",isbn:"978-1-83969-545-2",printIsbn:"978-1-83969-544-5",pdfIsbn:"978-1-83969-546-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"c77f99db5569e8d0325b856cb7d75b17",bookSignature:"Prof. Maged Marghany",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10854.jpg",keywords:"Optical, Radar, Algorithm, Programming, Big Data, Deep Learning, Image Processing, Time Series Data Analysis, Large Scale Methods, Signal Processing, Computer Vision, Remote Sensing",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 18th 2021",dateEndSecondStepPublish:"March 18th 2021",dateEndThirdStepPublish:"May 17th 2021",dateEndFourthStepPublish:"August 5th 2021",dateEndFifthStepPublish:"October 4th 2021",remainingDaysToSecondStep:"9 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:'Prof. Marghany was recently ranked among the top two percent scientists in a global list compiled by the prestigious Stanford University. A pioneering scientist in microwave remote sensing invented a new theory Quantum Nonlinear Ocean Dynamics " Quantized Marghany\'s Front".',coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"96666",title:"Prof.",name:"Maged",middleName:null,surname:"Marghany",slug:"maged-marghany",fullName:"Maged Marghany",profilePictureURL:"https://mts.intechopen.com/storage/users/96666/images/system/96666.png",biography:"Prof.Dr. Maged Marghany, recently, ranked among the top two percent scientists in a global list compiled by the prestigious Stanford University. Prof.Dr. Maged Marghany is currently a Professor at the Department of Informatics, Faculty of Mathematics and Natural Sciences, Universitas Syiah Kuala Darussalam, Banda Aceh, Indonesia. He is the author of 5 titles including Advanced Remote Sensing Technology for Tsunami Modelling and Forecasting which is published by Routledge Taylor and Francis Group, CRC and Synthetic Aperture Radar Imaging Mechanism for Oil Spills, which is published by Elsevier, His research specializes in microwave remote sensing and remote sensing for mineralogy detection and mapping. Previously, he worked as a Deputy Director in Research and Development at the Institute of Geospatial Science and Technology and the Department of Remote Sensing, both at Universiti Teknologi Malaysia. 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1. Introduction
With the advent of multifunctional nano delivery systems, simultaneous imaging and therapy aspires to detect and treat tumors at a very early stage with promising outcomes. In this context, numerous anti-cancer drug/gene delivery systems have been explored with the primary aim to increase the treatment efficacy without compromising safety. Secondary goals include enhancing bioavailability, specific targeting, apart from the enhanced stability of the formulation [1]. The multifaceted applications of nanoparticles are the direct result of their ability to deliver high pay loads of drugs or biomarkers to the desired sites within the body. Design and development of tumor specific nanoparticles could significantly amplify the delivering capacity to a specific target of interest, without affecting healthy cells [2]. Technological advances in nanomaterials and nanotechnology have paved the way for several carriers such as liposomes [3], dendrimers [4], and micelles [5], solid lipid nanoparticles (SLN) [6] and recently nanostructured lipid carriers [1, 7]. Polymeric micelles, or nanosized (~10–100 nm) supramolecular constructs composed of amphiphilic block-copolymers, are emerging as powerful drug delivery vehicles for hydrophobic drugs. Liposomes are currently the most popular nanosized drug delivery systems, with one or several lipid bilayers enclosing an aqueous core. Liposome-encapsulated formulations of doxorubicin earlier approved for the treatment of Kaposi’s sarcoma, are now used against breast cancer and refractory ovarian cancer. Breast cancer in particular has been the focus of many studies involving liposome-based chemotherapeutics, in part due to the clinical success of various drugs such as Doxil, which is a liposomal formulation currently used to treat recurrent breast cancer [7]. The anthracycline doxorubicin is the active cytotoxic agent and is contained within the internal aqueous core of the liposome. The encapsulation of doxorubicin within liposomes significantly reduces the cardiotoxicity that commonly results from the use of unencapsulated anthracyclines by decreasing the amount of the drug being delivered to the heart [7]. As such, patients can receive much higher doses of the chemotherapeutic in the liposomal formulation compared to unencapsulated, thereby allowing tumor tissue to potentially be exposed to a lethal dose of the drug while minimizing deleterious side effects. This inherent advantage associated with the use of liposomes as drug delivery vehicles also serves to minimize the many other toxic side effects associated with doxorubicin including gastrointestinal toxicity and complications arising from myelosuppression.
Each delivery system however, has its advantages and limitations. Advantages afforded for drug delivery include the presence of an inner core for lipophilic drug entrapment, as well as a hydrophilic outer shell that prevents particle aggregation and opsonisation [8]. This complexation prevents uptake by the reticuloendothelial system (RES), thereby improving circulation times which, combined with nanoscale sizing, confers preferential accumulation in tumor tissue. In general, nanovectors can be targeted to tumors by passive and active targeting approaches, where a passive strategy takes advantage of a nanvector’s small size permitting it to penetrate and accumulate in the tumor. Most solid tumors are sustained by extensive angiogenesis leading to hypervascular tissue with an incomplete vascular architecture. They also have an impaired lymphatic drainage and an increased production of permeability factors resulting in the accumulation and inefficient clearance of nanoparticles leading to the enhanced permeability and retention effect [9]. The hyperpermeable nature of tumor vasculature is characterized by a pore cut off size ranging between 380 and 780 nm allowing particles less than 780 nm to extravasate into the tumor interstitium [10]. In addition, active targeting to various tissues may be achieved via utilization of ligands on the surface of nanoparticles, reducing the side effects to the normal tissue by limiting drug/gene distribution to the target organ [11]. An excellent example is Abraxane, an albumin bound nanoparticle formulation of Paclitaxel (PTX), approved by FDA in January 2005 for the treatment of metastatic breast cancer. Abraxane has been shown to outperform standard PTX in the treatment of breast cancer [12]. Utility of this drug was initially limited due to its poor aqueous solubility [13], requiring use of an excipient, Cremophor, which is satisfied by novel engineered nanovectors. A recent Gynecologic Oncology Group Phase II evaluation of albumin-bound paclitaxel nanoparticles to treat recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer, concluded that these nanoparticles are as effective and tolerable in their cohort of refractory ovarian cancer patients previously treated with paclitaxel [14]. Nanoparticles fabricated with albumin [15], poly(lactic-co-glycolic acid) [16] and poly lactic acid have also been loaded with PTX and used to passively target tumors. Albumin has been shown to be nontoxic, non-immunogenic, biocompatible and biodegradable making it an ideal candidate to fabricate nanoparticles for drug delivery. Site-specific drug delivery allows for the clinical translation of chemotherapeutic agents with safer targeted cell killing, that are otherwise abandoned due to insolubility, toxicity and safety concerns. Moreover, these new delivery devices can preferentially confine treatments to tumors within the nodal space while sparing healthy tissues.
2. Solid lipid nanoparticles
Solid lipid nanoparticles [17] or lipospheres are rapidly emerging as new class of safer and efficient gene/drug delivery vectors. SLNs are sub-micron colloidal carriers, ranging from 50 nm to 1 μm, that are composed of physiological lipid dispersed in water or in aqueous surfactant solution (Figure 1). SLNs function as an alternative drug carrier system to other novel delivery approaches such as emulsions, liposomes, and polymeric nanoparticles. SLNs offer several advantages conferred by their colloidal dimensions including: i) feasibility of incorporation of lipophilic and hydrophilic drugs; ii) improved physical stability; iii) controlled release; iv) improved biocompatibility; v) potential for site specific drug delivery; vi) improved drug stability; vii) better formulation stability; viii) the ability to freeze dry and reconstitute; ix) high drug payload; x) controllable particle size; xi) the avoidance of carrier toxicity; xii) low production cost; and xiii) easy scale-up and manufacturing [18]. In addition, significant toxicity and acidity associated with a number of biodegradable polymeric materials are not observed with SLNs. And, in contrast to emulsions and liposomes, the particle matrix of SLNs is composed of solid lipids. SLNs can be prepared using wide variety of lipids including lipid acids, mono- (glycerol monostearate), di- (glycerol bahenate) or triglycerides (tristearin), glyceride mixtures or waxes (e.g. cetyl palmitate) and stabilized by the biocompatible surfactants(s) of choice (non-ionic or ionic). Lipids most commonly used are triglyceride esters of hydrogenated fatty acids, including hydrogenated cottonseed oil (Lubritab™ or Sterotex™), hydrogenated palm oil (Dynasan™ P60 or Softisan™ 154), hydrogenated castor oil (Cutina™ HR), and hydrogenated soybean oil (Sterotex™ HM, or Lipo™) as typical examples [19]. Various emulsifiers and their combination (Pluronic F 68, F 127) have also been added to stabilize the lipid dispersion by more efficiently preventing particle agglomeration.
