivery systems that have been developed, solid lipid nanoparticles (SLNs) have lead advancements in the field due to their unique capability to carry a wide variety of substances, structural versatility and biocompatibility of their components. There are many different drug delivery systems currently being developed such as polymeric and lipid micelles and nanoparticles. However, SLNs is one of the Nanoformulations that have recently been used further from scientists due to many advantageous, such as controlled drug release, non-biotoxicity of the carrier, increased bioavailability of drug and lower overall cost. This paper covers the techniques for the production of SLN, drug incorporation, loading capacity and drug release mechanisms and also the potential of SLNs in cancer treatment as an anti-cancer drug delivery vehicle.
Keywords: Cancer; Drug Delivery; Lipids; Nanoformulations; Nanoparticles; SLNs.
The past decade has witnessed a remarkable growth in the field of nanotechnology as it offers a great scope to deliver small molecular drugs and macromolecules which include peptides, proteins and genes at the targeted site. The nanometre size range is proved to have several advantages as drug delivery systems. The application of nanotechnology in the fields of medicine and drug delivery in particular is on rise and it is anticipated to bring remarkable changes in the diagnosis and treatment of various diseases.
Novel drug delivery systems offer the possibility of enhanced therapeutic effect of anticancer agents by either increasing drug concentration to tumour sites and/or reducing exposure to normal tissues sites. Lipid drug delivery systems currently serve as useful tools for delivery of active anticancer agents (for example lipid formulations with doxorubicin or paclitaxel). Among the variety of delivery systems that have been developed, solid lipid nanoparticles (SLNs) have created the most excitement due to their unique properties such as ability to carry a wide variety of substances, structural versatility and biocompatibility of their components. Moreover, lipid based drug delivery systems are able to modify the pharmacokinetics and pharmacodynamics of cancer cells, allowing an increase in the localised concentration of drug released into the target cell without losing drug properties, thus reducing exposure of normal cells to drug molecules.
SLNs are colloidal deliver systems made from solid (under room temperature) lipid, with a diameter between 50 to 500 nm. SLNs, unlike polymeric nanoparticles, can be produced by a variety of different conveniently methods, such as high-pressure homogenisation. The obtained SLNs can be stabilised by surfactant such as lecithin, Tween 80, Pluronic 68 or by the combination of different surfactants [1]. SLNs are invented in early 90s, and it's the latest development of lipid based colloidal delivery system after nanoemulsions (made from lipids that are liquid under room temperature). It quickly generated broad public attention within few years. The first safe emulsion for parental nutrition delivery was invented by Wretlind in 1961 [2], which marks the beginning of emulsion as colloidal delivery for lipophilic drugs, and after years of research some of them successively commercialised. By applying oil-in-water (O/W) emulsions were able to reduce injection dosage and thereby minimize side effect; o/w emulsion was designed and applied for drug delivery. Products such as Diazemuls and Diazepam-Lipuro were developed and placed into the market. Despite of the advantages, major limitations of these emulsions are also clear, such as the poor physical stability of drug containing emulsion. Moreover, the encapsulation of drugs is able to cause agglomeration, drug expulsion and poor ability to offer protection to liable compounds. Another lipid based carrier developed earlier is liposome, which normally composed of phospholipid. It is invented as early as 1965 with focus on cosmetic market. After one decade of research, several products such as lung surfactant for pulmonary instillation were put into the market. However, the total number of successful product is rather limited when compared to emulsion. Major obstacle is lack of commercially available production method. In another word, liposome product is only feasible in lab scale. Polymeric nanoparticles research has been under intensive research for 50 years. This delivery system is well commercialised like lipid based delivery system, however has encountered similar issues with liposomes; polymeric particles are difficult to be produced in large quantity, and also is been reported that polymeric particles have poor tolerability.
2. Solid Lipid Nanoparticles (SLNs)
SLNs were first introduced in 1991, and they represent alternative carrier systems to other traditional colloidal carriers namely O/W emulsions, liposomes, micro-particles and polymeric nanoparticles. SLN consists of spherical lipid particles in the nano-meter size range (Figure 1).
Figure 1. A diagrammatic representation of SLN.
SLN is used for the controlled and targeted delivery of drugs. The drugs are part of the solid lipid matrix. SLN is stabilised by a surfactant layer, which may consist of a single surfactant, but is normally composed of a mixture of surfactants. Generally, a solid lipid that is used in such delivery systems melts at temperatures exceeding body temperature (37 °C). Some of these lipids are fatty acids, steroids, waxes, triglycerides, acyl-glycerols or a combination thereof. Different classes and ratios of emulsifiers have been successfully utilised to stabilise SLNs. Some of the most common emulsifiers are lecithin, bile salts such as sodium taurocholate, non-ionic emulsifiers such as ethylene oxide/propylene oxide copolymers, sorbitan esters, fatty acid ehoxylates etc. SLN is claimed to be advantageous when compared to any other colloidal carriers, and is known to combine the advantages and avoid the disadvantages associated with numerous colloidal carrier systems [3]. SLN does have several disadvantages e.g. unpredictable particle growth or unexpected drug expulsion from the lipid core are known to be common phenomena. Table 1 shows the advantages and disadvantages on the se of SLNs as drug delivery systems [4].
Table 1. Advantages and disadvantages of SLNs.
Target based drug delivery system.
Particle growth.
Drug released for prolonged time.
High pressure induced drug degradation.
Less expensive.
Unpredictable gelation tendency.
Used for poorly water-soluble drugs.
Drug expulsion after polymeric transition during storage.
Long term stability.
Can be administered via different routes.
No bio-toxicity of the carrier.
3. SLN preparation methods
3.1. High pressure homogenisation
High pressure homogeniser (HPH) proved to be a very effective dispersing technique in the preparation of SLNs. A reduction of the average particle size from 474 to 155 nm (for example) can be obtained after the first homogenisation cycle at 800 bars. The dispersing grade of SLN depends on the power density and the power distribution in the dispersion volume. High power densities result in more effective particle disruption. High pressure homogenisers reach by far the highest power densities (~1013 energy input W/m3). A homogeneous distribution of the power density is necessary to obtain narrow size distributions, otherwise, particles localised in different volumes of the sample will experience different dispersing forces and therefore the degree of particle disruption will vary within the sample volume. Inhomogeneous power distributions are observed in high-shear homogenisers and ultrasonifiers. HPHs are characterised by a homogenous power distribution due to the small size of the homogenising gap (25–30 mm) [3].
3.1.1. Hot homogenisation
High temperature is used in hot homogenisation techniques. The temperature is kept above the melting point of the lipid(s); drug is dissolved in the melted lipid(s) and the mixture is dispersed in a hot surfactant solution. The pre-emulsion is made by mixing drug, lipid(s) and surfactant, which is then prepared by using an ultrasonic pre-homogeniser for 3 min. The solution is then passed through a homogeniser for 5 min depending on the pressure [5].
3.1.2. Cold homogenisation
In the cold HPH technique, lipid is melted above its melting point and drug is dissolved or dispersed in it. The system is cooled down by means of dry ice or liquid nitrogen. After solidification, the lipid mass is grounded using ball or mortar milling to yield lipid micro-particles in a range between 50 and 100 µm. Then a micro-emulsion is formed by adding these micro-particles into cold surfactant solution with stirring. This suspension is passed through a HPH at/or below room temperature and the micro-particles are broken down to nanoparticles. Lipid particles prepared using the cold HPH technique possess a slightly higher polydispersity index (PI) and mean particle size compared to the ones obtained by hot HPH technique [6].
3.2. Solvent emulsification evaporation
In this method, the lipid is dissolved in water immiscible organic solvents (e.g. chloroform), which is then emulsified in an aqueous phase before evaporation of the solvent under condition of reduced pressure. This method is suitable for the incorporation of highly thermolabile drugs due to avoidance of heat during the preparation, however presence of solvent residues in the final dispersion may create problems due to regulatory concerns [6].
3.3. Micro-emulsion technique
A warm micro-emulsion is prepared containing molten lipid, surfactant and co-surfactant is added with stirring. This solution is then dispersed in cold water while stirring. Excess water can be removed by freeze drying. This method has certain advantages which include no need for specialised equipment, energy for the production is not required and scale-up production of lipid nanoparticles is possible. The main disadvantage of the microemulsion technique is the dilution of the particles suspension with water, thus removal of excess water need additional efforts. In addition, high concentrations of surfactants and co-surfactants, in the formulation raise regulatory concern [6].
3.4. Ultra-sonication
SLNs can be obtained by high speed stirring using ultra-sonication. This method was used for the production of an O/W emulsion in which high speed stirring was applied to the melted lipid phase and hot aqueous dispersion of surfactant. After cooling the resulting emulsion, solid particles of lipid were obtained. The main drawback of this method is the use of a high amount of surfactant without which the production of nanometre size particles is not possible. Physical instability and micro sized range of particles are some of the disadvantages of this technique [7].
3.5. Supercritical fluid method
This technique is considered to be a relatively new approach for SLN production. There are several variations in this platform technology for powder and nanoparticle preparation. In this method, a gas such as carbon dioxide is used as a solvent. SLN can be prepared by the rapid expansion of supercritical carbon dioxide solutions (RESS) method. The gas mainly used in this process is carbon dioxide because of its non-toxicity, low critical temperature and pressure. Some of the advantages of this technique include no usage of organic solvents and ability to produce nanoparticle and micro-particles in the form of dry powders [8].
