Hybrid nanoparticles with different structural components and their applications.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"3627",leadTitle:null,fullTitle:"Mechatronic Systems Applications",title:"Mechatronic Systems",subtitle:"Applications",reviewType:"peer-reviewed",abstract:"Mechatronics, the synergistic blend of mechanics, electronics, and computer science, has evolved over the past twenty five years, leading to a novel stage of engineering design. By integrating the best design practices with the most advanced technologies, mechatronics aims at realizing high-quality products, guaranteeing at the same time a substantial reduction of time and costs of manufacturing.\r\n\r\nMechatronic systems are manifold and range from machine components, motion generators, and power producing machines to more complex devices, such as robotic systems and transportation vehicles. With its twenty chapters, which collect contributions from many researchers worldwide, this book provides an excellent survey of recent work in the field of mechatronics with applications in various fields, like robotics, medical and assistive technology, human-machine interaction, unmanned vehicles, manufacturing, and education. We would like to thank all the authors who have invested a great deal of time to write such interesting chapters, which we are sure will be valuable to the readers.\r\n\r\nChapters 1 to 6 deal with applications of mechatronics for the development of robotic systems. Medical and assistive technologies and human-machine interaction systems are the topic of chapters 7 to 13.Chapters 14 and 15 concern mechatronic systems for autonomous vehicles. Chapters 16-19 deal with mechatronics in manufacturing contexts. 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In 2005, I was a visiting PhD student at the EPFL Autonomous Systems Laboratory. Currently, I am a researcher at the Institute of Intelligent Systems for Automation (ISSIA), National Research Council (CNR) of Bari, Italy.\nMy main research interests include:\n- computer vision applied to robotics and intelligent systems\n- self-localization methods for mobile robots\n- robotic non-destructive inspection\n- robotic surveillance systems",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Institute of Intelligent Systems for Automation",institutionURL:null,country:{name:"Italy"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"17156",title:"Dr.",name:"Grazia",middleName:null,surname:"Cicirelli",slug:"grazia-cicirelli",fullName:"Grazia Cicirelli",profilePictureURL:"https://mts.intechopen.com/storage/users/17156/images/system/17156.jpg",biography:"Grazia Cicirelli received the Laurea degree (summa cum laude) in Computer Science from the University of Bari (Italy) in 1994. Until 2001 she held grants from the Italian National Research Council (CNR) for research activities in Robotics and Image Processing. From 2001 she is a Technologist Researcher at the Institute of Intelligent Systems for Automation (ISSIA) of CNR in Bari. Her principal interests include pattern recognition, artificial intelligence, image processing for robotic applications and intelligent systems for video-surveillance. She has worked on and directed numerous research projects in different research areas such as Quality Control, Intelligent Transportation Systems, Autonomous Mobile Robotics. She is author of numerous research papers published in International Conference Proceedings, National and International Journals. 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A variety of novel drug delivery systems and strategies emerged for diagnostic and therapeutic applications that explored the different structural components, fabrication methods and mechanisms of drug delivery and targeting [1]. These DDS emphasized on the use of multiple nanomaterials and therapeutic moieties that renovate the current pharmaceutical industry and biomedical sciences toward the better drug therapy [2]. These nanosized particles were utilized for the delivery of various molecules including different drugs, proteins, nucleic acid and other diagnostic agents. Some of these compounds may be encapsulated inside while others were adsorbed on the surface of these nanoparticles. These nanocarriers can amend the pharmacokinetics and pharmacodynamics of drug by enhancing the solubility, permeability and bioavailability in multiple ways. The availability of the encapsulated compound depends upon the nature of formulation components and the other external stimuli which enable the controlled as well as targeted delivery of these encapsulated compounds within the cellular microenvironment [3]. All these parameters ultimately achieve the higher concentration of the encapsulated drug that efficiently reaches the potential target site without affecting the normal tissues. These nanocarriers also aid to implement the concept of rational therapeutics by providing the tunable drug delivery systems based on the patient therapeutic demands.
\nDespite of excellent in-vitro performance, some drugs demonstrate poor in-vivo results because of low aqueous solubility, poor membrane penetrability, rapid clearance by the reticuloendothelial system, complex pathophysiological states of the disease and uncertain plasma levels leading to drug toxicity, thus, requiring such drug delivery systems that overcome these problems [4]. Latest developments in the material sciences, polymer engineering and nanotechnology have enabled multidisciplinary research to formulate and evaluate different novel drug delivery systems that claimed increased drug solubility, penetration and retention at the targeted site in the body [5].
\nAmong the different nanoparticulate systems, nanoparticles of different composition and lipid based vesicular carriers (liposome, lipid nanocarriers, solid lipid nanoparticles and drug lipid conjugates) have been frequently employed for the medical applications. The nanoparticles may provide versatility in terms of composition. As, these include the polymeric nanocarriers, mesoporous nanoparticles, metal coated (gold, iron and silver), inorganic nanoparticles, quantum dots, carbon nanotubes, dendrimers and magnetic nanoparticles [6, 7]. Furthermore, all these systems were modified to mimic the desired therapeutic properties through different modification method and ligands such as (i) increase in the retention time and stability of the system, (ii) stimuli triggered release, (iii) targeted delivery of various agents and (iv) administration of dual modalities simultaneously [8, 9].