Figure 1.
Schematics of Functionalized Solid Lipid Nanoparticles
The disavantages associated with SLNs relate mostly to their preparation, which generally involves high pressure and rapid temperature changes that can lead to high pressure-induced drug degradation, lipid crystallization, gelation phenomena and the co-existence of several colloidal species [20]. The drug loading capacity of a conventional SLN is limited by the solubility of drug in the lipid melt, the structure of the lipid matrix and the polymeric state of the lipid matrix. If the lipid matrix consists of highly similar molecules (i.e. tristearin or tripalmitin), a perfect crystal with few imperfections is formed. Since incorporated drugs are located between fatty acid chains, between the lipid layers and also in crystal imperfections, a highly ordered crystal lattice cannot accommodate large amounts of drug. This may also lead to the fast release of a large dose of drug initially, generally known as “burst effect”, followed by slow and incomplete release of drug. Since high lipid crystallinity is the major cause of burst release of drug from SLNs, this undesirable phenomenon may be minimized by choosing lipids that do not form good crystals, including mono- or di-glycerides, or triglycerides with chains of different lengths. For this reason, in formulation design use of more complex lipids is recommended for higher drug loading. Nanostructured lipid carriers or NLCs were designed to overcome these disadvantages with the main goal to increase drug loading and prevent drug expulsion [21]. For NLCs, the highest drug load could be achieved by mixing solid lipids with small amounts of liquid lipids (oils). These types of NLCs are called multiple types NLC, and are analogous to w/o/w emulsions since it is an oil-in-solid lipid-in-water dispersion.
3. SLN preparation methods
There are two main established SLN synthesis techniques, namely, the high-pressure homogenisation technique described by Müller and Lucks [21], and the microemulsion-based technique described by Gasco [22, 23]. SLNs are prepared from lipid, emulsifier and water/solvent using different methods, discussed below.
3.1. High Pressure Homogenization (HPH)
High Pressure Homogenization (HPH) is a very reliable technique in the production of SLNs. High pressure homogenizers are employed to push a liquid with high pressure (100–2000 bar) and the fluid accelerates on a very short distance to very high velocity (>1000 Km/h).. Very high shear stress and cavitation forces disrupt the particles down to the submicron range. Generally 5-10% lipid content is used but up to 40% lipid content has also been investigated. Typical SLNs production conditions are 500 bar and two or three homogenisation cycles. Two general approaches of HPH are hot and cold homogenization, both working on the same concept of mixing the drug in bulk of lipid melt.
3.1.1. Hot homogenization
Hot homogenization is carried out at temperatures above the melting point of the lipid and can therefore be regarded as the homogenization of an emulsion (Figure 2). A pre-emulsion of the drug loaded lipid melt and the aqueous emulsifier phase (same temperature) is obtained by high-shear mixing device. The quality of the pre-emulsion affects the quality of the final product to a great extent and it is desirable to obtain droplets in the size range of a few micrometers. HPH of the pre-emulsion is carried out at temperatures above the melting point of the lipid. Usually, lower particle sizes are obtained at higher processing temperatures because of lowered viscosity of the lipid phase [24].
Hot homogenisation is the most frequently applied technique in which even temperature sensitive compounds can be processed because of the short exposure time to the elevated temperatures [25]. However, high temperatures increase the degradation rate of the drug and the carrier. Increasing the homogenization pressure or the number of cycles often results in an increase of the particle size due to high kinetic energy of the particles. The cold homogenisation technique is therefore recommended for extremely temperature sensitive compounds and hydrophilic compounds, which might partition from the liquid lipid phase to the water phase during the hot homogenisation.
3.1.2. Cold homogenization
During cold homogenization, the drug containing lipid melt is cooled and, after solidification, the lipidic mass is ground to yield lipid microparticles [26]. The lipid microparticles are dispersed in cold surfactant solution by stirring, yielding a macro-suspension. This suspension is then passed through a high-pressure homogeniser at or below room temperature, where the microparticles are broken down to solid lipid nanoparticles. However, compared to hot homogenization, larger particle sizes and a broader size distribution are typical of cold homogenized samples.
3.1.3. Ultrasonication or high speed homogenization
SLNs are also developed by high speed stirring or sonication [27]. The ultrasonic dispersion may offer an appropriate alternative for laboratory scale productions due to its rapid nature and the relatively low cost of required apparatus. So far, its suitability has only been evaluated for SLN [17, 28]. The primary disadvantage of this method is the broader particle size distribution that is yielded, ranging into the micrometer range. Potential metal contamination due to ultrasonication is another issue presented by this method. To generate more stable formulations, high speed stirring and ultrasonication may be used in combination at high temperature.
3.2. Solvent emulsification/evaporation
In this method, the lipidic material, such as glyceride is dissolved in an organic solvent (e.g. chloroform, cyclohexane) and the solution is emulsified in an aqueous phase [29]. After evaporation of the solvent the lipid precipitates to form nanoparticles with a mean diameter of around 30 nm using cholesterol acetate as a model drug and lecithin/sodium glycocholate blend as an emulsifier [30]. The solution is emulsified in an aqueous phase by high pressure homogenization and the organic solvent is removed from the emulsion by evaporation under reduced pressure (40–60 mbar).
3.3. Supercritical fluid
This platform technology, with several variations for powder and nanoparticle preparation, is a relatively new technique for SLN production and offers the advantage of solvent-less processing [31]. SLNs can be prepared by the rapid expansion of supercritical carbon dioxide solutions (RESS) method, where carbon dioxide (99.99%) is a good choice as solvent.
4. Microemulsion method
This method is based on the dilution of microemulsions that are two-phase systems composed of an inner and outer phase (e.g. o/w microemulsions) [32]. They are made by stirring an optically transparent mixture at 65-70°C, which typically composed of a low melting fatty acid (e.g. stearic acid), an emulsifier (e.g. polysorbate 20), co-emulsifiers (e.g. butanol) and water. The hot microemulsion is dispersed in cold water (2-3°C) with stirring. SLN dispersion can be used as granulation fluid for transferring into solid product (tablets, pellets) by granulation process, but in case of low particle content, excess water must first be removed. High-temperature gradients facilitate rapid lipid crystallization and prevent aggregation. Due to the dilution step, achievable lipid contents are considerably lower compared with the HPH based formulations.
Figure 2.
Partitioning effects on drug during the hot homogenization technique production of SLNs. Left: Partitioning of drug from the lipid phase to the water phase at increased temperature. Right: Re-partitioning of the drug to the lipid phase during cooling of the produced O/W nanoemulsion. Source: Muller RH et al. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. European Journal of Pharmaceutics and Biopharmaceutics 50: (2000) 161-177.
4.1. Spray drying method
Spray drying is an alternative procedure to lyophilization in the transformation of an aqueous SLN dispersion into a solid drug product. This method results in particle aggregation due to high temperature, shear forces and partial melting of the particle. The use of lipid with melting point >70°C for spray drying is recommended [33]. Best results are obtained with an SLN concentration of 1% in a solution of trehalose in water or 20% trehalose in ethanol-water mixtures (10/90 v/v).
4.2. Double emulsion method
For the preparation of hydrophilic loaded SLN, double emulsion method, a novel approach based on solvent emulsification-evaporation can be employed. Here, the drug is encapsulated with a stabilizer to prevent drug partitioning to external water phase during solvent evaporation in the external water phase of w/o/w double emulsion [34]
5. SLNs cellular uptake, pharmacokinetics and bio-distribution
Research on cellular uptake mechanisms has repeatedly demonstrated that endocytosis is the preferred route of internalization of non-viral gene vectors via a number of distinct endocytic processes. The most studied mechanisms include macropinocytosis, circular dorsal ruffles, clathrin-mediated endocytosis and several clathrin-independent endocytic pathways [35]. Endocytic uptake mechanisms are highly dependent on cell type and on the nature of gene vectors [36]. Clathrin-mediated processes are limited to particles under 200 nm in size, whereas caveolae-dependent uptake prevails for particles between 200 and 500 nm [37]. The prevalent pathway for the cell internalization of PEI polyplexes is however, clathrin-dependent [38].