Warm water-in-oil-in-water (W/O/W) double micro-emulsions can be prepared in two steps. Firstly, w/o micro-emulsion is prepared by adding an aqueous solution containing drug to a mixture of melted lipid, surfactant and co-surfactant at a temperature slightly above the melting point of lipid to obtain a clear system. In second step, w/o prepared micro-emulsion is added to a mixture of water, surfactant and co-surfactant to obtain a clear w/o/w system. SLN can be obtained by dispersing the warm micro double emulsions in cold then washed with dispersion medium by ultra-filtration system. Multiple emulsions have inherent instabilities due to coalescence of the internal aqueous droplets within the oil phase, coalescence of the oil droplets, and rupture of the layer on the surface of the internal droplets. In case of SLN production, they have to be stable for few minutes, the time between the preparations of the clear double micro-emulsions and its quenching in cold aqueous medium, which is possible to achieve [8].
3.7. Solvent emulsification diffusion method
Using this method an average diameter of particle sizes between 50-100 nm can be obtained. One of the advantages of this technique is the avoidance of high temperatures during preparation. In this technique lipid is generally dissolved in the organic phase in a water bath at 50 °C and used as an acidic aqueous phase in order to adjust the zeta potential to form coacervation of SLN, and then separation can be done by centrifugation. The SLN suspension can be quickly produced. The entire dispersed system can then be centrifuged and re-suspended in distilled water [9].
4. Influence of ingredient composition on product quality
4.1. Ingredients
General ingredients for the production of SLN include solid lipid(s), emulsifiers and water. The term lipid is used here in a broad sense; these lipids can include triglycerides (e.g. tristearin), partial glycerides (e.g. Imwitor), fatty acids (e.g. stearic acid), steroids (e.g. cholesterol) and waxes (e.g. cetyl palmitate). Emulsifiers help to stabilise the lipid dispersion. It has been found that a combination of emulsifiers may prevent particle agglomeration [3]. Table 2 shows a list of excipients that can be used for the preparation of SLNs.
Table 2. An overview of ingredients that are commonly used for the preparation of SLNs.
Triglycerides (lipids) Hard fat types Surfactants
Tricapin
Glyceryl monostearate
Soybean lechitin
Trilaurin
Glyceryl behenate
Egg lechitin
Trimyristin
Glyceryl palmitostearate
Phosphatidylcholine
Tripalmitin
Poloxamer 188
Tristearin
Tristeain
Decanoic acid
Ploxamine 908
Sodium Cholate
Sodium glycocholate
Taurocholic acid and sodium salt
4.2. Influence of lipid
According to Muller et al., the critical parameters for the formation of nanoparticles are related to the usage of different lipids [10]. Some of the examples are the velocity of lipid crystallisation, the lipid hydrophilicity (influence on several self-emulsifying properties) and the shape of the lipid crystals, which in turn also influences the surface area. Moreover, most of the lipids used represent a mixture of several chemical compounds, and the quality of these chemical compounds can vary from different suppliers or vary for different batches from the same supplier. These small differences in the lipid composition can possibly have considerable impact on the quality of SLN dispersion (e.g. by changing the zeta potential, retarding crystallisation processes). According to Ahlin et al., lipid composition can supposedly influence the particle size of SLN that is produced by high shear homogenisation [11]. Increasing the lipid content over 5-10% in most cases results in larger particles (including micro-particles) and broader particle size distributions [12].
4.3. Influence of emulsifiers
The choice of the emulsifiers and their concentration is of great impact on the quality of the SLN dispersion [3]. Either surfactant or surfactant mixture affects the particle size of the lipid nanoparticles. According to Mehnert et al., SLN exhibited a much smaller particle size when the surfactant amount was increased [3]. The decrease in surfactant concentration resulted in increase of particle size during storage. One of the most characteristics of surfactant is that it decreases the surface tension between the interface of the particles causing portioning of the particles and thereby increasing the surface area [8].
5. Secondary production steps
5.1. Stability of the drug and SLNs
Stability considerations that are relevant to SLNs are the chemical stability of the drug and the physical stability of SLN. Prevention of degradation reactions such as hydrolysis is an important chemical stability parameter and examples for physical stability issues include the prevention of particle size growth and polymorphic changes of the solid lipid. Lipids and surfactants must be chosen carefully and should be mutually compatible to improve the chemical stability [13].
Particle size distribution determines the bio-distribution, shelf-life and route of administration of SLN formulation. The SLN dispersion should possess a narrow size distribution to avoid particle size growth due to Ostwald ripening. Ostwald ripening is a thermodynamically driven process, in which smaller particles dissolve and redeposit onto the surface of larger particles. This process occurs because smaller particles have larger surface area and higher surface energy and hence higher Gibbs free energy than the larger particles. All systems tend to attain lowest Gibbs free energy. In other words, larger particles are more energetically stable and favoured over smaller particles. Ostwald ripening can be reduced by minimising polydispersity in the particle size but it cannot be prevented [8].
In SLN dispersions there are three types of instabilities (creaming, flocculation and coalescence). In creaming process the less dense phase migrates to top of the dispersion under the influence of buoyancy or centripetal force. Creaming causes the SLNs to come close to each other which in turn also initiate Ostwald ripening, flocculation and coalescence. It has been reported that creaming phenomenon can be prevented by matching the density of the lipid and the aqueous phase. Flocculation is a process in which the nanoparticles are held together in loose associations by weak van der Waals forces. Coalescence is a process in which the nanoparticles fuse to form larger particles. The electrostatic repulsion and steric hindrance between particles produced in the presence of surfactants have been found to inhibit flocculation [14].
Electrostatic repulsion produces an electrical double layer around each nanoparticle in SLN dispersion. The electrical double layer comprises of two parts: an inner region (stern layer), in which the ions are tightly bound and an outer diffuse region, in which the ions are less firmly attached. A notional boundary forms between particles and ions within this diffuse layer. Ions within the boundary move with the particle and the ions outside the boundary do not move with the particle. This notional boundary is called as slipping plane. The potential at the slipping plane is known as zeta (ζ) potential. The magnitude of the ζ-potential is an important determinant of the stability of SLN dispersions. As the ζ-potential increases, the magnitude of electrostatic repulsion between the particles also increases, hence the particles will tend to repel each other and there is no tendency to flocculate. Colloidal dispersions with a ζ-potential of more positive than +30 mV and negative than -30mV are considered to be stable. Steric effects also play an important role in the stability of SLN dispersion by hindering the particles from coming closer to each other and thus preventing flocculation and coalescence. The polyoxyethylene chain present in non-ionic surfactants extends in the aqueous medium in the form of a coil and providing steric hindrance. Optimum surfactant concentration and sufficient chain length (≥ 20 ethylene oxide units) will impart steric effect mediated formulation stability. For long-term stability a balance between electrostatic repulsion and steric effect must be obtained.
5.2. Lyophilisation
Lyophilisation can play an important part to increase the chemical and physical stability of SLN over extended period of time. Lyophilisation had been required to achieve long term stability for a product containing hydrolysable drugs or a suitable product for per-oral administration. Transformation into the solid state would prevent the Oswald ripening and avoid hydrolytic reactions. In case of freeze drying of the product, all the lipid matrices used, can form larger solid lipid nanoparticles with a wider size distribution due to presence of aggregates between the nanoparticles. The conditions of the freeze-drying process and the removal of water promote the aggregation among SLNs. An adequate amount of cryo-protectant (such as sucrose, lactose, mannitol, polyethylene glycol etc.) can protect the aggregation of solid lipid nanoparticles during the freeze-drying process [15].
5.3. Spray drying
Compared to lyophilisation spray drying is cheaper. The usage of spray drying is more encouraged when the lipids melting point is more than 70 °C. According to Mehnert et al., the best results with spray drying were obtained with SLN concentration of 1% in a solution of trehalose in water or 20% trehalose in ethanol-water mixture [3]. The addition of carbohydrates and low lipid content favour the preservation of the colloidal particle size in spray drying. Freitas et al., illustrated that melting of the lipid can be minimised by using ethanol-water mixtures instead of pure water due to cooling leads to small and heterogeneous crystals [16].
6. Drug incorporation and release from SLNs
6.1. Drug incorporation
Three different models for the incorporation of active ingredients into SLN have been extensively studied [10]. These are homogeneous matrix model, drug-enriched shell model and drug-enriched core model (Figure 2). The structure that is obtained is a function of formulation composition, such as lipid, active compound, surfactant, and also of the production conditions (hot vs cold homogenisation). A homogeneous matrix with molecularly dispersed drug or drug being present in amorphous clusters is thought to be mainly obtained when applying the cold homogenisation method and when incorporating very lipophilic drugs in SLN with the hot homogenisation method [17]. During the cold homogenisation method, the bulk lipid matrix contains the dissolved drug in molecularly dispersed form, which afterwards is mechanically broken down high pressure homogenisation leading to the formation of nanoparticle. In hot homogenisation method the produced oil droplet is being cooled and crystallised. It is to note that no phase separation between lipid and drug occurs during the cooling process.
Drug enriched outer shell can be obtained when phase separation occurs during the cooling process from liquid oil droplet to the formation of SLNs. According to Muller et al., the lipid can precipitate first by forming a practically compound free lipid core [10]. Also during the forming process of lipid core, the concentration of active compound in the remaining liquid lipid increases continuously. Finally, the compound enriched shell crystallises, this model is assumed to give away a very fast release which is highly desired in various SLN applications. Core enriched with active compound can be formed when the opposite occurs, which means the active compound starts precipitating first and the shell will have distinctly less drug. This leads to a membrane controlled release governed by the Fick law of diffusion. The structure of SLN formed clearly depends on the chemical nature of active compound and excipients and the interaction thereof. In addition, the structure can be influenced or determined by the production conditions.