\nLiposomes and niosomes have been considered as most promising domains among the lipid vesicular carriers. Liposomes are defined as the lipid vesicles having the single or multiple layers of the lipid providing the encapsulation of different therapeutic moieties while niosomes have the same morphology but contain nonionic surfactants instead of phospholipids as major structural components. They provide the better biocompatibility profile, easy surface modification of the vesicles, versatility in the loading of hydrophobic and hydrophilic drugs and improved pharmacokinetic properties [10, 11]. However, drug leakage or fast release from the system, reproducibility, poor physical and chemical stability on storage, higher cost and scale up issues are the major drawbacks associated with the vesicular systems [12, 13].
\nNanoparticles (polymeric, organic/inorganic, mesoporous silica, calcium carbonate and different metals, i.e., iron, silver and gold) established the second domain of the nanocarriers. These systems prove superiority in terms of smaller particle size, structural integrity, versatility in the polymeric materials, improved drug loading and release profile. They also provide the targeting capabilities in the case of magnetic iron oxide nanoparticles and better cellular interactions in case of organic and inorganic nanoparticles [14]. Similar to that of vesicular systems, these polymeric nanoparticles have some limitations in term of polymer toxicity, presence of toxic organic solvents, poor entrapment of hydrophilic drugs, polymer degradation and drug leakage before reaching the site of action [15].
\nThe problems associated with the liposomes, polymeric nanoparticles and other carrier systems can be reduced by using a novel combinatorial approach of “hybrid nanoparticles” (HNPs) that utilizes the positive attributes of two different components. These hybrid nanoparticles (HNPs) exploit the benefits of both systems (lipid and polymer/organic and inorganic materials) and the release profile of drug is based on the erosion and degradation of the core material by hydrolysis with in turn determined by water permeation into the outer shell layer and composition of the polymer. The core materials may be protected by the application of multiple layers of the shell materials and the interface of these layer acts as a site for the functionalization of the carrier system for the dual modalities of treatment and diagnosis [16].
\nSimilarly, core shell hybrid nanoparticles using different oils, metal oxides, organic and inorganic components also provide newer system that has multilayered structure having the inner core outer shell with a suitable lipid or oil at the interface to develop a core shell hybrid structure. Recently, use of green approach offer more facile and potentially successful system with the added advantage of solvent-free nanohybrids with greater efficiency.
\nSuch novel system consists of three different structural components as follows:\n
The inner most core made up of different polymers (poly-lactic-co-glycolic acid [PLGA], polycaprolactone [PCL] and chitosan), lipids (cationic, anionic, zwitterion and neutral phospholipids and nonionic surfactants), inorganic materials (silica, iron oxide) and organic materials (polysaccharides) that encapsulate the therapeutically active moiety.
The intermediate lipid layer that covers the polymeric/inorganic core and enhance the biocompatibility of that system. It also acts as barrier to minimize the drug leakage and control the rate of polymer/inorganic core degradation by controlling the water permeation into the core.
The outer most lipid or polymer-conjugate which act as a layer for functionalization of the system by making it target specific through the use of different ligands or increased its circulation and retention time by coating with the PEG. This layer may be modified with a suitably charged moiety to attach the antibodies, aptamer and other such molecules by electrostatic forces [17]. Different types of the hybrid nanocarriers having different morphology and different structural components Figure 1.
Structure of lipid-polymer hybrid nanoparticles; (a) polymer core-lipid shell hybrid, (b) 3 layers polymer-lipid hybrid nanoparticles consisting of polymeric core (1) and two lipid layers (2,3) shell, (c) 4 layers hollow core lipid-polymer hybrid, consisting of hollow core (1) covered by reverse surfactant layer (2), polymeric shell (3), and outer shells of two lipids (4). (d) organic core-inorganic shell and inorganic core-organic shell hybrid, (e) inorganic (metallic)-protein hybrid nanoflowers, and (f) graphene oxide coated mesoporous silica-inorganic hybrid nanoparticles.
In this chapter, the different types of hybrid nanocarriers have been described with particular emphasis on the brief rationale for the development of these hybrid nanocarriers along with different fabrication approaches with greater emphasize on the lipid polymer hybrid nanoparticles. A brief description factors governing the optimized response characteristics and their potential application of these hybrid nanoparticles are also presented.
Different methods have been employed for the fabrication of hybrid nanocarriers depending upon their chemical composition and applications. The lipid-polymer hybrid, polymer-inorganic hybrid, metal (gold, silver or iron) polymer, silica (SiO2) based hybrid nanosystems and hybrid polymeric nanocarriers have been most widely investigated [18]. Most of these hybrid carriers utilized two distinctive fabrication approaches. First, a two-step conventional approach process, in which the inner core and outer shell are prepared separately and then are coincubated for the formation of hybrid nanoparticle. The second approach is the single step, in which various state-of-the art techniques of the self-assembling are being incorporated. These processes are further modified with different chemical moieties to obtain versatile hybrid nanoparticles meeting specific need of therapy [19]. In the present chapter, we will focus on the two step conventional as well as single step formulation approaches along with recent innovations have been presented in order to prepare the hybrid nanocarriers with versatile characteristics.
\nIt was the first technique employed for the fabrication of hybrid nanocarriers. The inner core and outer shell components are prepared in two separate steps employing suitable polymers and chemicals and are then combined to form the hybrid nanoparticle [17]. The foremost type of core shell hybrid nanoparticles contained a core of the polymeric nanoparticles and an outer shell of preformed lipid component such as liposome or lipoparticles in appropriate ratios [20]. Further, the single or multilayered shell is prepared with other techniques such as sonication [21], extrusion or high pressure homogenization and vortexing [22]. The polymeric core is prepared by emulsification-solvent evaporation or solvent diffusion [23], desolvation [24], nanoprecipitation [25, 26], sonication [27] and high pressure homogenization [28] depending upon the hydrophobicity of the loading drugs, their applications [29] and the size of the core.