Apart from overcoming cellular barriers of uptake, an anticancer drug must be specifically targeted to the tumor in order to maximize its therapeutic effect, and therefore biodistribution studies are critical to assess the safety of a nanomedicine. However, since most groups work on healthy instead of tumor-bearing animals, it is difficult to confirm whether SLNs can lead to increased tumor drug concentrations by way of enhanced permeability and retention [9]. Recently, Zhang et al. (2010) evaluated antitumor efficacy of docetaxel-loaded solid lipid nanoparticles (DSN) in a murine ovarian cancer model [39]. In this study, SLN biodistribution from RES more toward the circulation system was observed. Moreover, SLNs in comparison to the free drug demonstrated more potent in vivo anti-ovarian cancer activity with improved pharmacokinetics. In contrast, paclitaxel loaded in pegylated solid lipid nanoparticles were mainly taken up by the RES after intravenous administration in rats, showing 8-fold and 3-fold higher levels in liver and spleen, respectively, 8 h after administration compared to paclitaxel in Taxol® [40]. Moreover, paclitaxel levels in kidney, heart and lung were indistinguishable between the two formulations. The difference in biodistribution of SLNs reported in literature may be due to several factors including variations in size, surface functionalization and composition.
The biodistribution of an anticancer drug delivered by SLN may be further manoeuvred by route of injection to achieve the desired therapeutic goal. Harivardhan Reddy et al. (2005) compared the biodistribution of free 99 mTechnetium-labeled etoposide and radio-labeled etoposide loaded SLNs in Dalton\'s lymphoma tumor-bearing mice [41]. They showed that administration via the subcutaneous route resulted in high tumor uptake of etoposide and etoposide loaded tripalmitin nanoparticles and was the preferred route as compared to intravenous or intraperitoneal administration. However, elevated tumor drug concentrations were also found with intravenously administered etoposide loaded SLN in comparison to the free drug, (approximately 67% increase 1 h post-injection, 30% increase 24 h post-injection). In yet another study by Zara et al. (2002) duodenal administration of idarubicin-loaded SLN led to higher bioavailability than intravenously administered SLNs [42]. Also, idarubicin and its main metabolite, idarubicinol, were detected in the brain after IDA-SLN administration, indicating that the SLNs were able to pass the blood-brain barrier; an attractive attribute in the tratement of brain tumors. Thus, the route of administration of SLN formulation is a key consideration in the design of animal or clinical anti-cancer drug delivery studies.
6. SLNs as anti-cancer gene/drug delivery vectors: Challenges and successes
Solid lipid nanoparticles have rapidly established themselves during the past decade as stable, reliable and easy to produce vectors. SLN advantages over other existing transfection vectors include safety, good storage stability, possibility of lyophilization and a high degree of flexibility in design and optimization [25]. Cationic SLNs can efficiently bind DNA directly via ionic interaction and mediate gene transfection. However, as with all non-viral vectors, many cellular obstacles have to be overcome to achieve satisfactory levels of transfection activity: i) binding to the cell surface; ii) cellular internalization; iii) escape from the endolysosomal compartment; and iv) translocation through the nuclear envelope. In order to surmount these barriers, cationic SLNs are designed as multifunctional “smart” carriers for efficient gene expression [43]. Components such as chitosan [44] and surface functionalization moieties e.g. poly(styrene-4 sodium sulfonate) (PSS) and poly(L-lysine hydrochloride) (PLL) [45], folate–chitosan and cholesterol derivative (CHETA) [46], cetyltrimethyl ammonium bromide (CTAB) [47] and a phyto-ceramide [48] and TAT peptides [49], may each individually assist in overcoming the barriers of efficient transfection. In addition, protamine a cationic small protein rich in arginine exerts both DNA condensation activity and proton sponge effect facilitating endosomal escape as well as assisting nanovectors to enter the nucleus owing to its nuclear localization signal (NLS) [50]. Table 1 lists some of the successful SLN formulations evaluated as anti-cancer agents in various cancers.
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\n\t\t\t\tSLN Composition\n\t\t\t
\n\t\t\t
\n\t\t\t\tCharacterization\n\t\t\t
\n\t\t\t
\n\t\t\t\tIndication\n\t\t\t
\n\t\t\t
\n\t\t\t\tDrug/Gene\n\t\t\t
\n\t\t\t
\n\t\t\t\tReference\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Stearic acid, DOTAP, Pluronic F68 and dioleoylphosphatidylethanolamine (DOPE)
Solid Lipid Nanoparticles loaded with DNA/ Drug as anti-cancer delivery systems in various cancers.
Nanovectors offer the potential to both detect and treat cancer at a very early stage, thereby maximizing survival rates. The NCI (National Cancer Institute) Alliance for Nanotechnology in Cancer provides up-to-date information in nano-cancer research and its promise for cancer diagnosis and treatment (http://nano.cancer.gov/). Using siRNA molecules loaded in nanovectors, early proof-of-principle experiments in various tumor cells suggest that RNA silencing may have great potential as a strategy for treating cancer. However, siRNA therapeutics are hindered by poor intracellular uptake, limited blood stability and undesirable non-specific immune stimulation [61]. An interesting strategy used to target the vector employs three-amino-acid peptide, arginine-glycine-aspartic acid (known by its amino acid code RGD) that binds to integrins, which in turn are involved in angiogenesis, tumor cell growth, metastasis, and inflammation. Intravenous administration into tumor-bearing mice of nanoparticles combined with a dual strategy of siRNA inhibiting vascular endothelial growth factor receptor-2 and RGD peptide ligand attached at the distal end of the polyethylene glycol [40], conferred selective tumor uptake, and inhibition of both tumor angiogenesis and growth rate, achieving both tissue and gene selectivity [62]. In February 2012, Calando Pharmaceuticals, in Pasadena, Canada, and the National Cancer Institute (NCI) entered into a collaborative development program for a nanoparticle-based siRNA therapeutic aimed at treating neuroblastoma, the most common extracranial solid tumor in children less than five years of age. Previous attempts to develop targeted nanoparticles were unsuccessful due to the inherent difficulties of designing and scaling up a particle capable of targeting, long-circulating via immune-response evasion and controlled drug release. Very recently, Hrkach et al. (2012) reported the preclinical development and clinical translation of a docetaxel nanoparticle with prostate-specific membrane antigen, a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most non-prostate solid tumors including breast, head, lung, neck, prostate and stomach [63]. This targeted nanoparticle-based compound called “BIND-014” is currently the first one to enter clinical trial, although with small number of only 17 patients. Patients with advanced or metastatic cancer receive an injection of the nano-drug once every three weeks and are showing signals of efficacy even at relatively low doses. This initial but positive result shows promise and the potential impact of nanomedicines as a paradigm shift in the treatment of cancer.
Very recently, Vighi E et al. (2012) developed a multicomponent cationic SLN as a pDNA delivery vehicle. The formulations were prepared using stearic acid as the main component in the lipid phase, stearylamine, the main component in the aqueous phase, as cationic agent and protamine as transfection promoter along with the phosphatidylcholine (SLN–PC), cholesterol (SLN–Chol) or both (SLN–PC–Chol). Transfection results on various cell lines in this study revealed the best transfection for SLN–PC–Chol on COS-1 cells (African green monkey kidney cell line) [64]. However, lower transfection levels than poly [62] were observed on HepG2 cells (human hepatocellular liver carcinoma cell line), regardless of the SLN composition. Using COS-1 monkey kidney fibroblast-like cells, SLNs and liposomes formulated from the same cationic lipids, demonstrated equipotent in vitro transfection efficiencies [65]. This study suggests that only the lipid composition in the tested lipid-based formulations affected transfection efficiencies. The intrinsic toxicity that is common in cationic gene delivery vehicles may also be minimized, while maintaining high transfection efficiency, by selecting good combinations of two-tailed cationic lipids and matrix lipids. Hence, structural or compositional design changes of nanovectors may influence the outcome in relation with cell physiology, cell internalization pathways and transfection efficiency. The above results support the use of SLNs to serve as nano/microcarriers for anti-cancer gene therapies.