There are two main methods drug loading, passive loading and active or remote loading. Passive loading involves the loading of the entrapped agents before or during the manufacturing process. The alternative method, active or remote loading enables the entrapped agents to be introduced into the lipid formulations after the intact vesicles are formed. This method allows compounds with ionisable groups and amphiphilic molecules to be introduced. The active / remote loading method offers many advantages over the passive method, most importantly its high encapsulation efficiency. It produces a lipid particle with reduced leakage of the encapsulated compound and it avoids the handling of biologically active compounds during the preparation process.
Figure 2. Illustration of different drug incorporation modes.
6.2. Drug release from SLNs
Üner et al., have intensively investigated the effect of formulation parameters and production conditions on the release profile of SLNs [18]. For example, they investigated the release profile as a function of production temperature. In most cases, burst release is observed from SLNs. An initial burst release is afterwards followed by a prolonged release, this process is called biphasic. It has also been observed that the burst release phenomenon only takes place when hot homogenisation is used and very high temperatures are applied. For particles that travel through circulation system, prolonged release is desired [19]. Fabricated Doxorubicin SLNs with mean diameter of 199 nm using glyceryl caprate and dimethyl sulfoxide via high pressure homogenisation method, by prolonged the release of doxorubicin was observed by Xie et al. [20]. Doxorubicin-loaded SLNs were fabricated using tetradecanoic acid, palmitic acid, stearic acid respectively. On the other hand, biphasic release patterns are completely non-existent when cold homogenisation is used. The release kinetics can also depend on the release conditions (e.g. sink or non-sink conditions, release medium).
Surfactant concentration can also play a vital role in burst release, and different studies have suggested that high surfactant concentration can lead to high burst release. This was explained by redistribution effects of the active compound between the lipid and the water phase during the heating up process and subsequently the cooling down process after production of the hot o/w emulsion during the hot homogenisation process. Solubility of active compound in the water phase increases due to the heating of lipid/water mixture and the compound partitions from the melted lipid droplet to the water phase. After the homogenisation procedure is done the lipid core starts to crystallise with still a relatively high number of active compounds in the water phase. Further cooling leads to super saturation of the compound in the water phase, then the compounds partitions back into the lipid phase; a solid core has already started forming leaving only the liquid outer shell for compound accumulation. Therefore, it can be observed that as the solubility in water phase goes higher so does the burst effect, and the solubility increases drastically when increased temperature and increased surfactant concentrations are used [3].
7. Biological and pharmaceutical aspects of SLNs
Advances in biocompatible nanoscale drug carriers such as liposomes and polymeric nanoparticles, have enabled more efficient and safer delivery of numerous of drugs. Lipid drug delivery systems currently serve as a useful tool for the delivery of active anticancer agents and have been used successfully used as drug carriers in the treatment of many cancers, where many clinical studies have shown enhanced therapeutic activity of the drug compared with the free drug. Moreover, lipid based drug delivery systems are able to modify the pharmacokinetics and pharmacodynamics of cancer cells, allowing them to increase the localised concentration of the drug released into the target cell without losing their properties and reduce the exposure of normal cells to the drug molecules. Lipids can also be served as a means to deliver actives by both active and passive targeting to cancer cells and targeting of cancer cells using the Enhanced Permeability and Retention (EPR) effect. As with most anticancer agents, there is a need to attain a local and targeted delivery of the active agent and one of the unique properties of lipids are their natural ability to target cancer cells due to their enhanced permeability across cell membranes.
SLN is considered to be suitable also for parenteral drug delivery because of their small size. SLN may be injected intravenously (IV) and used to target drugs to particular organs. Upon administration into the systemic circulation, several colloidal carriers such as liposomes and polymeric nanoparticles are rapidly cleared by cells of reticuloendothelial system (RES). RES usually resides in the spleen, liver and in the form of Kupffer cells in the liver consisting of phagocytic cells, which is considered to be the major part of the immune system. RES is known to remove drug carriers within minutes identified as foreign objects [21].
Clearance by RES is beneficial only when the spleen or liver, lymph nodes are the target tumour site for other type of cancers RES is known to be the major barrier. When colloidal carrier surface is modified with hydrophilic polymer it increases the blood circulation time and resistance to clearance by RES. This type of surface modification of drug delivery systems by polymers is called long circulating drug carriers. Polyethylene glycols (PEG) have been employed widely to get the stearic stabilisation of colloidal carriers. PEGs are electrical neutrality, chain flexibility, lack of functional group and high hydrophilicity which prevent it from interacting with biological components unnecessarily. Other hydrophilic molecules have been tried are Brij 68, Brij 78, and Pluronic F188 [22]. In order to facilitate drug targeting a reticuloendothelial system avoidance facility these block polyoxyethylene (POE) polypropylene copolymers like Pluronic F188 can be used, in which the hydrophobic portion of the molecule forms the nanoparticle matrix while the water-soluble POE block forms a hydrophilic coating on the SLN increase the tumour accumulation and anticancer activity of drugs [23].
The administered particles are cleared from the circulation by liver and spleen because of the small size of SLN (below 1 μm), these lipid nanoparticle formulations can be used for systemic body distribution with a minimal risk of blood clotting and aggregation, which can lead to embolism. SLN can also provide a sustained release of drug when administered IV. Drug encapsulated inside the lipid core can be released gradually on erosion (e.g. degradation by enzymes) or by diffusion from the particles [24].
8. Use of SLN in various cancer therapies
Cancer is a condition where cells in a specific part of the body both grows and reproduces in an uncontrollable manner. The cancerous cells are known to invade and destroy surrounding healthy tissues, which includes organs as well. Apart from a few cancer types (e.g. breast cancer), for which hormonal therapy or immunotherapy is used, cytotoxic drugs are used as the major form of chemotherapy for cancer [25]. Particulate drug carrier systems can have a great promise to improve the therapeutic effectiveness and safety profile of this conventional form of cancer chemotherapy [26]. Because of the numerous advantages that SLN can offer, this relatively new drug carrier is considered be an emerging drug carrier system in the field of anticancer drug delivery.
A tumour is normally associated with a defective, leaky vascular architecture as a result of the poorly regulated nature of tumour angiogenesis. Moreover, the interstitial fluid within a tumour is usually inadequately drained by a poorly formed lymphatic system. Due to this phenomenon, submicron sized particulate matter may preferentially extravasate into the tumour and be retained. This is often quoted as the "enhanced permeability and retention" (EPR) effect. This EPR effect can be taken advantage of by a properly designed nanoparticle system such as SLN to achieve passive tumour targeting. By doing this, the aforementioned poor tissue specificity problem can be partly solved. Furthermore, with the advances in surface-engineering technology, the biodistribution of SLN can be further manipulated by modifying the surface Physicochemical properties of SLN to target them to the tissue of particular interest [3]. As a result of this, the chances of drugs reaching the tumour sites can be further enhanced and systemic drug toxicity can be reduced. Cytotoxic drug delivery systems such as polymeric nanoparticles and liposomes possess several problems in terms of physical stability, protection of labile drugs from degradation and controlled release. SLN tends not to demonstrate such disadvantages [24]. Delivery of drugs from active form to solid tumours can be difficult. It is known that most anticancer agents have a large volume if distribution upon administration and subsequently narrow therapeutic index due to a high level of toxicity in healthy tissues. Through the successful encapsulation of these drugs in a drug delivery system, such as SLN, the volume of distribution can be significantly reduced and the concentration of drug in the tumour site can be increased [27]. SLN formulations of different anticancer agents have been shown to be less toxic than the free drug. Table 3 shows a list of anti-cancer drug encapsulated SLNs. Although there is still a lack of clinical studies of the use of SLN for cancer treatment, preclinical studies using cell culture systems or animal models have so far been very promising [28].
Table 3. A summary of SLN formulations used for the delivery of drugs with anticancer properties and the significant works based on these formulations (adapted from [26]).
Drug Research Group Focus of studies
Anticancer drugs
Camptothecin Yang 1
Yang 2
SLN preparation and characterisation.
SLN characterisation, pharmacokinetics and biodistribution studies in mice.
Doxorubucin Gasco
Serpe/Gasco
Wu 1
In vitro evaluation in colon cancer cell line.
In drug-resistant breast cancer cell lines.
In vitro evaluation of doxorubicin.
Etoposide Murthy SLN studies in tumour bearing mice.
Paclitaxel Gasco
SLN preparation, in vitro, in vivo cytotoxicity.
Retinoic Acid Kim SLN preparation and characterisation.
Verapamil Wu Verapamil SLN preparation and characterisation.
8.1. Brain tumour
The incidences of primary brain tumours in the United States have been estimated at approximately 43,800 per year. SLN is considered to be one of the best nanoscale lipid based compound for brain tumour drug delivery. Although the exact mechanism by which these SLNs cross Blood Brain Barrier (BBB) is still unknown, internalisation is hypothesised to be mediated by endocytosis of SLNs by endothelial cells. Endocytosis procedure is initiated by the successful absorption of circulating plasma proteins to the SLN surface [29]. Drug loading and any sort of possible drug degradation can be altered by lipid matrix. Drug unloading within the tumour tissues can also be controlled. This control can be achieved by the respective surface coating of the SLN with these constituent lipids [24]. Different studies suggested that nanoparticles with tween surfactants, resulted in transport of drugs across the BBB [30]. SLN have the potential to revolutionise both preoperative and intraoperative brain tumour detection.