\nThe single step method is applied when the core materials such as polymers, silica and organic substances are miscible with the drug payload and also are solubilized in the organic solvent [30, 31]. The double emulsification step is employed when the compound is immiscible with the organic solvents and does not form covalent linkage with the core material. As this method requires multiple steps for mixing of different components, relatively larger hybrid nanoparticles are produced [32]. Further, any of the suitable technique such as ultrasonication or extrusion by high pressure homogenization also reduces the particle size as the polymer solution is passed through the nozzle under high pressure. Furthermore, the freeze drying or cooling at normal temperature produced free flowing characteristic particles [33, 34]. Another recent innovation is the application of nanoprecipitation method for the preparation of polymeric core. The polymer is dissolve in the suitable solvent and then precipitated by using the nonsolvent component [26].
\nThe formed polymeric core and lipid vesicles are mixed by vortexing, extrusion, film hydration and ultrasonication techniques in order to formulate the hybrid nanoparticles. The mixing processes provide the energy for the fusion or adsorption of the shell on the inner core material. Additionally, the electrostatic forces among these components also play their role for fabrication of hybrid nanoparticles [35]. It is worth mentioning here that mixing process must be carried out above the phase transition temperature of the lipid component. The formed hybrid nanoparticles are separated by the ultracentrifugation process [36, 37]. Different investigators such as Liang et al. [38] and Zhao et al. [39] prepared the hybrid nanoparticles and nanocells by the emulsification solvent evaporation technique employing the paclitaxel loaded polymeric nanoparticles as core and the PEG or folic acid conjugated octadecyl-quaternary lysine-modified chitosan and cholesterol as lipid shell [38, 39].
The modifications to the conventional two step method such as spray drying and lithographic molding processes have also been employed for fabrication of hybrid nanoparticles [29]. The inner core is prepared by the spray drying which is dispersed in an appropriate solvent containing the lipid, polymer or any inorganic material. The spray dried lipid coated core shell hybrid nanoparticles were collected after the completion [17].
\nFreeze or spray dried inhalation hybrid nanoparticles of levofloxacin, ciprofloxacin and isoniazid coated with multiple layers of the lipids were prepared using double emulsion solvent evaporation technique. These hybrid nanoparticles showed better inhalation efficiency, emitted particle size and diameter compared to the conventional two step methods [37, 40]. Another investigations employed nanospray drying for fabrication of hybrid nanoparticles using polyglutamic acid, poly lysine nanoparticles coated with the lipid materials [41]. Recently, Keloglu et al. [42] employed jet spray drying technique for the fabrication of hybrid microfibers-nanoparticles having low density and greater strength using PLGA and poly lactic acid (PLA) [42].
\nA soft lithography particle molding technique was also utilized for the preparation of hybrid nanocarriers for the delivery of genes to various diseases. De Simon and his coworkers prepared the nanosized particles using the particle replication approach on the silicon wafers. The technique was referred to as Particle Replication in Nonwetting Templates (PRINT) [43]. The process involve the dissolution of the polymer (e.g., PLGA, PLA) in an organic solvents such as dimethyl formamide, methyl acetate and/or dimethyl sulfoxide along with the material to be encapsulated. The PRINT molding device was employed to fabricate the nanoparticles which later were harvested with the help of polyethylene terephthalate sheet [43]. It produces the particles of different shapes and a wide size range depending upon the size of the molding cavities [44].
The low encapsulation efficiency due to the leakage of the drugs from the inner core during second step, batch variability and large time consumption are the common problems associated with the conventional two step methods [45]. These constraints can be overcome by designing the simple method that utilized the single step approach and also provide better control on the content uniformity, reproducibility and other characteristics of the system. The method involves the mixing of two different solutions containing the polymer and lipid that self-assembled to form the particles with the core shell hybrid structure [46]. The polymer is dissolved in an appropriate organic solvent while the lipid solution is prepared in the water that may utilize the small fraction of organic solvent as solubilizing agent. The solution containing polymer is added to the lipid phase where the polymer precipitate to formed the nanoparticles and the lipid is self-assembled at the surface to form the hybrid nanoparticles. Single-step preparation is usually achieved by nanoprecipitation, emulsification-solvent evaporation and solvent diffusion methods. These methods and their appropriate modifications are discussed here.
\nEmulsification solvent evaporation method is the most commonly employed single step approach for the fabrication of hybrid nanocarriers. The single emulsification solvent evaporation [47] and double emulsification solvent evaporation (DESE) techniques are employed depending upon the nature and solubility of encapsulating drug. In the ESE method, the oil phase is formed by dissolving the polymer and the drug in the water immiscible organic solvent. The aqueous solution containing the lipid portion which act as a stabilizer itself during the self-assembling process [48, 49]. The organic phase is then added dropwise into the aqueous phase under the sonication or stirring at the constant speed that results in the formation oil in water emulsion. During the emulsification process, the hydrophobic part of the lipid is adsorbed on the inner core material while the hydrophilic parts arrange themselves toward the aqueous medium forming the lipid coated hybrid nanoparticles [45, 50].