Under optimised conditions SLNs can be designed to incorporate lipophilic or hydrophilic drugs and seem to fulfil the requirements for an optimum particulate carrier system. Stability studies were performed on SLNs loaded with all-trans retinoic acid (ATRA), another compound that is sensitive to light, heat and oxidants, and quickly degrades into less active products such as isotretinoin and all-trans-4-oxo [66]. After 3 months of storage at 4 °C, more than 90% of the ATRA drug molecules in SLN remained chemically intact. This can be compared to approximately 50% drug degradation when stored at the same temperature in the form of methanol solution or 1% polysorbate-80 solution for only 1 month. Hence, SLNs are useful for the protection of anticancer compounds that are sensitive to light, and probably heat and oxidants as well. In a study conducted by our group, modulatory effects of encapsulated and free forms of sesamol (anti-oxidant and anti-cancer compound) were evaluated by the topical delivery systems in a skin cancer mice model. Both free sesamol and SLN dispersion were applied as gels (using 1% w/v of Carbopol 934P®) on the skin of mice. Encapsulated or nanosesamol was found to safely exert chemopreventive effects by decreasing the lipid peroxidation levels and increasing the anti-oxidant levels, thereby decreasing the development and promotion of skin tumors. Immunofluorescence studies of pro- and anti-apoptotic markers, bcl-2 and bax protein expression revealed higher expression of anti-apoptotic protein, bcl-2, in the tissue sections of tumor bearing mice in comparison to their control counterparts and groups which received sesamol treatment, reinforcing the role of bcl-2 in skin carcinogenesis. Higher expression of bax was also observed in sesamol treated animals as compared to the tumor bearing mice. Up-regulation of bax in the control and sesamol treated groups suggests that it follows the intrinsic pathway of apoptosis (unpublished results).
Ongoing work by our group compared neutraceutical curcumin-loaded SLNs to the free form as a chemopreventive topical delivery system in 7,12-dimethylbenz [a]anthracene (DMBA) induced skin cancer model mice. In order to understand the molecular events underlying nanocurcumin-mediated chemoprevention, protein expression of various biomolecules e.g. anti and pro inflammatory cytokines (Il-4 and Il-1β) were analyzed by Western immunoblotting and immunoflourscence. For cancer induction, male Balb/c mice were subcutaneously injected with 30 mg/Kg body weight of DMBA (in olive oil) once a week for three weeks. DMBA skin cancer induced mice were topically applied free and encapsulated curcumin (50mg/Kg b.w) as a chemopreventive agent from one week before DMBA injection to the experiment’s end (18 weeks). We found that free and nanocurcumin treatment of DMBA treated mice reduced the levels of malondialdehyde, a by-product of lipid degradation (Figure 3). Antioxidant analysis revealed increased levels of enzymes (SOD, Catalase, Reduced Glutathione, Total Glutathione) in encapsulated nanocurcumin treated group as compared to free curcumin group (Figure 4-7). Immunofluorscence studies and western blot analysis of Il-4 and Il-1β suggest enhanced anti-inflammatory potential of encapsulated curcumin in comparison to mice treated with free curcumin. Mice bearing skin tumors showed increased expression of pro-inflammatory interleukins when compared to the control, which was decreased on treatment with curcumin (Figure 8). Furthermore, the immunoflourscence assay of anti-inflammatory interleukin (IL-4) showed a far greater increase in IL-4 expression by topical treatment with encapsulated curcumin as compared to the free curcumin in mice bearing skin tumors (Figure 9).
7. Conclusion
Solid Lipid Nanoparticles serve as efficient and safe DNA/ drug loaded nanosystems in both the imaging and treatment of cancer. Traditional drug delivery systems are often hindered by their low bioavailabilty, low solubility, toxicity and rapid clearance. In future, clinicians and researchers will be able to “tune and time” the amount of DNA/Drug delivery by controlling the release at specific location thereby minimizing their toxicity and side- effects.
Figure 3.
Effect of encapsulated and free curcumin on lipid peroxidation (LPO) in control and experimental groups. Control (C), DMBA (D), Free Curcumin (FCC), Free Curcumin + DMBA (FCD), Encapsulated Curcumin (CGC), Encapsulated Curcumin + DMBA (CGD).
Figure 4.
Effect of encapsulated and free curcumin on reduced glutathione in control and experimental groups. Control (C), DMBA (D), Free Curcumin (FCC), Free Curcumin + DMBA (FCD), Encapsulated Curcumin (CGC), Encapsulated Curcumin + DMBA (CGD).
Figure 5.
Effect of encapsulated and free curcumin on total glutathione in control and experimental groups. Control (C ), DMBA (D), Free Curcumin (FCC), Free Curcumin + DMBA (FCD), Encapsulated Curcumin (CGC), Encapsulated Curcumin + DMBA (CGD).
Figure 6.
Effect of encapsulated and free curcumin on superoxide dismutase in control and experimental groups. Control (C ), DMBA (D), Free Curcumin (FCC), Free Curcumin + DMBA (FCD), Encapsulated Curcumin (CGC), Encapsulated Curcumin + DMBA (CGD).
Figure 7.
Effect of encapsulated and free curcumin on Catalase in control and experimental groups. Control (C ), DMBA (D), Free Curcumin (FCC), Free Curcumin DMBA (FCD), Encapsulated Curcumin (CGC), Encapsulated Curcumin + DMBA (CGD).
Figure 8.
Photomicrographs (20X) showing expression of IL-1Beta in paraffin sections by immunofluoroscence after 18 weeks of treatment.
Figure 9.
Photomicrographs (20X) showing expression of IL-4 in paraffin sections by immunofluoroscence after 18 weeks of treatment.
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Introduction",level:"1"},{id:"sec_2",title:"2. Solid lipid nanoparticles",level:"1"},{id:"sec_3",title:"3. SLN preparation methods",level:"1"},{id:"sec_3_2",title:"3.1. High Pressure Homogenization (HPH)",level:"2"},{id:"sec_3_3",title:"3.1.1. Hot homogenization",level:"3"},{id:"sec_4_3",title:"3.1.2. Cold homogenization",level:"3"},{id:"sec_5_3",title:"3.1.3. Ultrasonication or high speed homogenization ",level:"3"},{id:"sec_7_2",title:"3.2. Solvent emulsification/evaporation ",level:"2"},{id:"sec_8_2",title:"3.3. Supercritical fluid",level:"2"},{id:"sec_10",title:"4. Microemulsion method",level:"1"},{id:"sec_10_2",title:"4.1. Spray drying method",level:"2"},{id:"sec_11_2",title:"4.2. Double emulsion method ",level:"2"},{id:"sec_13",title:"5. SLNs cellular uptake, pharmacokinetics and bio-distribution",level:"1"},{id:"sec_14",title:"6. SLNs as anti-cancer gene/drug delivery vectors: Challenges and successes",level:"1"},{id:"sec_15",title:"7. 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Pharm Res 2012Jun.'},{id:"B54",body:'WangSChenTChenRHuYChenMWangYEmodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies. Int J Pharm 2012Jul;430(1-2):238-46.'},{id:"B55",body:'FangY. PLinY. KSuY. HFangJ. YTryptanthrin-loaded nanoparticles for delivery into cultured human breast cancer cells, MCF7: the effects of solid lipid/liquid lipid ratios in the inner core. Chem Pharm Bull (Tokyo) 2011Feb;59226671'},{id:"B56",body:'ShuhendlerA. JCheungR. YManiasJConnorARauthA. MWuX. YA novel doxorubicin-mitomycin C co-encapsulated nanoparticle formulation exhibits anti-cancer synergy in multidrug resistant human breast cancer cells. Breast Cancer Res Treat 2010Jan;119225569'},{id:"B57",body:'SiddiquiAGuptaVLiuY. YNazzalSDoxorubicin and MBO-asGCS oligonucleotide loaded lipid nanoparticles overcome multidrug resistance in adriamycin resistant ovarian cancer cells (NCI/ADR-RES). Int J Pharm 2012Jul;431(1-2):222-9.'},{id:"B58",body:'YuY. HKimEParkD. EShimGLeeSKimY. BKimC. WOhY. KCationic solid lipid nanoparticles for co-delivery of paclitaxel and siRNA. Eur J Pharm Biopharm 2012Feb;80226873'},{id:"B59",body:'JinJBaeK. HYangHLeeS. JKimHKimYJooK. MSeoS. WParkT. GNamD. HIn vivo specific delivery of c-Met siRNA to glioblastoma using cationic solid lipid nanoparticles. Bioconjug Chem 2011Dec;2212256872'},{id:"B60",body:'TaveiraS. FAraujoL. Mde S, Nomizo A, de Freitas LA, Lopez RF. Development of cationic solid lipid nanoparticles with factorial design-based studies for topical administration of doxorubicin. J Biomed Nanotechnol 2012Apr;8221928'},{id:"B61",body:'SchiffelersR. MsiRNA based approaches in medicinal chemistry and drug discovery. Curr Top Med Chem 2012122678'},{id:"B62",body:'SchiffelersR. MAnsariAXuJZhouQTangQStormGMolemaGLuP. YScariaP. VWoodleM. CCancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res 2004Nov;32(19):e149.'