Moreover, delivery of drugs to brain is a subtle task in the therapy of many severe neurological disorders, with SLNs easily diffuse the BBB due to their lipophilic nature. According to Singh et al. ligand conjugation on SLN surface enhances the targeting efficiency, by reporting Lactoferin (Lf) conjugated SLN system for effective brain targeting [31]. A study by Neves et al., has used resveratrol-loaded SLNs that have been functionalised with apolipoprotein E, and show that these systems might be a promising strategy for resveratrol delivery into the brain [32]. Graverini et al., have reported the preparation of SLNs to deliver andrographolide (AG) into the brain [33]. SLNs were prepared using Compritol 888 ATO as solid lipid and Brij 78 as surfactant and applying emulsion/evaporation/solidifying method as preparative procedure. The ability of SLN to cross the BBB was evaluated in vitro and in vivo in healthy rats.
8.2. Breast cancer
Breast cancer is the most common malignancy in women in most countries of the world and is one of the cancers most frequently observed in industrialised countries. There are over 1.4 million cases of cancer worldwide, 30% of which involve breast cancer with approximately 50,000 and 400 new cases in women and men respectively, diagnosed with the disease each year in the UK (Cancer Research UK). In recent decades, the death rate in breast cancer patients has been significantly reduced due to the implementation of periodic check-ups and treatments such as chemotherapy, hormone therapy, radiotherapy, and surgery.
Among the major challenges in effective breast cancer chemotherapies are inadequate drug concentrations reaching the tumour, their rapid elimination, systemic toxicity and adverse effects SLN has the potential to overcome current chemotherapeutic barriers in breast cancer treatment and to solve the problems associated with traditional chemotherapy and multidrug resistance [34]. Chemo-resistance or multidrug resistance can generally result from either of the two means firstly by physically impairing delivery to the tumour (e.g. poor absorption, increased metabolism/excretion, and/or poor diffusion of drugs into the tumour mass), and secondly through intracellular mechanisms that raise the threshold for cell death. Nanoparticles are beneficial tumour targeting vehicles due to their passive targeting properties by the EPR effect.
Campos et al., investigated the potential of modified SLNs for the delivery of paclitaxel (PAX) and found that these systems were stable and reproducible [35]. Their funding's have reveal that chitosan-hyaluronic-coated SLNs facilitated the targeting, cellular uptake and the time-/dose-controlled delivery and release of PAX. Wang at al., have formulated resveratrol-loaded SLNs to treat MDA-MB-231 cells, and by comparing these with free resveratrol has shown that the Res-SLNs displayed a superior ability in inhibiting the proliferation of MDA-MB-231 cells [36]. Another added advantage in SLN drug delivery system is the development of proteins (transferrin) and commercial antibody conjugated SLN formulations for active targeting of breast cancer [37].
8.3. Colorectal cancer
Colorectal cancer (CRC) ranked second in females and third in males among all type of cancers diagnosed in United States, and also known to be the most common cancer in several other western countries. SLN have been proposed as a new approach of drug carrier for colorectal cancer. SLN carrying cholesteryl butyrate, doxorubicin and paclitaxel had previously been developed [38]. Rajpoot & Jain developed and optimized oxaliplatin (OP) loaded SLNs containing tristearin, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), Lipoid S75, and Tween 80 [39]. They have shown that drug entrapped in OP-SLNs have higher sensitivity of HT-29 cells compared to OP-SLNs and OP solution, which is a promising approach for the management of CRC. Other studies have shown that 5-fluorouracil (5-FU) loaded SLNs can produce superior anticancer activity than pure 5-FU for the treatment of CRC [40].
8.4. Lung cancer
One of the leading causes of cancer related deaths worldwide is lung cancer. Adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma, which together make up the majority of lung cancers, are referred to as ''non-small cell lung cancers'' (NSCLCs). Patients with early stage NSCLC are typically treated with surgery with a 5-year survival rate ranging from 25% to 80%. This survival rate also depends vastly on the stage of the disease. The causes of lung cancers are generally characterised by mutations in p53 gene. These mutations can lead to an exponential loss of tumour-suppressor function, increase drug resistance, loss of mutational repair, increase of angiogenesis, inhibition of cells and proliferation of apoptosis. SLNs have gained increasing attention as a promising colloidal carrier system. As a substitution for viral delivery systems it was reported the use of p53 gene/cationic lipid complexes for the treatment of early endobronchial cancer [41]. Bakhtiary et al., reported the development of erlotinib (ETB) loaded SLNs based formulation of dry powder inhaler (DPI), which displayed a suitable flowability and aerodynamic traits and by Next Generation Impactor (NGI) analyses have confirmed deep inhalation pattern of the formulations [42].
8.5. Prostate cancer
Prostate cancer is known to be one of the most important cancer in men, especially in the industrialised countries of the western world. According to several reports the incidence of prostate cancer has been increasing over the last decade. The reason behind this rapid increase of incidence is thought to be due to the heterogeneous and peculiar nature of individual cancers, and moreover the inability to target therapies to neoplastic cells [43]. The usage of SLN as a drug delivery system considered to be advantageous for inhibition of prostate cancer cells, such as LNCaP. One of the many advantages of using SLN is the usage of well tolerated compound's while making these nanoparticles, and moreover the avoidance of organic solvents, alongside good physical stability. SLN have a great potential as a drug delivery system for prostate cancer cells since it is capable of enhanced accumulation in the target tissue through a passive targeting mechanism (e.g. enhanced permeability and retention effect, EPR), an increased accumulation and cell uptake through receptor-mediated endocytosis can be obtained if specific binding agents are attached on the surface of SLNs.
Akanda et al., reported the formulation of retinoic acid (RTA) loaded SLNs by tuning the process parameters (e.g. pressure/temperature) and by using different lipids to develop nanodispersions with enhanced anticancer activity [44]. The RTA-SLN dispersions were produced by high-pressure homogenisation and the anticancer efficiency was evaluated by incubating RTA-SLNs with human prostate cancer (LNCap) cells, which demonstrated reduced cell viability with increased drug concentrations (e.g. 9.53% at 200 μg/ml) while blank SLNs displayed negligible cytotoxicity.
9. Marketed products and current studies on SLN
Since early nineties, researchers turned their attention to lipid nanoparticles because of their nontoxicity and cost/effectiveness relationship. In spite of the advantages, formulating with lipid nanoparticles has been suffering some drawbacks. Because of the gastro intestinal tract (GIT) conditions, most of promising drugs do not reach clinical trials. The stability of particles must be comprehensively tested due to pH changes and ionic strength as well as the drug release upon enzymatic degradation [45]. Lipid nanoparticles absorption through GIT occurs via transcellular (through M cells or enterocytes) or paracellular (diffusion between cells). If the major drug uptake occurs through M cells, the portal vein to the liver is bypassed, resulting in higher drug concentrations to the lymph rather than to plasma [46].
Despite the low number of lipid nanoparticles formulations on the market for drug delivery, Mucosolvan retard capsules (Boehringer Ingelheim) is a story of success. Mucosolvan retard capsules was the first generation. It was produced by highspeed stirring of a melted lipid phase in a hot surfactant solution obtaining an emulsion. This emulsion was then cooled down to room temperature obtaining the so-called "lipid nanopellets for oral administration". Successful in vivo studies also include rifampicin, isoniasid, and pyrazinamide that are used in tuberculosis treatment. These drugs achieved higher bioavailability when incorporated into SLN compared to the free solutions. Rifampicin has poor cellular penetration which requires high doses to reach effective concentrations. Rifamsolin is a rifampicin-loaded SLN under preclinical phase by AlphaRx. The methodology employed for production is acceptable by the regulatory agencies and has been addressed by various papers and patents [47]. Poor water-soluble drugs, such as camptothecin, vinpocetine, and fenofibrate, can have their solubilisation improved if incorporated into SLN. Potta et al., in two studies in 2012 have developed SLNs for enhanced the solubility of poorly soluble drugs such as Cyclosporine (CyA) [48] and ibuprofen [49].
Another example is insulin, commonly administered parenterally in the treatment of diabetes mellitus. Injections are often painful and must be administered daily, which result in low patient compliance. Unfortunately, oral administration of insulin, produced by solvent emulsification-evaporation method based on a w/o/w double emulsion, has limitations such as low bioavailability due to degradation in the stomach, inactivation and degradation by proteolytic enzymes, and low permeability across the intestinal epithelium because of lack of lipophilicity and high molecular weight [46]. The main advantages of incorporate insulin into SLN would be the enhancement of trans mucosal transport and protection from the degradation in the GIT. New investigations will need to be designed with the aim of developing anti-cancer drug encapsulated SLNs which are capable of enhancing the bioavailability of the drug molecule.
The fast-developing science of nanotechnology is one of many areas that are expected to have a significant impact on medicine and how medicine delivered. There are several varieties of particles available, however, SLNs have attracted special interest in the last few decades and can be produced by different methods with many advantages, and have a great potential to be used as vehicle for the treatment of cancer with least side effects.
Pardeike, J., Hommoss, A., Müller, R.H. Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. International journal of pharmaceutics 2009, 366(1), 170-184.
Schubert, O., Wretlind, A. Intravenous infusion of fat emulsions, phosphatides and emulsifying agents. Acta Chir Scand Suppl 1961, 13, 278.
Mehnert, W., Mäder, K. Solid lipid nanoparticles: production, characterization and applications. Advanced drug delivery reviews 2001, 47(2), 165-196.
Mukherjee, S., Ray, S., Thakur R.S. Solid lipid nanoparticles: Modern formulation in drug delivery system. Indian journal of Pharmaceutical Sciences 2009, 71(4), 349-358.