\nThe single ESE method is employed for the encapsulation of hydrophobic drugs with low aqueous solubility [51]. Recently, the folate conjugated lipid polymer hybrid nanoparticles have been prepared by the emulsification solvent diffusion method for the targeted delivery of the doxorubicin using phosphatidylcholine (lecithin 99%) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DPSE)-PEG-COOH as lipid portion and PLGA as a polymeric portion [52]. The ESE method was also employed to formulate duel ligand hybrid nanocarriers for the targeted delivery of docetaxel. The hybrid nanoparticles possessed a uniform monolayer of the lipid over the polymeric core. The cell interaction studies revealed better endocytosis profile with sustained release of the drug by preventing the diffusion of the aqueous medium in the polymeric core. However, the particle were relative larger compared to that prepared by the nanoprecipitation method. This might be attributed to higher drug loading that maintained the therapeutic concentration for the longer period of time [53].
\nThe double emulsification solvent evaporation (DESE) has been employed for the hydrophilic drugs and nucleic acid such as siRNA (small interfering ribonucleic acid) which are not dissolved in different organic solvents along with the other suitable polymers or the core/shell materials [54]. The aqueous solution of desired substance is prepared and is then emulsified in the organic/oil phase containing the lipid and polymer. The resultant primary emulsion is again added to another aqueous solution containing the lipid (lecithin, phosphatidylcholine or DSPE) or surface ligand (PEG, half antibodies, aptamer) and a water-in-oil-in-water (w/o/w) multiple emulsion is prepared. The evaporation of the organic phase results in the formation of hybrid nanoparticles [55]. The particles with hollow core covered with an appropriate shell provide the space for the internalization of hydrophilic and small molecules. The evaporation of the organic solvent provides the multilayered shell which has larger size as compared to the other methods [17].
\nSu et al. [56] prepared the reduction sensitive hybrid nanoparticles of doxorubicin using chitosan with the sodium dodecyl sulfate employing the double emulsification solvent evaporation method. The amphiphilic chitosan and lipid base micelles core provided a unique nanoconfiguration that is enveloped by the triglycerides which enhanced the loading efficiency and provided the drug release profile up to eight folds [56].
This method is also known as salting out method. It is a well known method for fabrication of hybrid nanoparticles of size less than 100 nm. This method employs two miscible solvents with different solubilizing capacity for the polymer. First, the polymer core is formed by solubilizing in solvent of greater solubility designated as good solvent which is then added to less soluble solvent designated as poor solvent. The two solutions are mixed by dropwise addition, stirring or sonication. Good solvent being miscible with poor solvent diffuses into later, leaving behind the core nanoparticles due to the precipitation of the polymer [19].
\nThe core forming polymer and lipophilic drug are solubilized in a water-miscible organic solvent like acetone, acetonitrile or ethanol [57]. The lipids, inorganic salts or silica are dispersed in water with moderate heating (~60–75°C) and/or addition of hydroalcoholic mixtures for proper dispersion of the lipids.
\nThe hydrophilic drugs are added to the aqueous phase containing dispersed lipids [58]. The polymer containing organic phase is then added dropwise to lipid dispersion with continuous stirring to precipitate the polymer into nanoparticles. The monodispersed hybrid nanoparticles are collected after suitable application of vortexing, homogenization or ultrasonication [55, 59]. Concurrent to the precipitation process, the self-assembly of lipid molecules around the polymer molecules occurs due to the hydrophobic interactions. The polymer core captures the hydrophobic tails of lipid while the heads are facing toward the aqueous phase [17, 60]. Continuous stirring of dispersion for several hours is helpful in uniform lipid coating of hybrid nanoparticles and to ensure the complete removal of organic solvent [55]. Rotary evaporator may also be helpful for the removal of organic solvents [58].
\nThe literature suggests 10% ethanolic solution is employed for solubilization of lipids and PEG may enhance the stability of hybrid nanoparticles [61]. According to the study of Ling et al. [58], dextran sulfate and lecithin/PEG-PLGA hybrid nanoparticles can entrap higher amounts of hydrophilic moiety, the vincristine.
\nWang et al. [62] developed PLGA/TPGS-lecithin hybrid nanoparticles using a modified nanoprecipitation method. The PLGA was dissolved in acetone while lipids were dispersed in either aqueous or 4% ethanolic aqueous solution. An inverse-phase nanoprecipitation method (i.e. aqueous phase was added dropwise into organic phase consisting of acetone, the PLGA and the paclitaxel). Initially, the formation of hybrid nanoparticles was slow due to the higher proportion of organic phase in the mixture. Continuous stirring and addition of water boosted the diffusion which leads to solidification of the hybrid nanoparticles. A stable hybrid nanoparticle formulation with low value of PDI (~0.1) was observed at 5:1 aqueous to organic phase ratio [62].
Sonication is a fast technique for the fabrication of hybrid nanoparticles which utilizes ultrasonic waves rather than vortexing, solvent evaporation or heating. In this method, the two solutions designated as organic and aqueous phases lead to formation of inner core (polymer) and outer shell or coating materials (lipids), respectively. The sonication has been employed by Fang et al. [63] for the fabrication of hybrid nanoparticles of lecithin-PEG and PLGA by using this approach. The PLGA was dissolved in acetonitrile while the lecithin and the PEG were added in 4% ethanol solution. The former solution was carefully pipetted into the hydro alcoholic solution (aqueous to organic ratio was kept as 10:1). The hybrid nanoparticles were produced as this ‘cocktail’ mixture was placed in sonicator bath for five minutes at a frequency of 42 kHz and a power of 100 W. The main advantage of this technique is the formation of stable hybrid nanoparticles with short processing time and production rate is 20 times than other processes [63].