},{id:"B63",body:'HrkachJVon HD, Mukkaram AM, Andrianova E, Auer J, Campbell T, De WD, Figa M, Figueiredo M, Horhota A, Low S, McDonnell K, Peeke E, Retnarajan B, Sabnis A, Schnipper E, Song JJ, Song YH, Summa J, Tompsett D, Troiano G, Van Geen HT, Wright J, LoRusso P, Kantoff PW, Bander NH, Sweeney C, Farokhzad OC, Langer R, Zale S. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med 2012Apr;4(128):128ra39.'},{id:"B64",body:'VighiEMontanariMHanuskovaMIannuccelliVCoppiGLeoEDesign flexibility influencing the in vitro behavior of cationic SLN as a nonviral gene vector. Int J Pharm 2012Sep;(12):10.'},{id:"B65",body:'Ho Lun Wong RBAMRYLXYWChemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles. Advanced Drug Delivery Reviews 59 [6], 4915042007Ref Type: Journal (Full)'},{id:"B66",body:'LimS. JLeeM. KKimC. KAltered chemical and biological activities of all-trans retinoic acid incorporated in solid lipid nanoparticle powders. J Control Release 2004Nov;10015361'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Tranum Kaur",address:null,affiliation:'
Department of Biophysics, Panjab University, Chandigarh, India
School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
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Hunting",authors:[{id:"54287",title:"Prof.",name:"Darel",middleName:null,surname:"Hunting",fullName:"Darel Hunting",slug:"darel-hunting"},{id:"58047",title:"Dr.",name:"Tsvetan",middleName:null,surname:"Gantchev",fullName:"Tsvetan Gantchev",slug:"tsvetan-gantchev"}]},{id:"22725",title:"The Influence of Individual Genome Sensitivity in DNA Damage Repair Assessment in Chronic Professional Exposure to Low Doses of Ionizing Radiation",slug:"the-influence-of-individual-genome-sensitivity-in-dna-damage-repair-assessment-in-chronic-profession",signatures:"Mirta Milić, Ružica Rozgaj, Vilena Kašuba, Ana Marija Jazbec, Patrizia Hrelia and Sabrina Angelini",authors:[{id:"40591",title:"Dr.",name:"Mirta",middleName:null,surname:"Milić",fullName:"Mirta Milić",slug:"mirta-milic"},{id:"57808",title:"Dr.",name:"Ružica",middleName:null,surname:"Rozgaj",fullName:"Ružica Rozgaj",slug:"ruzica-rozgaj"},{id:"57809",title:"Dr.",name:"Vilena",middleName:null,surname:"Kašuba",fullName:"Vilena Kašuba",slug:"vilena-kasuba"},{id:"57810",title:"Prof.",name:"Anamarija",middleName:null,surname:"Jazbec",fullName:"Anamarija Jazbec",slug:"anamarija-jazbec"},{id:"57811",title:"Dr.",name:"Sabrina",middleName:null,surname:"Angelini",fullName:"Sabrina Angelini",slug:"sabrina-angelini"},{id:"57812",title:"Prof.",name:"Patrizia",middleName:null,surname:"Hrelia",fullName:"Patrizia Hrelia",slug:"patrizia-hrelia"}]},{id:"22726",title:"Application of Host Cell Reactivation in Evaluating the Effects of Anticancer Drugs and Environmental Toxicants on Cellular DNA Repair Activity in Head and Neck Cancer",slug:"application-of-host-cell-reactivation-in-evaluating-the-effects-of-anticancer-drugs-and-environmenta",signatures:"Yi-Shan Tsai, Jau-Ling Huang and Chang-Shen Lin",authors:[{id:"57600",title:"Dr.",name:"Chang Shen",middleName:null,surname:"Lin",fullName:"Chang Shen Lin",slug:"chang-shen-lin"},{id:"57606",title:"Dr.",name:"Yi-Shan",middleName:null,surname:"Tsai",fullName:"Yi-Shan Tsai",slug:"yi-shan-tsai"},{id:"57607",title:"Dr.",name:"Jau-Ling",middleName:null,surname:"Huang",fullName:"Jau-Ling Huang",slug:"jau-ling-huang"}]},{id:"22727",title:"Role of Radioprotectors in the Inhibition of DNA Damage and Modulation of DNA Repair After Exposure to Gamma-Radiation",slug:"role-of-radioprotectors-in-the-inhibition-of-dna-damage-and-modulation-of-dna-repair-after-exposure-",signatures:"Dharmendra Kumar Maurya and Thomas Paul Asir Devasagayam",authors:[{id:"56167",title:"Dr.",name:"Thomas Paul Asir",middleName:null,surname:"Devasagayam",fullName:"Thomas Paul Asir Devasagayam",slug:"thomas-paul-asir-devasagayam"},{id:"56170",title:"Dr.",name:"Dharmedra K",middleName:null,surname:"Maurya",fullName:"Dharmedra K Maurya",slug:"dharmedra-k-maurya"}]},{id:"22728",title:"DNA-Binding Radioprotectors",slug:"dna-binding-radioprotectors",signatures:"Pavel Lobachevsky, Alesia Ivashkevich, Olga A. Martin and Roger F. Martin",authors:[{id:"50843",title:"Dr.",name:"Olga",middleName:"A.",surname:"Martin",fullName:"Olga Martin",slug:"olga-martin"},{id:"58135",title:"Dr",name:"Pavel",middleName:"N.",surname:"Lobachevsky",fullName:"Pavel Lobachevsky",slug:"pavel-lobachevsky"},{id:"58136",title:"Dr.",name:"Alesia",middleName:null,surname:"Ivashkevich",fullName:"Alesia Ivashkevich",slug:"alesia-ivashkevich"},{id:"58137",title:"Dr.",name:"Roger F.",middleName:null,surname:"Martin",fullName:"Roger F. Martin",slug:"roger-f.-martin"}]},{id:"22729",title:"DNA Damage Response and Repair: Insights into Strategies for Radiation Sensitization",slug:"dna-damage-response-and-repair-insights-into-strategies-for-radiation-sensitization",signatures:"Joshua D. Lawson, Kristopher T. Kahle, Kimberly Ng, Bob Carter, Santosh Kesari and Clark C. Chen",authors:[{id:"62462",title:"Prof.",name:"Clark",middleName:null,surname:"Chen",fullName:"Clark Chen",slug:"clark-chen"},{id:"85623",title:"Prof.",name:"Kimberly",middleName:null,surname:"Ng",fullName:"Kimberly Ng",slug:"kimberly-ng"},{id:"86785",title:"Dr.",name:"Joshua",middleName:null,surname:"Lawson",fullName:"Joshua Lawson",slug:"joshua-lawson"},{id:"86788",title:"Dr.",name:"Santosh",middleName:null,surname:"Kesari",fullName:"Santosh Kesari",slug:"santosh-kesari"},{id:"86789",title:"Dr.",name:"Bob",middleName:null,surname:"Carter",fullName:"Bob Carter",slug:"bob-carter"},{id:"86790",title:"Dr.",name:"Kirstopher",middleName:null,surname:"Kahle",fullName:"Kirstopher Kahle",slug:"kirstopher-kahle"}]},{id:"22730",title:"The Botanical Extract Feverfew PFE Reduces DNA Damage and Induces DNA Repair Processes",slug:"the-botanical-extract-feverfew-pfe-reduces-dna-damage-and-induces-dna-repair-processes",signatures:"Michael D. Southall, Simarna Kaur and Khalid Mahmood",authors:[{id:"42297",title:"Dr.",name:"Michael",middleName:null,surname:"Southall",fullName:"Michael Southall",slug:"michael-southall"},{id:"54272",title:"Dr.",name:"Simarna",middleName:null,surname:"Kaur",fullName:"Simarna Kaur",slug:"simarna-kaur"},{id:"54559",title:"Dr.",name:"Khalid",middleName:null,surname:"Mahmood",fullName:"Khalid Mahmood",slug:"khalid-mahmood"}]},{id:"22731",title:"Food Factors and Oxidative DNA Damage / DNA Repair Systems",slug:"food-factors-and-oxidative-dna-damage-dna-repair-systems",signatures:"Takeshi Hirano and Kazuyoshi Tamae",authors:[{id:"41165",title:"Prof.",name:"Takeshi",middleName:null,surname:"Hirano",fullName:"Takeshi Hirano",slug:"takeshi-hirano"},{id:"41284",title:"Dr.",name:"Kazuyoshi",middleName:null,surname:"Tamae",fullName:"Kazuyoshi Tamae",slug:"kazuyoshi-tamae"}]},{id:"22732",title:"Enhancing DNA Repair by Combining only Dietary Supplement Ingredients that do not Metabolically Compete in Order to Achieve Synergism",slug:"enhancing-dna-repair-by-combining-only-dietary-supplement-ingredients-that-do-not-metabolically-comp",signatures:"Ronald W. Pero",authors:[{id:"56402",title:"Prof.",name:"Ronald",middleName:null,surname:"Pero",fullName:"Ronald Pero",slug:"ronald-pero"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"68312",title:"Allergic March",doi:"10.5772/intechopen.85553",slug:"allergic-march",body:'\n
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1. Introduction