Almeida, A.J., Souto, E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Advanced drug delivery reviews 2007, 59(6), 478-490.
Chaturvedi, S.P., Mishra, A Production technique of lipid nanoparticles. Research Journal of pharmaceutical, biological and chemical sciences 2012, 3(3), 525-541.
Souto, E. B., Muller, R.H. Lipid nanoparticles (solid lipid nanoparticles and nanostructured lipid carriers) for cosmetic, dermal, and transdermal applications. Drugs and the pharmaceutical sciences 2007, 166, 213.
Ekambaram, P., Sathali, A.A.H, Priyanka, K. Solid lipid nanoparticles: A review. Scientific reviews and chemical communications 2011, 2(1), 80-102.
Trotta, M., Debernardi, F., Caputo, O. Preparation of solid lipid nanoparticles by a solvent emulsification–diffusion technique. International journal of pharmaceutics 2003, 257(1), 153-160.
Muller, R.H., Mader, K., Gohla, S. Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. European journal of pharmaceutics and biopharmaceutics 2000, 50(1), 161-177.
Ahlin, P., Kristl, J., Smid-Korbar, J. Optimization of procedure parameters and physical stability of solid lipid nanoparticles in dispersions. Acta pharmaceutica 1998, 48(4), 259-267.
Siekmann, B., Westesen, K. Melt-homogenized solid lipid nanoparticles stabilized by the nonionic surfactant tyloxapol. I. Preparation and particle size determination. Pharmacopeia pharmacological letters 1994, 1(3), 123-12694-197.
Lim, S.J., Lee, M.K., Kim, C.K. Altered chemical and biological activities of all-trans retinoic acid incorporated in solid lipid nanoparticle powders. Journal of controlled release 2004, 100(1), 53-61.
Porter, M.R. Handbook of surfactants. 1994.
Ohshima, H., Miyagishima, A., Kurita, T., Makino, Y., Iwao, Y., Sonobe, T., Itai, S. Freeze-dried nifedipine-lipid nanoparticles with long-term nano-dispersion stability after reconstitution. International journal of pharmaceutics 2009, 377(1), 180-184.
Freitas, C., Muller, R.H. Spray-drying of solid lipid nanoparticles (SLN TM). European Journal of Pharmaceutics and Biopharmaceutics 1998, 46(2), 145-151.
Yadav, N.E.H.A., Khatak, S.U.N.I.L., Sara, U.V. Solid lipid nanoparticles: a review. International Journal of pharmaceutics 2013, 5(2), 8-18.
Üner, M., Yener, G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. International journal of nanomedicine 2007, 2(3), 289.
Subedi, R.K., Kang, K.W., Choi, H.K. Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin. European journal of pharmaceutical sciences 2009, 37(3), 508-513.
Xie, S., Zhu, L., Dong, Z., Wang, X., Wang, Y., Li, X., Zhou, W. Preparation, characterization and pharmacokinetics of enrofloxacin-loaded solid lipid nanoparticles: influences of fatty acids. Colloids and surfaces biointerfaces 2011, 83(2), 382-387.
Moghimi, S.M., Szebeni, J. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Progress in lipid research 2003, 42(6), 463-478.
Chimmiri, P., Rajalakshmi, R., Mahitha, B., Ramesh, G., Noor Ahmed, V.H. Solid lipid nanoparticles: a novel carrier for cancer therapy. International Journal of biological pharmaceutical research 2012, 3(3), 405-413.
Zara, G.P., Cavalli, R., Fundaro, A., Bargoni, A., Caputo, O., Gasco, M.R. Pharmacokinetics of doxorubicin incorporated in solid lipid nanospheres (SLN). Pharmacological research 1999, 40(3), 281-286.
Wissing, S.A., Kayser, O., Müller, R.H. Solid lipid nanoparticles for parenteral drug delivery. Advanced drug delivery reviews 2004, 56(9), 1257-1272.
Ewesuedo, R.B., Ratain, M.J. Principles of cancer chemotherapy. In Oncologic Therapies Publisher: Springer Berlin Heidelberg, 2003, pp. 19-66.
Wong, H.L., Bendayan, R., Rauth, A.M., Li, Y., Wu, X.Y. Chemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles. Advanced drug delivery reviews 2007, 59(6), 491-504.
Speth, P.A.J., Van Hoesel, Q.G.C.M., Haanen, C. Clinical pharmacokinetics of doxorubicin. Clinical pharmacokinetics 1998, 15(1), 15-31.
Pardeshi, C., Rajput, P., Belgamwar, V., Tekade, A., Patil, G., Chaudhary, K., Sonje, A. Solid lipid based nanocarriers: An overview/Nanonosači na bazi čvrstih lipida: Pregled. Acta pharmaceutica 2012, 62(4), 433-472.
Nagayama, S., Ogawara, K.I., Fukuoka, Y., Higaki, K., Kimura, T. Time-dependent changes in opsonin amount associated on nanoparticles alter their hepatic uptake characteristics. International journal of pharmaceutics 2007, 342(1), 215-221.
Kreuter, J. Influence of the surface properties on nanoparticle-mediated transport of drugs to the brain. Journal of nanoscience and nanotechnology 2004, 4(5), 484-488.
Singh, I., Swami, R., Pooja, D., Jeengar, M.K., Khan, W., Sistla, R. Lactoferrin bioconjugated solid lipid nanoparticles: a new drug delivery system for potential brain targeting. Journal of Drug Targeting 2016, 24(3).
Neves, A.R., Queiroz, J.F., Reis, S. Brain-targeted delivery of resveratrol using solid lipid nanoparticles functionalized with apolipoprotein E. Journal of Nanobiotechnology, 2016, 14, 27. doi:10.1186/s12951-016-0177-x.
Graverini, G., Piazzini, V., Landucci, E., Pantano, D., Nardiello, P., Casamenti, F., Pellegrini-Giampietro, D.E., Bilia, A.R., Bergonzi, M.C. Solid lipid nanoparticles for delivery of andrographolide across the blood-brain barrier: in vitro and in vivo evaluation. Colloids Surf B Biointerfaces. 2017, 27(161), 302-313. doi: 10.1016/j.colsurfb.2017.10.062.
Bassiouni, Y., Faddah, L. Nanocarrier-Based Drugs: The Future Promise for Treatment of Breast Cancer. Journal of applied pharmaceutical science 2012, 2(05), 225-232.
Campos, J., Varas-Godoy, M., Haidar, Z.S. Physicochemical characterization of chitosan-hyaluronan-coated solid lipid nanoparticles for the targeted delivery of paclitaxel: a proof-of-concept study in breast cancer cells. Nanomedicine 2017, 12(5), 473-490.
Wang, W., Zhang, L., Chen, T., Guo, W., Bao, X., Wang, D., Ren, B., Wang, H., Li, Y, Wang, Y., Chen, S., Tang, B., Yang, Q., Chen, C. Anticancer Effects of Resveratrol-Loaded Solid Lipid Nanoparticles on Human Breast Cancer Cells. Molecules 2017, 22, 1814.
Du, W., Hong, L., Yao, T., Yang, X., He, Q., Yang, B., Hu, Y. Synthesis and evaluation of water-soluble docetaxel prodrugs-docetaxel esters of malic acid. Bioorganic & medicinal chemistry 2007, 15(18), 6323-6330.
Nielsen, D., Maare, C., Skovsgaard, T. Cellular resistance to anthracyclines. General Pharmacology: The vascular system 1996, 27(2), 251-255.
Rajpoot, K., Jain, S.K. Colorectal cancer-targeted delivery of oxaliplatin via folic acid-grafted solid lipid nanoparticles: preparation, optimization, and in vitro evaluation. Artificial Cells, Nanomedicine, and Biotechnology 2017, In Press. doi: 10.1080/21691401.2017.1366338.
Patel, M.N., Lakkadwala, S., Majrad, M.S., Injeti ER, Gollmer, S.M., Shah, Z.A., Boddu, S.H., Nesamony, J. Characterization and evaluation of 5-fluorouracil-loaded solid lipid nanoparticles prepared via a temperature-modulated solidification technique. AAPS PharmSciTech 2014, 15, 1498-1508.
Zou, Y., Zong, G., Ling, Y.H., Hao, M.M., Lozano, G., Hong, W.K., Perez-Soler, R. Effective treatment of early endobronchial cancer with regional administration of liposome-p53 complexes. Journal of the national cancer institute 1998, 90(15), 1130-1137.
Bakhtiary, Z., Barar J., Aghanejad, A., Saei, A.A., Nemati, E., Ezzati Nazhad Dolatabadi, J., Omidi, Y. Microparticles containing erlotinib-loaded solid lipid nanoparticles for treatment of non-small cell lung cancer. Drug Development and Industrial Pharmacy 2017, 43(8), 1244-1253.
Sanna, V., Lubinu, G., Madau, P., Pala, N., Nurra, S., Mariani, A., Sechi, M. Polymeric Nanoparticles Encapsulating White Tea Extract for Nutraceutical Application. Journal of agricultural and food chemistry 2015, 63(7), 2026-2032.
Akanda, M.H., Rai, R., Slipper, I.J., Chowdhry, B.Z., Lamprou, D.A., Getti, G., Douroumis, D. Delivery of retinoic acid to LNCap human prostate cancer cells using solid lipid nanoparticles. Int. J. Pharm. 2015, 493 (1-2), 161-171.
Mathur, V., Satrawala, Y., Rajput, M.S., Kumar, P., Shrivastava, P., Vishvkarma, A. Solid lipid nanoparticles in cancer therapy. International journal of drug delivery 2011, 2(3), 212-223.
Harms, M., Müller-Goymann, C.C. Solid lipid nanoparticles for drug delivery. Journal of drug delivery science and technology 2011, 21(1), 89-99.
Wei, W., Shi, S. J., Liu, J., Sun, X., Ren, K., Zhao, D., …Gong, T. Lipid nanoparticles loaded with 10-hydroxycamptothecin–phospholipid complex developed for the treatment of hepatoma in clinical application. Journal of drug targeting 2010, 18(7), 557-566.
Potta, S.G., Minemi, S., Nukala, R.K., Peinado, C., Lamprou, D.A., Urquhart, A.J., Douroumis, D. Development of solid lipid nanoparticles for enhanced solubility of poorly soluble drugs. J. Biomed. Nanotech. 2010, 6(6), 634-640.
Potta, S.G., Minemi, S., Nukala, R.K., Peinado, C., Lamprou, D.A., Urquhart, A.J., Douroumis, D. Preparation and characterization of Ibuprofen solid lipid nanoparticles with enhanced solubility. J. of Microencapsulation 2010, 28(1), 74-81.
© 2017 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Business Bliss Consultants FZE. (November 2018). Solid Lipid Nanoparticles in Cancer Treatment. Retrieved from https://ukdiss.com/examples/cancer-treatment-solid-lipid-nanoparticles.php?vref=1
"Solid Lipid Nanoparticles in Cancer Treatment." ukdiss.com. 11 2018. Business Bliss Consultants FZE. 01 2023 <https://ukdiss.com/examples/cancer-treatment-solid-lipid-nanoparticles.php?vref=1>.
"Solid Lipid Nanoparticles in Cancer Treatment." Business Bliss Consultants FZE. ukdiss.com, November 2018. Web. 27 January 2023. <https://ukdiss.com/examples/cancer-treatment-solid-lipid-nanoparticles.php?vref=1>.
Business Bliss Consultants FZE. November 2018. Solid Lipid Nanoparticles in Cancer Treatment. [online]. Available from: https://ukdiss.com/examples/cancer-treatment-solid-lipid-nanoparticles.php?vref=1 [Accessed 27 January 2023].
Business Bliss Consultants FZE. Solid Lipid Nanoparticles in Cancer Treatment [Internet]. November 2018. [Accessed 27 January 2023]; Available from: https://ukdiss.com/examples/cancer-treatment-solid-lipid-nanoparticles.php?vref=1.
{{cite web|last=Answers |first=All |url=https://ukdiss.com/examples/cancer-treatment-solid-lipid-nanoparticles.php?vref=1 |title=Solid Lipid Nanoparticles in Cancer Treatment |publisher=ukdiss.com |date=November 2018 |accessdate=27 January 2023 |location=Nottingham, UK}}
Business Bliss Consultants FZE, 'Solid Lipid Nanoparticles in Cancer Treatment' (ukdiss.com, January 2023) <https://ukdiss.com/examples/cancer-treatment-solid-lipid-nanoparticles.php?vref=1> accessed 27 January 2023
Content relating to: "Biomedical Science"
Biomedical Science focuses on how cells, organs and systems function in the human body and underpins much of modern medicine. Biomedical Science applies parts of natural and/or formal sciences to help develop advances in healthcare.
Prevention of Erectile Dysfunction from Diabetes Mellitus
To determine the possible prevention of deleterious consequences of Diabetes Mellitus on erectile function with administration of PDE5 inhibitors....
Dissertation on Schistosoma Mansoni Antibody Detection
The objective of our work was to assess an antibody detection method using ELISA with recombinant proteins for investigating the exposure to the parasite Schistosoma Mansoni....
The Effects of 3-ABA on Human THP-1 Cells Treated with Etoposide
This study will test the effects of 3-ABA and Etoposide onto the human monocytic THP-1 cell line, both individually and in combination....