\nThe sonication technique has been employed for PLGA and docetaxel hybrid nanoparticles by Liu et al. [64]. In another study, Mandal et al. [65] developed erlotinib loaded hybrid nanoparticles of PCL in which erlotinib and PCL were dissolved in acetone and added to the aqueous phase containing lipids. Hybrid nanoparticles were produced after sonication for 10 minutes at a frequency of 67 kHz and a power of 200 W [65].
\nA unique method using the combination of modified nanoprecipitation and sonication methods is presented for the fabrication of hybrid nanoparticles. In this method, the lipids melt was mixed with ethanolic solution of Elacridar, a chemosensitizer, and placed in vacuum oven until complete removal of solvents. The doxorubicin being hydrophilic drug was added in water with surfactant (Pluronic-F68) and heated (72–74°C). The drug and surfactant dispersion was mixed with Elacridar-lipid mixture. The whole mixture was stirred for 10 min and then ultrasonicated for two cycles of three minutes. It produced submicron sized lipid emulsion which was dispersed in 4–9 times higher volume of cold water (maintained 4°C) which leads to the formation of hybrid nanoparticles [66, 67].
The use of green technology has revolutionized the synthesis of hybrid nanocarriers due to the ecofriendly procedures that mitigate the threats of toxic impurities and use of the organic solvents. These ecofriendly approaches also provided low operating cost, better stability, compatibility and minimum health hazards [68]. The literature has suggested the successful implementation of solvent free approaches to formulate nanosized systems for the targeted delivery of different therapeutic and diagnostic moieties.
\nThe heat chill method has been employed to prepare micelles using the amphiphilic diblock and triblock copolymers of polycaprolactone (PCL) for the encapsulation of insulin without using any organic solvent and has provide better stability of the entrapped proteins which are liable to denaturation in the presence of different organic solvents [69].
\nKumar et al. prepared the green PLGA-oil hybrid nanoparticles of resveratrol employing the acrysol oil (a derivative of castor oil) as nontoxic solvent. The nanoparticles have a smooth outer morphology with improved drug release and stability profile [70].
The concept of combining the characteristics of organic and inorganic components is quite old since the time of Egyptian inks. However, the modern organic-inorganic hybrid systems are not prepared by simple mixing these materials but may involve the weak electrostatic linkages (H-bonding or van der Waals forces) or strong chemical bonds, i.e., covalent bonds [71]. Multiple strategies are employed for the preparation of these hybrid particles. These include (i) polymerization of the different monomers, organosilanes and the metal oxides, (ii) self-assembly of different structural components at nanoblock level with different organic and metal components, (iii) the functionalization of preformed nanocarriers with different organic compounds and (iv) making the core with organic materials and coating with the silica and different metallic components [72, 73].
\nIn conventional sol-gel approach, the hydrolysis process is used to obtain the hybrid system. The reaction involves the organically modified metal oxides which crosslinks with the polymers of multiple functionalities. These components may or may not be present in the organic solvents and possibly trapped within the inorganic material. However, use of self-assembling procedures in last few decades provided new methods for the fabrication. During the process, the inorganic materials (triblocks) were arranged by the use of organic surfactants. The preparation of the mesoporous hybrid with multiple functionalities provide highly porous surface which further modified based on the applications [74].
\nShen and Shi [75] reported a method for preparation of the organic/inorganic hybrid based dendrimers. The metal or inorganic nanoparticles were entrapped in the dendrimers template to provide a modified surface morphology which can be tuned by different functional components to provide the biocompatibility and better colloidal stability [75] (Table 1).
Structural components | Physicochemical properties | Application | References | ||
---|---|---|---|---|---|
Size (nm) | Zeta potential (mV) | Entrapment efficiency (%) | |||
PLA DPPC PEG‐PE | 278 ± 16 | (+) 20 to 50 | N/A | Steric stabilization of hybrid nanoparticles was enhanced at least up to 150 mM NaCl (for more than 1 year at 4°C). | [27] |
Paclitaxel PLGA PEGylated octadecyl‐quaternized lysine modified chitosan | 194 ± 7 | 22 ± 4 | 87 ± 2 | Folic acid modified polymer core lipid shell hybrid carrier for targeted anti‐cancer therapy. Higher internalization up to 14.8 folds was observed in flow cytometry. It also showed higher cytotoxicity than commercial preparation (Taxol®). After 2 hours administration, it showed 3.70 fold higher bio distribution than Paclitaxel injection. | [39] |
Levofloxacin Ciprofloxacin Ofloxacin PLGA Phosphatidylcholine (PC), Stearic Acid (SA) | 420 260 360 | -26 +26 -22 | 19 4 5 | The amount of the polymer and lipid were optimized for highly efficient hybrid system. Hybrid nanoparticles showed higher size and drug encapsulation in comparison to polymeric carriers. Different antibiotics like levofloxacin, ciprofloxacin and ofloxacin were encapsulated. Ciprofloxacin showed less EE due to less lipophilicity. Oppositely charged drug and lipid prevented nanoparticle formation which was remedied by the addition of counter ionic surfactant. | [45] |