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Allergic diseases are the most common chronic condition in childhood. Epidemiological studies observed increase in the prevalence of allergic diseases from the middle of the twentieth century, which is explained by environment and lifestyle changes and improvements in modern Westernized societies. At the beginning of the twenty-first century, stagnation in the prevalence of asthma while increase in the prevalence of food allergy was noticed, which announced the second wave of allergy epidemics [1, 2, 3]. The first atopic phenotype that starts in early infancy is atopic dermatitis (AD). It is estimated that it affects up to 20% of children. Disrupted integrity of the skin barrier contributes to the development of sensitization to food and aeroallergens and also increases the risk for the development of food allergy. It is considered that 30% of children with AD have food allergy, and 30% develop asthma and 75% allergic rhinitis [4]. About 3–5% of children have been diagnosed with food allergy, and up to 50% of them have AD [1]. AD and food allergy can coexist and can also appear independently in infancy and in the first years of life. In the following years, wheezing induced by viruses like respiratory syncytial virus or rhinovirus and sensitization to inhalational allergens can be observed. As the child grows up, respiratory symptoms are more common and occur outside of the infection; introduction of anti-inflammatory drugs is needed, i.e., the signs of asthma occur. Preschool and school age are the time of appearance of allergic sensitization to pollen of grass, weed and tree pollen, and the beginning of allergic rhinoconjunctivitis which persists in adolescence and the young adult age.
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At the same time, remission of atopic dermatitis and food allergy is noticed, while asthma and rhinitis symptoms continue. Sensitizations to pollen and cross-reactions to nuts, fresh fruits and vegetables may induce oral allergy syndrome, the type of food allergy that occurs in the school age. Asthma may disappear in teenage years, but after some period of remission, skin and respiratory symptoms can appear once again. In early adulthood, skin and lung symptoms are related to tobacco smoking, occupational exposures and lifestyle, and they manifest like contact dermatitis or asthma-chronic obstructive pulmonary disease overlap syndrome [5].
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Atopic dermatitis, food allergy, asthma and allergic rhinitis in childhood share the common genetic, epigenetic and environmental risk factors, while the underpinning pathogenesis is marked with disrupted skin, lung and gut barriers, altered microbiome and local and systemic Th-2-driven immunological pathways. Those allergic conditions can comanifest or occur in temporal sequence. The hypothesis that has been proposed to clarify time sequence and associations of allergic disease is called allergic march. This concept means that allergic disorder starts in early infancy with the first hallmark of atopy and atopic dermatitis and then appears food allergy, and later in childhood comes asthma and allergic rhinitis. Some investigators presumed that the underlying allergic inflammation of the skin could progress from atopic dermatitis to asthma. In addition, some preventive measures like improving skin barrier before skin disease onset can reduce the risk for respiratory allergy. Those observations support the causal link between atopic dermatitis and asthma. Although described longitudinal appearance of all allergic diseases was noticed only in small proportion (~7%) of children [6, 7], others had different trajectories of one or more allergic diseases which can occur in different point of time in childhood. Last explanations are talking about a cluster of coexistence-related allergic diseases rather than a progression.
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2. Atopic dermatitis, disrupted skin barrier and allergic sensitization: is it the beginning?
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Atopic dermatitis is the most common chronic skin disorder in childhood. It appears in early childhood with dry, itchy skin and eczema on the cheeks, wrists and other parts of the body. Up to 20% of children experience AD in childhood. The majority outgrows eczema, but one proportion of them continues to have symptoms into adulthood [8]. According to the recently published cohort, six latent classes representing subphenotypes of AD were identified. These classes can be summarized in four classes as follows: unaffected individual or transient AD (61.9%); early-onset-persistent AD (10.7%); early-onset late resolving, early-onset early resolving and mid-onset resolving by age 11 years of age (16.5%); and later-onset AD after age 3.5 years (10.9%) [9].
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AD is a systemic disorder characterized by disrupted skin barrier. It is considered that factors associated with damage of skin barrier are complex and influenced by a combination of structural, genetic, environmental and immunological factors. Structural changes are caused by altered lipid composition, decreased structural proteins, increased skin pH and reduced skin microbiome diversity. Cutaneous permeability defects can be assessed by measuring transepidermal water loss (TEWL) which correlates with disease severity. Several genetic defects encoding skin barrier proteins contribute to the breakdown of skin barrier. Inherited loss-of-function mutations in filaggrin gene, which encodes structural epidermis proteins, are associated with early-onset AD that is more often persistent and closely related with asthma and food allergy [10]. Polymorphisms in the thymic stromal lymphopoietin (TSLP) gene, SPINK5 gene and corneodesmosin have also been linked to AD and the development of food allergy [11, 12, 13]. The inflammatory responses induced by AD are manifested by increased production of Th2 cytokines such as IL-4, IL-13, IL-25, IL-33 and TSLP. TSLP is one of the major inductors of systemic Th2 response, and it is considered that it could be the link between skin and respiratory allergy. It is expressed in skin keratinocytes, pulmonary airway and intestinal epithelium, while increased expression was observed in the skin of AD patients and respiratory epithelium of asthma patients [14].
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Skin microbiome dysbiosis is characterized by the dominance of Staphylococcus aureus which through various mechanisms worsens chronic skin inflammation [15]. Skin barrier dysfunction is associated with innate immune activation that results in dysregulated immune response to environmental antigens (like allergens and bacteria) and skin inflammation leading to the evolution of allergic sensitization [16]. Several studies on animals and humans support the concept that damaged skin promotes sensitizations. In mouse, exposure to egg and peanuts through disrupted skin induces sensitization [17] and, after exposure to egg aerosol, could induce asthma-like airway hyperresponsiveness [18]. In children, applications of peanut oil to inflamed skin were positively associated with the development of peanut food allergies [19], and the use of wheat-containing facial soap was positively associated with the development of wheat food allergy [20]. Application of oat-based creams on the skin of children with AD can induce oat sensitization in one third of children [21]. The concept of allergic march has been supported by cross-sectional and longitudinal birth cohort studies. Several birth cohorts have shown associations between early-onset AD and development of asthma and allergic rhinitis in school age [22, 23]; risk is greater in children with early-onset persistent AD phenotype [24]. Children with AD and allergic sensitization had increased risk of food allergy, asthma and allergic rhinitis compared to non-sensitized children without AD [25]. Food sensitizations in the first 2 years of life were associated with increased risk of asthma and allergic rhinitis in school age [26]. Peanut, milk and egg food allergy also increased the risk of developing asthma and rhinitis later in childhood [27]. Meta-analyses of birth cohort studies which investigated atopic march observed that early-life food sensitization was associated with an increased risk of infantile eczema, childhood wheeze/asthma, eczema and allergic rhinitis and young adult asthma [28].
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The development of sensitization is complex, and except skin barrier defect and environmental allergen exposure, the presence of other factors is important because they may function as adjuvants, and some of them are bacterial colonization of the skin, allergens with intrinsic protease activity and exogenous adjuvants [29].