text:
Chapter 734 Nine-Profundity Immortal Wok
The hall was perfectly silent.
Chen Xi silently returned to his earlier seat before carefully sensing the changes in his Dao Heart.
This dish, Unsettled Mind, allowed him to suddenly comprehend a mysterious force that came from the Dao Heart, and it seemed to be illusory and ethereal, yet it was present everywhere.
He was faintly able to sense that this 'mysterious energy' was extremely shocking, and it wasn't inferior to True Essence, Shaman Energy, and Divine Sense, and it was a type of energy that came from the heart.
As the saying goes, the heart of man was unfathomable. Cultivation was like the cultivating of the heart, and the emotions and ups and downs of life caused all living beings to undergo change within their hearts at all times.
Unfortunately, there were very few people that knew how to grasp this sort of energy.
Because it was too illusory and ethereal to the point that even Chen Xi was only faintly capable of sensing the existence of this mysterious energy after his Dao Heart broke through, and he was very far away from controlling it.
"Divine skill!" While Chen Xi was sensing his gains in a meditative state, a voice that was filled with emotion suddenly broke the silence and shook the hall, causing everyone to seem as if they'd awoken from a dream and recover from their shock in unison.
The person that let out this emotional sigh was the Patriarch, Tao Zhentian. At this moment, he had an emotional expression as he looked at the cooked dish, and he didn't conceal his admiration in the slightest.
At this moment, he'd stopped thinking about the resentment, gains, and losses between his Taotie Clan and Chen Xi because his heart was filled with admiration and fondness towards this dish. As a descendant of the primeval ferocious beast, Taotie, deep love towards delicacies flowed within his bones as well.
"This dish used a mere four types of ingredients, yet was cooked into such a perfect delicacy. This level of attainment in the Culinary Dao can really be said to be divine!" Everyone sighed successively with emotion, and the gazes they shot at Chen Xi were filled with astonishment and disbelief, causing it to be extremely complicated. Who could have imagined before this that a young man like this would be capable of accomplishing this?
The expressions of all the elders of the Taotie Clan were slightly gloomy. But they had no choice but to admit in their hearts that this dish Chen Xi cooked was truly too beautiful and perfect!
Earlier, even they'd been terribly shocked…
Master Qiu Feng was slightly worried about his position in the contest. His expression was indeterminate as he looked at the dish 'Unsettled Mind' that Chen Xi had cooked, and he even seemed to be slightly apprehensive and anxious.
He'd spoken confidently about cooking to the point 'flames rose out of water yet never dispersed and Yin embraced Yang while Yang shot into the skies.' That was the method of cooking he felt was the most perfect, and this method obtained the uniform agreement of all the other spirit chefs in the hall.
But at this moment, he noticed that the method of cooking Chen Xi utilized was much superior to his own, and it formed the perfect state of fire and water merging while Yin and Yang circulated. Chen Xi's unique attainment in the Culinary Dao caused him to feel ashamed of his inferiority.
The second round came to an end here, and it was time to proclaim the results next.
Tao Zhentian led all the elders to start tasting the 100 dishes one by one before passing judgment.
Of course, the final outcome could only be known after all the dishes had been tested, and then 10 would be selected to advance to the final round.
This period of time was so unbearable to all the spirit chefs in the hall because even though Tao Zhentian and the others were giving exaggerated judgments of the dishes, it didn't represent the final outcome, and it caused everyone to be slightly unsettled in their hearts.
In next to no time, it was the turn of Chen Xi's dish.
When they intended to try Chen Xi's dish, Tao Zhentian spoke abruptly. "Don't allow your mental state to affect the taste of your tongues."
The other elders were stunned. Some nodded seriously while others remained indifferent.
Meanwhile, the gazes of the other spirit chefs in the hall converged over in unison because they wanted to listen to the judgment obtain by this dish that revealed a shocking scene.
After that, a scene that caused everyone to be astounded appeared.
Amongst these elders that had tasted the dish, some revealed intoxicated expressions as they praised it profusely and applauded as if they'd had dragon liver and phoenix marrow.
However, another portion of the elders had expressions of detest and kept spitting as if they'd eaten a fly. They seemed as if it tasted terrible to them, and their expressions didn't seem to be faked.
This caused everyone to be curious. It's only a simple dish, yet how has reactions of two extremes appeared?
Everyone was surprised and bewildered.
Only Chen Xi's expression remained composed and without the slightest ripple, and he seemed as if he'd expected this scene to occur.
Tao Zhentian frowned and was extremely furious in his heart. He'd just tasted the dish moments ago, and its taste was so superb that it absolutely stood above the other dishes. It was even to the extent that he couldn't refrain himself for tasting another mouthful.
Even though he detested Chen Xi as well. But he had to admit that Chen Xi's culinary skill had subdued his taste buds in this competition.
But now, he'd clearly warned them not to be influenced by personal emotions, yet these elders just didn't listen and intentionally went against him. Moreover, they even bluntly criticized this dish as trash. How could he not be infuriated?
"That's enough all of you!" Tao Zhentian was infuriated and berated in a low voice.
"Patriarch, we're absolutely not making unfounded criticism. The taste we tasted is really horrible to the extreme, and it tastes like sawdust." Fourth elder didn't give in and spoke with a serious expression.
"You dare make excuses!?" Tao Zhentian was infuriated to the point his lips trembled. Could it be that these idiots don't know shame? There are so many spirit chefs watching here!
"Patriarch, we can take an oath!" At this moment, it wasn't just fourth elder, and even those other elders couldn't help but speak up.
"Huh…" Tao Zhentian was stunned, and he faintly felt something was strange.
The other spirit chefs were astounded as well. What exactly is going on?
"There's no need to argue, what all of you have tasted is its truest taste." Right at this moment, a rough and deep voice suddenly resounded within the entire hall.
A wisp of dazzling immortal glow suffused the hall along with this voice, and then a middle aged man that wore a high crown walked out from within the glow. He was tall and robust, had a rough appearance, twisting muscles, and an immortal radiance flowed all over his body, causing him to seem like a war god that had descended from the heavens and emitted an exceedingly terrifying aura.
In merely an instant, the entire hall erupted with boundless radiance from his arrival, and even the air was cheering while the entire surroundings were bathed in an atmosphere of calmness, peace, and order.
"Ancestor!" Tao Zhentian and all the elders were shocked and swiftly knelt on the ground with respectful expressions that revealed heartfelt reverence.
Ancestor?
Isn't that the Nine-Profundity Immortal Wok?
The bodies of all the other spirit chefs trembled as they stood up hastily as well before bowing themselves. Never had they imagined that this existence would be alerted at this moment.
Even Chen Xi stood up swiftly while revealed a shocked expression because the aura emitted by the tall middle aged man was too terrifying and concentrated. It was like a deep abyss that gave others an extremely oppressive and suffocating feeling just from looking at him from afar.
The Nine-Profundity Immortal Wok… This is its Artifact Spirit?
Instantly, Chen Xi thought of many things. According to rumor, this immortal wok had existed since the primeval times, and it was the weapon of a god whose might shook the three dimensions, causing it to have extremely terrifying origins.
But Chen Xi was bewildered because both the Dark Parasol Divine Tree and the Exalted Ant Emperor from the primeval times had suffered calamity and fallen, so why was the Artifact Spirit of this immortal wok capable of surviving until now?
"When the heart isn't pure, it's impossible to differentiate between immortal and devil, let alone a dish? Your mental states have been affected, so how can you distinguish the quality of a dish?" The tall middle aged man spoke with a voice that was like the rumbling of thunder, and he seemed like the ruler that controlled the world while being covered in an immortal glow.
Even though his voice didn't sound like he was berating in a stern tone, Fourth Elder and the others seemed as if they were struck by lightning and revealed ashamed expressions.
The other spirit chefs came to an understanding, and they felt even more shocked in their hearts. A dish was capable of creating different dishes according to the difference in one's state of mind? Exactly how high must one's attainments in the Culinary Dao be to achieve this?
In merely an instant, they were completely subdued by Chen Xi, and they didn't have the slightest intention to feel displeased or suspicious anymore. Even the Nine-Profundity Immortal Wok had been alerted, and merely this was sufficient to explain everything.
"This second round ends here, and this 'Unsettled Mind' is the first." The tall middle aged man spoke indifferently with a profound gaze while an immortal glow curled up from him, and he decided the outcome with this single sentence.
"Ancestor is wise!" Tao Zhentian and the other elders knelt as they spoke respectfully.
"Young brother, there's no need for you to participate in the final competition with your level in the Culinary Dao. Care to join me for a chat?" The tall middle aged man turned his head abruptly and looked at Chen Xi, and his tone eased up unconsciously.
Everyone in the hall was shocked and envious when they noticed this slight change. Exactly what ability does this kid have to actually obtain such favor from Ancestor?
Chen Xi was stunned and pondered for a moment before he cupped his hands. "It's my pleasure."
He faintly sensed that the Artifact Spirit of the Nine-Profundity Immortal Wok had absolutely not come looking for him merely because of the dish, Unsettled Mind, that he'd cooked.
The second round ended, and the list of the top 100 was placed all over the streets of Taotie City.
The person in the position of first on the list was shockingly Chen Xi!
Everyone in the city was shocked and exploded into an uproar when they saw this name.
Even though the second round of the Spirit Chef Gold Rankings wasn't the final round, Chen Xi's name was actually able to appear at the position of first, and it still caused them to feel that it was absurd and question it.
He cheated!
He surely cheated!
Even Master Qiu Feng who's renowned throughout the world is actually ranked beneath Chen Xi! Such an outcome is simply a joke!
This caused everyone to feel that the Spirit Chef Gold Rankings this time was filled with underhanded tricks because no matter how terrifying Chen Xi's combat strength was, how could he possibly compare to Master Qiu Feng in the Culinary Dao?
Some people felt indignant and went over to inquire about it with the spirit chefs that participated in the second round, but they obtained as astonishing answer. Chen Xi's position as first was actually judged personally by the Nine-Profundity Immortal Wok!
This caused most people to be speechless. That was the Nine-Profundity Immortal Wok! It had no need to try so hard to flatter Chen Xi with its identity! Obviously, it was impossible for it to act in such a way.
Most shocking of it all was that even Master Qiu Feng himself expressed that Chen Xi's attainments in the Culinary Dao were extraordinary and far from his reach. Moreover, his tone even carried undisguised admiration as he said this.
Now, the entire Taotie City was stirred!
Everyone knew that not only did Chen Xi possess ferocious combat strength, even his cultivation in the Culinary Dao had actually reached the peak of perfection. Even Master Qiu Feng felt embarrassed of his inferiority while the Nine-Profundity Immortal Wok expressed its admiration towards him…
On the other hand, at this moment, Chen Xi was within a secret realm in the depths of Taotie Palace, and he was looking at a bronze box the tall middle aged man passed over to him with a shocked expression.