Doxorubicin PLGA DEPE‐PEG Lecithin | 118.7 ± 0.75 | 15.19 ± 3.85 | 45.76 ± 6.58 | Folate receptor mediated drug delivery of anti‐cancer agent, doxorubicin, resulted in higher cell internalization and enhanced cell‐killing effect toward MCF‐7 cells with a significantly lower IC50. | [52] |
PLGA DSPE‐PEG Poly (β‐aminoester) poly‐1 | 280 ± 70 | (+) 40 ± 7 | N/A | mRNA loaded pH sensitive particles reached cytosol offering low cytotoxicity followed by translation at a frequency of ∼30%. Intranasal administration of abovementioned system led to in vivo expression of protein as soon as 6 hours after administration. | [57] |
Vincristine PLGA Poly ethylene glycol (PEG) Dextran sulfate | 121.8–133 | -8.5 to -14.6 | 64.7 to 93.6 | Vincristine loaded hybrid nanocarriers resulted in 3.3‐fold increase in apparent bioavailability, while its uptake was 12.4‐fold higher than plain drug solution. | [58] |
Docetaxel PLGA Lecithin PEG | 70–80 | -30 to -35 | 59 ± 4 | Docetaxel loaded Hybrid nanoparticle exhibited 20 hourrs as T5o. These carriers also exhibited good stability in 10% bovine serum albumin and in 10% plasma solution. | [59] |
Paclitaxel PLGA Soybean lecithin D‐α‐tocopheryl polyethylene glycol 1000 succinate (TPGS) | 120–150 | -15 to -20 | >80 | Developed carriers provided sustained release up to 8 days with a high tumor targeting potential through EPR effect. It also showed superior antitumor efficacy by inhibiting 58.8% volume of tumor at day 28. | [62] |
PLGA DSPE‐PEG | 65 | -47.7 | N/A | A new quick single step preparation method is reported which needs 5 min to get accomplished. This method increased the production rate 20‐fold without compromising determinant features of hybrid particles. Particles developed such exhibited good colloidal stability in PBS and serum over 5 days. | [63] |
Docetaxel PLGA DEPE‐PEG2000 | 263.6 | -20.74 | 66.88 | Folic acid conjugation increased 38.2% for 0.5 hour incubation and 54% increase for 2 hours incubation during cell uptake study. Cell viability studies showed that formulation was 93.65% more effective than commercial preparation Taxotere®. | [64] |
Erlotinib DEPE‐PEG2000 Dipalmitoylphosphatidylcholine (DPPC) N‐[1‐(2,3‐Dioleoyloxy)propyl]‐N,N,N‐trimethylammonium methyl‐sulfate (DOTAP) | 161–271 | -47 | 77.18 | Erlotinib loaded Core Shell Lipid Polymer Hybrid Nanoparticles demonstrated 170 nm size with 66% Entrapment efficiency and greater uptake and efficiency in A549 cells. | [65] |
Doxorubicin Elacridar Pluronic F‐68 | 187–272 | -19.7 to -22.9 | 71.2–89.3 | Formulation shows up to 89% encapsulation efficiencies of Dox and GG918 in PLN with more uptake and cytotoxicity of Dox to MDR cells | [67] |
Resveratrol PLGA | 375 ± 13 | -22 ± 1.6 | 76 ± 4.2 | G‐PONHs have higher biocompatibility and stability, but moderate cytotoxicity compared to standard NPs. It also involves the application green synthesis approach for the hybrid nanocarriers | [70] |
Paclitaxel Poly‐lactic‐co‐glycolic acid (PLGA) Soybean lecithin 1,2‐Distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE‐PEG) | 186.9 ± 8.52 | -29.5 ± 2.0 | 81.34 ± 3.41 | More drug reaches target site crossing Blood brain barrier and survival time for mice was PtxR‐FPLNs (42 days), Ptx‐FPLNs (38 days) compared to PtxR (18 days) and Paclitaxal (14 days) | [76] |
Melatonin Poly lactic acid (PLA) Didodecyldimethylammonium bromide (DDAB) Cetyltrimethylammonium bromide (CTAB) | 180–218 | +15.4 to -36.1 | 90.35 | Coating with cationic lipids provides sustained and prolonged drug release, a pronounced benefit in ophthalmic application | [77] |
Docetaxel PLGA DEPE‐PEG2000 Soybean lecithin | 60–70 | -40 to -60 | ∼62 | The system provides 62% entrapment efficiency and almost 50% drug release in 20 hours. The incorporation of PEG provides stability over 120 hours. TC 50 value ranged between 4.58 and 5.55 mg. | [78] |
PLGA DSPE‐PEG | 50–150 | N/A | N/A | Different lipid ratios were evaluated for the entrapment, particle size, stability of the system. The current system provides that pH sensitive release and targeting which aggregate the drug in the acidic tumor microenvironment. | [79] |
Poly caprolacton (PCL) Glyceryl tripalmitate | 58–2009 | -5.82 to -46.31 | 5.81–60.32 | The system indicates biphasic release of the drug in which the burst release id presented in the initial hour. The cellular uptake was 83.3% in L929 cells. It also provides better colloidal stability over 120 hours. | [81] |
Human IgG Poloxamer‐188 | 135–799 | +16.7 to +17.9 | 30.3–60 | The system was loaded with the SiRNA. Which show the loading capacity of up to 2.04%, entrapment efficiency 60% in the optimized formulation. It provides the targetibility with the antibody and the sustain release was demonstrated by 20% release over the study time. | [82] |
PCL Grape leaf extract Curcumin | ∼291 | -24.3 | The resulting drug delivery system improves the antimicrobial efficacy against two bacterial strains in addition to antifungal activity and can be an alternative approach to antibacterial agents. | [83] | |
Doxorubicin Epoxidized soybean oil Pluronic F68 | 200–350 | -23.1 | 70 to 80 | The system promotes cytotoxicity of DOX against MDR to about eightfolds. Uptake and retention of drug by MDR was also significantly increased. | [84] |