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3. Why is allergy increasing? Hypothesis-driven strategy
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Allergic diseases of the skin, gut and lung are complex disorders with multiple phenotypes and underlying genotypes. They occur as a result of environmental exposures during early life in individuals with genetic susceptibility to allergy. Gene-environment interactions are accountable for different influences of the environment on individual level. There are several hypotheses of allergy increase in the twentieth century. According to the hygiene hypothesis, decreased exposure to microorganisms in modern society, through increased hygiene and decreased prevalence of infection in early life, disrupts immune tolerance and directs immunological reaction toward Th2 direction [30].
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The beginning of hygiene hypothesis can be found in the David Strachan study from 1989. He observed that children who grew up in large families, with large number of older siblings, have less allergy and concluded that exposure to infection in early life (prenatally and early childhood) can prevent allergy [31]. This was confirmed by subsequent studies which linked less allergies with viral, bacterial or protozoic pathogens, transmitted by the fecal-oral route [32]. In 1990 hygiene hypothesis was supported by the observation that growing up on farms, regular contact with farm animals, stables and drinking unpasteurized milk were protective against allergy [33]. Farms are microbe-rich environment. Endotoxin, lipopolysaccharide, part of the outer layer of Gram-negative bacteria, is a marker of microbe surroundings. Its protective effect on atopy is produced by stimulation of immune system in Th1 direction. Preventive effect of endotoxin was seen only for early-life exposure (prenatal and early childhood, before development of allergic sensitization) [33, 34].
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In the past 20 years, hygiene hypothesis was expanded by “old friends hypothesis” and “biodiversity hypothesis” [35, 36]. According to that hypothesis, contact with natural environment and its species (included microbes and parasites) protects against allergy. Children are exposed to the environment indirectly (through mother during prenatal life) and directly through the skin, gut and lung. Changes in the microbiome of the gut, skin and nose reduced microbiome diversity, and loss of symbiotic relationship with parasites and bacteria increased the risk for allergic disease [37]. Stability and diversity of gut microbiome are developed during early life (first 1000 days of postnatal life). This process can be influenced with different factors like mode of birth, infant feeding, fiber content in the mother’s and child’s diet and older siblings and exposure to pets and/or farm animals during childhood. Environment and dietary habits of mother and previous generations can change microbe diversity of neonate’s trough epigenetic modification [38, 39, 40, 41, 42].
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The second hypothesis dual-allergen exposure hypothesis is based on observations that allergic sensitization occurs through disrupted skin in AD, while early ingestion of food (before development of sensitization) allows development of oral tolerance [43]. Delayed introduction of solid food in infancy, which were recommended at the end of the twentieth was not protective for food allergy development [44]. This hypothesis was confirmed by several randomized clinical trials like Learning Early About Peanut Allergy (LEAP) and Enquiring About Tolerance (EAT). EAT was looking at the early introduction of six common food allergens at 3 months of age alongside breastfeeding compared to exclusive breastfed infants. It found that prevalence of egg allergy was lower among infants with early introduction [45]. LEAP assessed oral tolerance induction of peanut in group of high-risk infants between 4 and 11 months of age. It compared early and regular peanut consumption, average of 6 grams of peanut protein a week, in relation to completely avoiding peanut protein until 60 months of age. Early introduction of peanut protein results in significant reduction in peanut allergy. LEAP-On study was an extension of LEAP, in which protective effect of early introduction on peanut allergy was observed, even after cessation of peanut consumption [46, 47]. According to the findings from the studies like LEAP and EAT, guidelines for complementary feeding were remarkably changed. Pediatric and allergy societies have published consensus statements about early introduction of peanuts in high-risk infants. Also, current recommendations advise against delayed introduction of allergenic food into infant diet [48, 49].
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Recent researches report about the important role of vitamin D in the pathogenesis of allergy. Vitamin D has positive impact on foetal lung development and an immunomodulatory effect; it stimulates differentiation of T lymphocytes, induction of Treg, while its deficiency induces Th2 response [50]. It was observed that rise in allergy prevalence occurs with increasing vitamin D deficiency especially among populations less exposed to the sun [51]. Deficit of vitamin D is associated with increased risk of peanut and egg food allergy, atopic dermatitis and asthma. The severe form of the diseases was observed with higher vitamin D deficiency [52, 53].
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4. Allergic march: causal link or cluster of related diseases
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The allergic march is a real phenomenon, but there is a great debate about underlying mechanisms. Some researchers argue that there is a causal link between AD and other allergic diseases in childhood, in which AD is the first disease with local and systemic immunological response. Systemic response could trigger multisystem allergic disease. Longitudinal, prospective population-based cohorts or cohorts of high-risk infants reported about increased risk of asthma and allergic rhinitis among children with previous or current AD [54, 55, 56, 57, 58, 59].
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Meta-analysis of 13 prospective birth cohort studies reported that odd ratio of asthma among children with AD in the first 4 years of life was 2.14% (95% CI 1.67–2.75), while the prevalence of asthma at the age of 6 years in eczema cohort studies was 29.5% (95% CI, 28.2–32.7%). The conclusion was that only one in every three children with eczema develops asthma during later childhood [4]. According to the results of high-risk birth cohort, 26.7% children with AD developed AR at 7 years of age, while the risk is higher among children with persistent and late-onset AD (OR 2.68, 95% CI 0.97–7.41) [57]. Sensitization to food allergen increased the risk for AR (OR 1.2, 95% CI 0.6–2.2), but the associations is stronger among children who had co-sensitization to both food and aeroallergens (OR 3.1, 95% CI 1.2–7.8) [28]. In the PASTURE study, children with early-persistent AD phenotype and those with late phenotype had an increased risk of developing allergic rhinitis. Early AD phenotype did not associate with AR, while the risk increased among children with early AD and food allergy [60]. According to these results, there was a new question: can we predict which phenotype of AD will be linked to asthma? More information come from longitudinal cohorts which analyzed different phenotypes of AD based on disease course and determined which classes are at highest risk for other atopic diseases [9, 60, 61]. According to the results from those studies, the early-onset, severe, persistent phenotype is associated with the highest risk for allergic comorbidities. Polysensitization, atopic heredity and filaggrin loss-of-mutation contribute to increased risk [62]. Children with high-risk phenotype of AD are candidates for preventive measures, which could delay or stop the occurrence of asthma and allergic rhinitis. But, it is considered that there is not enough evidence that AD causes asthma and allergic rhinitis. Paller et al., in recent review, presumed existence of inherited predisposition to one or more atopic disorders. Occurrence of the disease is a result of complex interplay between different underlying genotypes and environmental exposures during maturation of immune system, with tissue-specific peak time of clinical manifestation. Allergic diseases have different phenotypes and different trajectories that form clusters [62].
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Simultaneously with AR, local allergic rhinitis (LAR) can appear in the preschool age. This entity of rhinitis is marked with local synthesis of specific IgE but without systemic allergy (allergic sensitizations and specific IgE). It was observed that LAR is a separate, well-defined phenotype of noninfectious rhinitis, which is stable over time [63, 64]. But, among younger patients and children, LAR can be the first step in the natural evolution to classical AR, especially when starting in the first two decades of life and in polysensitized patients [65]. In the German Multicentric Allergy Study, it was observed that over one third of the children developing a typical grass pollen-related seasonal AR had no serum-specific IgE to pollen. These children develop a systemic IgE sensitization to grass pollens in the second or third pollen season following the onset of their rhinitis symptoms [66, 67]. If patients with LAR have AR over time, this supports atopic march.
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5. Can we prevent and/or stop atopic march?
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Better understanding of underpinning mechanisms of atopic dermatitis and atopic comorbidities as well as environmental risk factors induces further researches of preventive interventions aimed at stopping atopic march. Those interventions could be started during pregnancy and early life among healthy or high-risk infants before onset of disease (primary prevention) or among children with one atopic disease in order to prevent appearance of other atopic comorbidities (secondary prevention).
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Disrupted skin barriers promote sensitizations and increase the risk for allergic disease. Improvement in skin barrier through regular application of emollients beginning in the neonatal period can prevent AD among high-risk children. Protective effect was observed if treatment lasted up to 6–8 months of age [68, 69, 70]. There was favorable effect at the 12 months of age, even after treatment was ceased [69]. These researches support original hypothesis of skin barrier dysfunction as a beginning of atopy march, but it is still unclear if this protective effect is long-lasting or onset of AD is delayed. The effect of emollients on food allergy was unclear. Only one research showed a trend for decreased food sensitization at 6 and 12 months of age [69], while two other were not powered to measure food sensitization [68, 70]. Some of undergoing studies aim to investigate the effect of emollients in prevention of AD among general population.