redpajama_set_name: RedPajamaCommonCrawl


text:
Q: Picking cards from deck How many ways can I pick 2 cards from a deck where the first card is a spade and second is not a queen.
How can I solve this, and account for the queen of spades?

A: Just separate it into cases.  The first card can be the queen of spades-how many draws are possible?  The first draw can be a non-queen spade-how many of those are there and how many second cards are available?

redpajama_set_name: RedPajamaStackExchange


CK Hall of Fame Announcement – Your Thoughts?
So, what do we think about THIS ANNOUNCEMENT by Creating Keepsakes regarding the Hall of Fame?
1. I'm glad Kristina Contes was disqualified. I can't believe I'm saying I'm 'glad' about ANYONE losing ANYTHING because I'm the kind of person who is happy for and in admiration of people like her, who obviously work hard and are good at what they do. But ~ there's always a BUT, isn't there? ~ she did so many things that are objectionable to me that I can say that I'm 'glad' she was disqualified. By her own admission, she took only 40 minutes to complete her entry and didn't really read the rules because she was busy with her book. Then perhaps it wasn't a good year to enter, if she couldn't devote the time that should've been required of an entry that important. She said she didn't expect to win, as if that's an excuse for not reading/complying with the rules. She seemed to blame CK for not catching the error, instead of blaming herself for committing it. Then to top it all off, Kristina makes a blog entry that, I mean, gosh, I can't even comment on it here without saying things I shouldn't say. I refuse to 'get personal' on people and I only base my comments on what came from their own mouth (blog, website,…). I'll just say that I thought it was inappropriate. There, wasn't that nice? Although, in her defense, I will say that I think people were TOO hard on her for that blog entry. She must be under inordinate amounts of stress over this, her traveling, a busy restaurant, teaching projects, etc. Also, and I mean this with all love for New Yorkers, but 'I have friends from New York' (LOL) and Boston and they kinda' just tell it like it is. I'm from California where it's the opposite, all 'no, you first', and 'oh, I'm so sorry', and 'don't you look GREAT today!'. Sometimes I wish people would be more like Kristina and just say, 'Damn, you look like crap.' I digress…what I mean is that she may be more plain-talking than most and it shocked people. But I think we need to cut her some slack, especially now. I can't imagine, even with all the positive comments she gets, how hard it must be to be Kristina Contes right now.
2. I'm curious to see what will happen with the other winners who also used photos that couldn't be their own work. Since they have to sign this big, serious document this time, no one will let them get by with fibbing again. I suppose you could set your camera on a tripod to take photos of yourself climbing onto a horse. C'mon, it could happen! But how do you take photos of yourself running in a race? Anyway, interesting stuff to come. This is NOT over by any means.
3. I'm happy to see they addressed the HOF contest rules because there are many scrappers currently working on or getting ready for HOF 2008, and they have been requesting clarification. I just send Happy Thoughts to all those ladies (wait, I can't say Ladies anymore!)…to all those people who will enter. I admire you mucho.
4. I admire CK for listening, for reading those endless message board posts and e-mails, for the sleepless nights they must have endured these last couple of weeks, all resulting in a good decision. As I suspected, and talked about in an EARLIER POST, things like this happen in large companies sometimes. They don't always have evil intent and, when mistakes are discovered, it may be perceived that it's too late to fix them. I think CK learned that it wasn't too late, and that they should've come clean way back when it was first discovered. It would've been a pebble in the pond instead of a huge meteor. The re-issue of the HOF mag will cost them a lotta snap but I think they realize how much NOT doing it was going to cost them.
5. For all the drama, I think the discussions that resulted from this issue have been good ones. It got everyone talking about Right vs. Wrong, for standing up when you believe in something, and for how to be effective consumers who should have a say-so since we spend all our money with these companies. I was heartened to see so many who believed, like I do, that we have to own up to our mistakes, even if it means forfeiting notoriety, cash, and prizes. I was disheartened to see all the back-biting on CKMB, 2peas, etc and so many who thought this was 'no big deal, get over it, move on.' It stunned me that one scrapper did not have another scrappers back. It made me feel like we are a family, a sisterhood…but only to a point for some people. I know, I know, I take all this scrapbooker-girl stuff too seriously, right?


Most people are aware that exposure to household mold can have negative health affects in humans. Did you know it can also make your pets sick? Although we don't hear much about it, and there has been less research on the effects of mold on pets, it makes sense if you think about it. The respiratory systems of cats and dogs are not that different than those of humans. The relatively small size of household pets (maybe nine pounds for a cat, maybe 80 pounds for a large dog, compared to 140 pounds for an adult human) also makes them more susceptible to even small amounts of mold, much like we know infants are.
Unfortunately, pets can't tell us when they aren't feeling well and it can be hard to tell when something is wrong. If your pet is acting odd in some way, check with your vet, especially if you are aware of a household mold problem. Ask your vet for more information about what to look for in your pet.
If you think mold is making your pet sick, see your vet as soon as possible. Let your vet know that you think mold may be causing your pet's symptoms. Your pet may need steroids, antibiotics or other medications to treat the symptoms.
In addition to treating your pet for mold-related illness, you'll need to have the mold thoroughly removed from your home in order to make the living environment safe for your pet, as well as for your family. Even with veterinary treatment, your pet is unlikely to recover if he continues to be exposed to mold.
Ask your vet if it is safe for your pet to be in your home until you can have the mold removed. You may need to board your pet at your vet's office or elsewhere until the home is mold-free.
Even if your vet gives the OK for your pet to remain in the home until you can have the mold removed, it's probably best to have him out of the home during the actual mold removal process. The process of removing mold stirs up a lot of mold spores, which are very light and very tiny and easily inhaled. Mold removal professionals take steps to minimize the spread of mold spores during the mold removal process, but your pet could end up being exposed to greater amounts of mold during the cleanup process, making his condition worse.
In addition, having strangers in the home can be stressful for pets, especially when those strangers wear protective gear and bring strange equipment with them. Uncaged pets may take the opportunity to try to slip out the door when people are going in and out. Your pet may be happier and safer spending a few days away from home while the mold is removed.
We recommend consulting with an experienced mold removal professional, even if you plan to handle the cleanup yourself. Mold removal specialists often provide free in-home consultations, during which they will inspect your home to make sure you've located all areas of mold, advise you about the cleanup process, and answer any questions you may have. Ask about safety precautions during the cleanup process and how to protect your pets if they remain in the home during the cleanup. To find qualified mold removal professionals offering free home inspections and consultations in your areas, just follow the link.


text:
Lee Ranaldo, Mike Patton, Ensemble Offspring – City Recital Hall, Sydney 16/01/14
Donné Restom Jan. 17, 2014
Throw an orchestra behind a rock band and everyone's a fan. The orchestra imbues depth, a grandeur that makes ordinary music just so much more epic. Or does it? Hurricane Transcriptions, an experimental piece by Sonic Youth noise rock legend Lee Ranaldo was a shining example of what happens when you get too big for people to tell you when your ideas are shite.
It began with a crescendo so slight as to be barely perceptible to the human ear. The initial roll on the percussionist's gong was given away by the movement of hands more than the sound itself. Roland Peelman conducted the Ensemble Offspring without time, his hands moving with the grace and fluidness of a mantis. Cellos punctuated the swelling tide with sharp staccato, a brisk introduction to quivering strings and bowed cowbell. Violins like rusty swings swiftly slipped in as we waited for the hurricane to come.
Finally we heard that to which all the grandiosity had been building. Ranaldo's acoustic guitar severed this swirling orchestra with a country lilt that came across as, well, pathetic. Add to this some horrific vocal intonation and a mic sound that should have seen the engineer shot in the head, and you couldn't help but be horribly dismayed by the tragedy that befell the orchestra the minute the rock legend opened his mouth. This preceded yet more jarring transitions.
Somehow, despite the fact that the rather extraordinary orchestral arrangement had been entirely composed by Ranaldo, one of the great guitarists of our time was coming across as an amateur. In short, the audience was treated to a haunting and deeply moving film, interrupted by some unfortunate ad breaks that just happened to be the artist's songs.
Following Ranaldo's conclusion, the opening of Luciano Berio's Laborintus II couldn't help but make you feel like you were in a school hall watching end-of-year shows by the academy's best students. The student was Mike Patton and everyone knew he was the school prodigy. You could tell by the way he walked onto the stage, score under arm, sitting so calmly, his mic held like a cigarette in the left hand. What followed was a flawless example of how one heads an orchestra.
First, you tear its parts into an exquisite, disarrayed cacophony, then you have it put itself together again piece by piece, until instruments and voices, in growing multiples of speckled sound, form a ravenous sound-bed. Finally, you rise, until with megaphone in hand, your tirade of maniacal Italian screams leads the ensemble irresistibly in pursuit of you.
Most interesting about the piece was the fact that, while it was not written or even led by Patton, it felt like it could have been. We sat in Patton's absurdist opera of screams, in a world that would make Luigi Russolo dance with glee, and with it, The Art of Noises was momentarily lifted from the dusty shelves of academia and hurtled passionately back into the public domain.
With Patton at the helm, a miracle occurred: high art was embraced simply because some rock fans would pay anything to hear their hero scream. Put the two acts together? You just witnessed an American get schooled by a countryman who decided that being Italian is better.
OFF! Announce April Release For New Album 'Wasted Years'
Richie Sambora, Filter And More Join Soundwave 2014 Lineup
Lee RonaldoMike PattonSydney Festival 2014