Carboxymethyl chitosan Calcium phosphate PEG | 102 ± 1.7 | -8.25 ± 0.76 | 78 | It gives excellent delivery of siRNA to cancer proximity through EPR effect. Particularly hTERT containing nanoparticles promotes silencing of hTERT expression and induction of cell apoptosis pathways. | [85] |
Doxorubicin Sorafenib | 126.3 ± 16.4 | -21.4 ± 4.6 | 90.5 ± 3.4 and 70.8 ± 2.8 | DOX‐SOR combination in iRGD conjugated HNPs produces more apoptotic rates up to 44.7% than 33.4% with plain drug combinations or 37% with HNPs without iRGD. | [86] |
Doxorubicin Mitomycin C | ∼150 | ∼ -25 | >90 | Co delivery of anticancer agents using HNPs is more effective than simple combination therapy with advantages of high local delivery. It provides the 2–4 fold increase in the cellular uptake of the drug in the cancer cells. | [87] |
Lipid modified PEG | 24 ± 5 | -38 ± 1 | N/A | The system describes engineering of functionalized lipid conjugated polymeric nanoparticles with more specific targeting approach and imaging and bio sensing based on fluorescence. | [88] |
Doxorubicin Combretastatin A4 PLGA PC DSPE‐PEG Cholesterol | 180–200 | N/A | N/A | The system contains two different therapeutic agents which provide the site targeted release of the anti‐angiogenesis agent and the anti‐cancer drugs. | [89] |
Curcumin PLGA DPPC DSPE‐PEG | 171.6 ± 8.2 | N/A | N/A | By treating the metastatic breast cancer cells with the lipid‐polymer hybrid nanoparticles of Curcumin decreased the adhesion onto tumor necrosis factor by 70% in capillary flow. | [90] |
Docetaxel PLA Chitosan | 208–255.7 | -21.3 to + 52.4 | 75.9 | PLA/chitosan nanoparticles provide rapid initial release of 40% drug in 5 hours and 70% cumulative release in 24 hours. | [91] |
Docetaxel Curcumin PLGA | 169.6 ± 4.6 | -35.7 ± 1.9 | 89.8 ± 3.1 and 81.9 ±5.6 | The drugs loaded hybrid nanoparticles showed enhanced cytotoxicity and tumor growth inhibition. | [92] |
Docetaxel DSPE‐PEG PLGA | 110 ± 13.5 | -25.67 ± 1.45 | 77.65 ± 0.57 | The system increases the cellular update of docetaxel 2.5 folds and anti‐proliferative activity 2.69–4.23 folds. | [93] |
Doxorubicin Chitosan Hyaluronic acid | 264 ± 2.2 | -12.3 ± 2.0 | 97.8 ± 1.3 | It is used to deliver anticancer drugs which results in enhanced circulation half‐life and reduce the elimination of drug | [94] |
Hybrid nanoparticles with different structural components and their applications.
Hybrid nanoparticles are trimmed to an acceptable level of particle size, drug carrying capacity and site specificity through incorporation and adjustment of ratios of different chemical components. The variations of structural components of HNPs have an obvious influence on HNPs’ characteristics [17, 96]. The principal factors of HNPs’ formulation are (i) lipid/polymer ratio, (ii) PEGylation and (iii) polymer nature.
\nThe lipid covering the polymeric core provides substantial benefits to HNPs and their distinction over nonhybrid nanoparticles. The ratio of two building blocks (lipid-polymer) of hybrid particles have significant role in stabilizing the formulation, monodispersibility and encapsulation efficiency [45, 97].
\nAt a lower L/P ratio, the nanoparticle surfaces are not entirely covered with lipids, which can form bridges with lipid part of other particles causing aggregation and formation of larger particles. At a relative higher lipid concentration, it tends to decrease the production yield as whole amount is not incorporated in particles and free lipids will arrange themselves to form liposomes can affect the homogeneity of formulation. Therefore, the concentration of lipids should be optimized that cover to polymeric core on the basis of particle size and production yield [59, 98]. Chew et al. prepared HNPs with PC and PLGA carrying antibiotics with WPC/WPLGA value <15- up to 90%. At lipid amount below 15% larger particles were formed (800–1000 nm) and a sharp decrease in particle size was observed at an optimum concentration i.e. 30% lipids, an optimum particle size (260–400 nm) and 80% production yield was achieved. The lipid ratio above the optimum concentration i.e. 30% did not reduce particle size but it decreased the yield as the entire lipid was not utilized [45].
\nAn optimum lipid to polymer ratio also provides the colloidal stability of HNPs by providing an optimum surface charge density which is responsible for electrostatic repulsive forces that prevent particle coalescence and stabilizes the formulation. In case where the lipid part is insufficient and the resulting electrostatic repulsive forces are weak, some agents like PEG can be incorporated in the formulations to provide steric repulsion and stabilization of the HNPs [52, 80–98].
\nThe charge on lipid part which is responsible for electrostatic repulsion between particles is shielded when mixture of cationic and zwitterionic lipids is employed. Anionic heads of zwitterionic lipids face outwards which reduces of cationic lipids charge and promotes aggregation of particles. However, the higher cationic lipid concentration may overcome this charge screening and aggregation can be minimized [59, 99]. The zwitterionic lipid such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) produces less aggregation than a cationic lipid, 1,2-dipalmitoyl-3-trimethylammonium propane (DPTAP). Therefore, it zwitter ionic lipid provides more stability than ionic lipids [55, 59].