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Local and system inflammatory response is a hallmark of AD, and anti-inflammatory therapy is effective in control of exacerbations, but study of Schneider et al. showed ineffectiveness of pimecrolimus in stopping atopic march [71]. Skin microbiome dysbiosis can increase the risk for onset or exacerbation of AD and comorbidities [72]. Recent researches showed that topical application of skin commensal bacteria can improve lesions in AD [73, 74]. Apart from local use of bacteria, the great interest of researchers is the role of probiotics in protection of allergy. Several studies have shown positive effect of probiotics like that adding Lactobacillus rhamnosus in diet of pregnant women can reduce the risk of AD [75]. Adding probiotics like Bifidobacterium lactis, Lactobacillus salivarius or Lactobacillus GG to the infant formula reduced the severity of AD [76]. But recent randomized control trial has shown opposite result. The study concluded that early supplementation with LGG in the first 6 months of life does not appear to prevent eczema at 2 years of age [77]. However, systematic reviews and meta-analyses report protective effect of the probiotics for the primary prevention of atopic dermatitis [78, 79, 80]. Probiotics are ineffective in prevention of asthma, food allergy and allergic rhinitis. Medical societies like the American Academy of Pediatrics, the European Academy of Allergy and Clinical Immunology and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition do not recommend the use of probiotics for primary prevention of allergic disease [49, 81, 82, 83]. The World Allergy Organization recommends the use of probiotics in diet of mothers of high-risk infants during pregnancy and lactation and in diet of those infants in order to prevent AD [84]. There is no consensus for the most effective specific strain of probiotics. The strain, dosage, timing of introduction and duration of probiotics usage are still uncertain. These questions are the aim of the future investigations.
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Early introduction of allergenic food like peanut and egg can prevent food allergy, but the effect on other allergic diseases is not known. Exposure to furry pets in home like dogs and cats in early life can prevent sensitization, but this protective effect can be modified by endotoxin exposure [85]. Deficiency of vitamin D has been associated with onset and exacerbation of allergy. According to this immunomodulatory effect, it has been assumed that supplementation of vitamin D might protect against allergy. But recent researches does not support protective role of vitamin D in allergy [86, 87].
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In the prevention of allergic diseases, protective effect was observed for antihistamines. In infants with atopic dermatitis or with high risk for allergy, ketotifen treatment was associated with lower incidence of asthma [88], while the use of cetirizine decreased the risk for asthma in grass pollen-sensitized children [89]. Allergen immunotherapy (AIT) has been used over the last 100 years and is the only therapy with disease-modifying effect. The role of AIT in primary and secondary prevention was investigated in several studies. Sublingual AIT applied for the primary prevention of allergy among high-risk infants has no protective effect on the developing of first allergic disease [90]. Oral AIT decreased the risk of asthma, among children with grass pollen allergic rhinitis [91]. Recent systematic review and meta-analysis found no evidence that AIT decreased the risk for developing a first allergic disease. However, AIT reduced the risk of asthma among patients with allergic rhinitis. This effect was observed 2 and more years after the AIT was completed. AIT can reduce the onset of new sensitizations, but the evidence was not clear [92, 93].
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6. Conclusion
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Allergic diseases like atopic dermatitis, asthma and allergic rhinitis have sequential appearance with typical peaks of incidence during childhood. This temporal association is observed in the whole children population, and it starts with atopic dermatitis and food allergy in infancy, followed with asthma in the preschool age and finishes with allergic rhinitis. During growing up, the remission of atopic dermatitis and asthma was noticed, while symptoms of allergic rhinitis persist through adolescence and young adult age. The occurrence of all allergy diseases among the same child in temporal appearance was noticed only in smaller proportion of children in which causal link between AD, asthma and AR can be presumed; while, among others, common occurrence of allergic diseases follows different trajectories, without typical allergic sequence. For those children, complex interplay of allergic predisposition, systemic and local immunological responses and environmental influences during maturation of immune system triggers the appearance of those coexistence of allergic disease.
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\n\n',keywords:"allergic march, atopy, children",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68312.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68312.xml",downloadPdfUrl:"/chapter/pdf-download/68312",previewPdfUrl:"/chapter/pdf-preview/68312",totalDownloads:294,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 17th 2018",dateReviewed:"February 28th 2019",datePrePublished:"September 6th 2019",datePublished:"December 4th 2019",dateFinished:null,readingETA:"0",abstract:"Atopy is an inherited tendency of producing immunoglobulin E on common proteins from the environment like pollen, house mites and food. The presence of atopy represents a risk for the development of allergic diseases like atopic dermatitis, asthma, allergic rhinitis and food allergy, although atopy can also be present only in the form of asymptomatic sensitization. Allergic diseases share common inherited and environmental risk factors, immunologic patterns of allergen-specific Th2 response and efferent phase of immunologic reaction characterized with the production of IgE and activation of granulocytes. The presence of one disease increases the risk for developing other diseases. Allergic diseases demonstrate characteristic sequence of incidence in childhood which is called allergic/atopic march and starts with atopic dermatitis in early infancy. Disrupted integrity of the skin in atopic dermatitis contributes to the development of sensitization and increases the risk for development of other allergic diseases. The discovery of filaggrin gene mutation opens the possibility for causative incidence of allergic diseases and for prevention of development of atopic march. But, the causal link from atopic dermatitis to asthma is still a matter of debate.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68312",risUrl:"/chapter/ris/68312",signatures:"Blaženka Kljaić Bukvić, Mario Blekić and Marija Pečnjak",book:{id:"7062",title:"Rhinosinusitis",subtitle:null,fullTitle:"Rhinosinusitis",slug:"rhinosinusitis",publishedDate:"December 4th 2019",bookSignature:"Balwant Singh Gendeh and Mirjana Turkalj",coverURL:"https://cdn.intechopen.com/books/images_new/7062.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"67669",title:null,name:"Balwant Singh",middleName:null,surname:"Gendeh",slug:"balwant-singh-gendeh",fullName:"Balwant Singh Gendeh"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"289739",title:"Dr.",name:"Blaženka",middleName:null,surname:"Kljaić Bukvić",fullName:"Blaženka Kljaić Bukvić",slug:"blazenka-kljaic-bukvic",email:"blazenka.bukvic@gmail.com",position:null,institution:null},{id:"296533",title:"Dr.",name:"Marija",middleName:null,surname:"Pečnjak",fullName:"Marija Pečnjak",slug:"marija-pecnjak",email:"mpecnjak@gmail.com",position:null,institution:null},{id:"296535",title:"Dr.",name:"Mario",middleName:null,surname:"Blekić",fullName:"Mario Blekić",slug:"mario-blekic",email:"blekic1978@yahoo.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Atopic dermatitis, disrupted skin barrier and allergic sensitization: is it the beginning?",level:"1"},{id:"sec_3",title:"3. Why is allergy increasing? Hypothesis-driven strategy",level:"1"},{id:"sec_4",title:"4. Allergic march: causal link or cluster of related diseases",level:"1"},{id:"sec_5",title:"5. Can we prevent and/or stop atopic march?",level:"1"},{id:"sec_6",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Boyce JA et al. Guidelines for the diagnosis and management of food allergy in the United States: Summary of the NIAID-sponsored expert panel report. The Journal of Allergy and Clinical Immunology. 2010;126(6):1105-1118'},{id:"B2",body:'Nwaru BI et al. Prevalence of common food allergies in Europe: A systematic review and meta-analysis. Allergy. 2014;69(8):992-1007'},{id:"B3",body:'Prescott S, Allen KJ. Food allergy: Riding the second wave of the allergy epidemic. 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DOI: 10.1111/pai.12661'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Blaženka Kljaić Bukvić",address:"blazenka.bukvic@gmail.com",affiliation:'
Pediatric Department, General Hospital “Dr. Josip Benčević”, Croatia
School of Medicine, Josip Juraj Strossmayer University of Osijek, Croatia
Faculty of Dental Medicine and Health Care, Josip Juraj Strossmayer University of Osijek, Croatia
Pediatric Department, General Hospital “Dr. Josip Benčević”, Croatia
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