The 26th edition of the Pune Festival kick-started on Friday evening with a host of celebrities from Bollywood and Maharashtra politics in attendance.
The festival, which is a blend of vocal and instrumental music, dance, drama, sports and culture, was inaugurated at the city's Ganesh Kala Krida Rangmanch.
The event opened with Hema Malini -- who has presented a new ballet for 23 times during last 25 years in Pune Festival -- performed the 'Ganesh Vandana' with her daughter Esha and their troupe.
Then, actress Gracy Singh showcased a classical dance performance. Her performance was based on Krishna's love for Radha.
Chhagan Bhujbal, Maharashtra's minister for public works and tourism, Harshvardhan Patil, minister for co-operation, industrialist Rahul Bajaj, dancer Hema Malini, Shivajirao Adhalrao-Patil (MP), Rajni Patil (MP), Udayanraje Bhosale (MP) along with actors Jitendra, Karishma Kapoor, Aftaab Shivdasani, Esha Deol, Raja Murad, Bindu and Sachin Pilgaonkar were some of the guests at the event.
Speaking about his association with Ganeshotsav, actor Jitendra said, "Since I was brought up in chawl and middle-class Marathi neighbourhood in Mumbai, I was always a part of public Ganeshotsav. It made me what I am today."
Another special programme was 'Devotional Maharashtra' -- based on devotional songs related to places of worship in the state like Pandharpur, Tuljapur, Kolhapur and Jejuri.
The attraction of the evening was a fusion performance of lavani, tribal, koli and Bollywood dance choreographed by Nikita Moghe and performed by movie artists Prajakta Mali, Pooja Sawant, Prarthana Behere, Tejaswini Lonari, Pushkar Jog, Madhav Devcha and Pravin Tarade among others.


text:
Supporting more effective water supply in Za'atari Refugee Camp, Jordan
Voices from the Field : Featured Article
Jordan : 120,000 Syrians are currently finding refuge in Za'atari refugee camp in north Jordan, situated in Mafraq governorate less than 10 kilometres from the border with Syria. Providing refugees with their essential daily needs is a challenging task that requires careful analysis of the situation and extensive coordination. Of top priority for the refugees and all actors in the camp is ensuring a fair distribution of water across the camp.
A key challenge for promoting a fair distribution of water was the lack of information about the private and public water storage capacity throughout the different sectors of Za'atari; this was compounded by lack of accurate information on the total number of people residing in the camp. To overcome such challenges REACH, with the support of UNICEF, conducted two assessments that surveyed all households in the camp. As a result, for the first time the size of the refugee population could be compared to the water storage capacity. Leading from this, REACH was then able to much more accurately determine the water supply needs per district of the camp.
In order to inform effective humanitarian planning among relevant aid actors working in the camp, the findings of REACH's assessment were disseminated through maps, factsheets as well as several presentations to coordinating bodies.
The impact of REACH's intervention was significant, enabling humanitarian actors to accurately and effectively plan the camp's water supply infrastructure. With a high level of internal mobility in the camp and with the water supply infrastructure requiring constant maintenance, a greater level of knowledge of the needs of individuals and local water storage has made a strong impact on the planning of this service. Relevant water supply agencies have as a result of REACH's assessment changed their water supply strategy to ensure a fairer distribution of water to all refugees in Za'atari, meaning that the delivery of aid will become more effective and the essential needs of more refugees will be met.
To read more about the developments in Jordan and how REACH is contributing to better planning, please browse through our latest publications from the field or visit the Jordan country page.
Tags: Al Za'atari, Jordan, Syria
Press release: New Situation Overview from northwest Syria shows that living conditions of new arrivals remain dire
Data collected on 9 March shows that the displaced population is highly vulnerable, and many basic humanitarian needs are unmet. Living conditions of new arrivals remain dire too. REACH continues to inform the world, and humanitarian actors, on the evolution of the situation of displaced families in NW Syria.
Renewed violence in northern Syria forces another 300,000 away from home- but where can they go?
Shelling and airstrikes forced over 300,000 people to flee their homes in Syria between May and June. Many families have been escaping grave danger in their own country for the second or third time since the conflict's onset nine years ago. Today, potential destinations for those seeking safety are becoming increasingly limited.
Returning decision-making to communities: Could cash-assistance be the way forward in northeast Syria?
Over eight years of destructive conflict has taken a heavy toll on Syria's economy. Massive internal displacement, emigration and mortality have greatly weakened the population, out of which more than half are estimated to be in the need of assistance. With this in mind, REACH conducted an in-depth cash and markets assessment across northeast Syria to better understand the feasibility and implications of scaling up cash-based interventions.
Farmers' hopes of a golden harvest turn to ashes − rising food insecurity in northwest Syria
Vulnerabilities mount and an already strained humanitarian response is forced to stretch to new limits as fires turn crops to ashes in northwest Syria. The fires come right at harvest season and are expected to worsen food security in the months to come.
Press release: INTENSIFICATION OF AERIAL BOMBARDMENT AND SHELLING DISPLACES MORE THAN 180,000 IN IDLEB
Southern Idleb and northern Hama, part of the last opposition-held territory in Syria, have seen renewed intensification of conflict. Due to the intensity of escalation and the seizing of key opposition-held areas, the ongoing clashes could develop into a final offensive which is feared to spiral into one of the worst humanitarian tragedies of the 21st century.
Displaced Syrians face overcrowded latrines and limited access to safe drinking water – A snapshot of WASH needs and conditions in Syria
Hostilities in Syria have seen an overall reduction since the beginning of the conflict in 2011, yet two-thirds of the population remain in need of humanitarian assistance. Among the priority needs of the civilians living in conflict-affected regions, are access to water, sanitation and hygiene – the building blocks of life and health.
Displaced, returned, reintegrated? While returns to north-east Syria continue, durable solutions for returnees and those remaining in displacement remain out of sight
Without improved material, legal and physical conditions in areas of origin, populations returning home in Syria struggle to reintegrate in safety and with dignity. Yet, during the first half of 2018, 750,000 internally displaced persons and 15,000 Syrian refugees were reported to have returned.
Syria: Threats of shelling, lack of healthcare and no access to education – The needs of IDPs in Idleb mount as conflict continues
An estimate of 1.4 million internally displaced persons or IDPs reside in Idleb governorate and the surrounding opposition-held areas of western Aleppo and north-western Hama. The figure has come to represent one of Syria's largest IDP populations and a vast number of people who continue to live in dire conditions in overburdened host communities. These […]


Our customers and employees are our main priority. It is because our employees are experts in their field that our products have achieved the quality they are known for, and it is because our employees are self-starters that we are excellently positioned in our markets.
Worldwide, more than 400 personnel work at BBM Akustik Technologie and its subsidiaries.


MineWolf provides a range of manned and unmanned platforms for the clearance of explosive threats.
MineWolf products have proven superior performance in a variety of environments against landmines and improvised explosive devices (IEDs). Durability, reliability and survivability are inherent in the design and manufacture of both the platforms and their attachments.
The quality and unique multi-purpose nature of its clearance platforms enable mechanical solutions to be tailored for different applications according to customer requirements. The same platform can be used for mine clearance, counter-IED, runway clearance and general engineering tasks by using the appropriate attachment. This flexibility ensures the machines are able to fulfil operational requirements in any environment.
MineWolf platforms are a powerful route clearance assets used for the effective clearance of landmines and designed to counter the numerous challenges faced when demining.
Interchangeable attachments, including a tiller and flail, are used to optimise the platform to particular tasks. A lifter can be integrated to the rear for quality assurance. The system has been proven during demining operations over many years and has excellent reliability.


In the mid-1980s, the Haitian government estimated that the average daily nutritional consumption level in the country was 1,901 calories per person, including 41.1 grams of protein. These figures represented 86 percent and 69 percent, respectively, of the World Health Organization's recommendations for adequate nutrition. In rural areas, the average person consumed about 1,300 calories, including 30 grams of protein per day. A national survey in 1978 showed that 77 percent of children in Haiti were malnourished. Anemia was also a common problem among children and women.
Infant and child health were poor. The infant mortality rate was 124 per 1,000 live births in 1983. A quarter of all registered deaths occurred among infants who were younger than one year old; half of all deaths occurred among children under five. Most of these deaths resulted from infectious diseases, especially diarrheal illnesses. Malnutrition and acute respiratory illness also presented serious problems for infants and children. For adults, malaria was among the more serious problems; some 85 percent of the population lived in malarial areas. Tuberculosis and parasitic infections continued to be serious health hazards, and typhoid fever was endemic. Poor sanitation contributed to poor health indicators. In 1984 less than 20 percent of the population had toilets or latrines. Only one-fourth of the rural population had access to potable water. Life expectancy at birth was forty-eight years in 1983, and the general mortality rate was 17 per 1,000 population.


Festival of Lights International ist Partner des Taikoo Li Sanlitun Light Festival & Halloween Festival in Peking. Zwischen 13.10. und 05.11. stellten zahlreiche Künstler rund um das Taikoo Li Sanlitun in Peking aus und verzauberten die Besucher in der Weltmetropole.
Dabei waren unter anderem die weltbekannten "Wächter der Zeit".
Festival of Lights International is partner of Taikoo Li Sanlitun Light Festival & Halloween Festival in Beijing. From 13th October to 5th October numerous artist showed their work and enchanted the visitors of the metropolis.
Displayed were among other world-renowned installation "The Guardians of Time".


Quite different from its original is the decades-old "You Are My All In All," in which Griffith's solo voice is joined by Profitt's, woven together as they lead into a grand final chorus.
Griffith is currently a student at Cedarville College in Ohio working toward her worship degree. She is a worship leader at the college chapel and sings in several worship bands. She has already recorded a solo project of original songs.
This is their first recording as a duo.
The lone Profitt-penned song on this new project is a worship ballad, "I'd Rather Have You."
The singer's efforts include a music video release schedule for each of the eight new songs on Profitt's YouTube channel (www.youtube.com/tommeeprofitt). The next song to be posted is "Here's My Heart" on May 6.
Album: "Even So Come: A Worship Album"