\nThe two potential benefits that lipid augments to the HNPs are the encapsulation efficiency and retardant release of the incorporated drugs. The former is achieved by preventing drug leakage during self-assembling process, whereas the latter is due to reduced interaction of lipids with dissolution medium [17, 100]. The charge on the surface of lipids and drugs also affects the entrapment efficiency due to interaction of surface charge of HNPs and the charge of the drug. The loading of ciprofloxacin in the PLGA-PC hybrid system is not successful due to the interaction of cationic drug with the anionic lipids [19, 78].
\nA significant higher percent encapsulation of docetaxel (59 ± 4) was achieved in HNPs assembled from lecithin, DSPE-PEG and PLGA i.e. compared to PLGA-PEG nanoparticles with 19 ± 3 (mean ± SD). This effect is attributed to the fencing action of lipids which keeps hydrophobic drugs within the core and retards water penetration. The lipid-polymer hybrid formulations also provide a sustained release of drug when compared with nonhybrid formulation due to less water penetration and reduced escape of drug molecules from polymeric core. A consistent 50 % release of docetaxel from lecithin-PLGA hybrid system was observed compared to the PLGA-PEG NPs and PLGA NPs released same amount of drug in 10 hours and 7 hours, respectively. The pH of the dissolution media also affected the encapsulation of drugs, for example, the erlotinib EE % was 77.1%, 28.83% and 18.45% at pH values of 7.4, 5.4 and 3.4, respectively [55, 59, 78, 100].
The steric stabilization of HNPs systems to withstand salt solutions, buffer actions and uptake by macrophages is provided by the appropriate surface modification by employing PEG. The term is called as PEGylation. PEGs can escalate circulation times of HNPs by preventing particle aggregation, opsonization and adsorption of plasma proteins [27, 78].
\nIncorporation of PEG-lipid affects the colloidal stability of HNPs by two ways (i) chain length of PEG-lipid and (ii) molar Ratio of PEG-lipid. HNPs coated with PEG-lipid longer chains exhibited more stability than the shorter chain PEG-lipid coated particles. Similarly, at the fixed chain length more PEG-lipid incorporated onto polymer core and thickness of lipid shell increased which lowered the zeta potential and hence stability is enhanced [78, 80].
\nYang et al. studied the effect of lipid/polymer ratio and PEGylation on HNPs prepared from PLA/mPEG-PLA polymer and BHEM-Chol cationic lipid. HNPS prepared from mPEG-PLA were smaller and more stable in PBS at the given lipid/polymer ratio than PLA alone [61].
\nFang et al. formulated HNPs using 0.10–0.35 lipid-PEG/PLGA ratios without incorporating lecithin. Initially particle reduced with increase in lipid amount and optimized at 0.30 lipid-PEG/PLGA ratio after which further increase in lipids did not affect particle size and PDI. At an optimized (0.30 lipid-PEG/PLGA) ratio, lipid-PEG was replaced with mole equivalents of lecithin. The stable particles of 60 nm were obtained at 50% lipid-PEG replacement. Upon 70% lipid-PEG replacement, the size was increased to 100 nm and at 80% lipid-PEG replacement with lecithin, the unstable particles were obtained. This instability of particles is due to the replacement of higher lipid-PEG content, a major stability component of HNPs [63].
The characteristics such as density and surface charge play an important role in the fabrication of HNPs [35]. The density of polymer also has substantial effect on stability and particle size [59, 78]. HNPs fabricated from high density polymer are less stable toward increasing ionic strength of medium due to the higher sedimentation rate when electrostatic charges are shielded. PLA is 1.18 times denser than poly(styrene); hence, HNPs prepared with PLA core have less colloidal stability toward increasing ionic strength of medium [35]. Zhang et al. evaluated that change in viscosity of PLGA polymer from 0.19 to 0.82 resulted a decrease in particle diameter from 92.7 nm to 66.7 nm [59].
\nAdsorption of lipid over polymeric particle surface to form lipid shell depends upon curvature and surface charge of particle. Cationic lipids exhibit more adsorption than zwitter ions toward the anionic polymeric core due to the electrostatic attractions polymeric core from anionic polymer PLA has greater affinity for DPTAP cationic lipid than the zwitterionic DPPC. Lipid rearrangement around polymeric core can be quick and complete if the affinity between polymer and lipid is high. Larger size distribution and free lipid structures are observed when lipids cannot rearrange around polymeric core due to weaker affinity. Modification in pH of medium can improve the affinity of polymer for lipid by surface charge variation at different pH levels [35, 101, 102].
Hybrid systems combine properties of two or more materials, thus, appear superior to individual material system. Usually, one component of hybrid system is active, whereas other is used to improve biocompatibility, circulation life and targeting. Many new hybrid systems use second material to improve efficiency of first materials. By suitable selection of materials, hybrid systems find wider applications in medical field. Hydrophilic polymers have been widely used to impart stealth property to nanoparticles. However, stealth coating does not improve or impart new functional aspect of nanoparticles. Thus, many researchers do not regard PEG coated as hybrid systems. Similarly, nanoparticles conjugated with targeting ligands cannot be regarded as hybrid system.
\nLPHN consists of a drug containing polymeric core which is coated by a lipid shell. In these systems, inner polymer core contains drug and lipid shell is used to enhance penetration through biological membranes and to control drug release. Polymeric core can be made from hydrophilic or hydrophobic polymer. Term lipid-polymer hybrid is also used for systems that contain polymer core with lipid coating. Lipid is preferred carrier material for hydrophobic drugs due to higher encapsulation efficiency and extended release pattern. A polymeric coating is applied over lipid core to impart certain characteristics required for novel biomedical applications.
\nIn addition of polymeric and lipid layers, surface of LPHN may be modified with different materials. In one study, a hydrophobic drug was loaded in a hydrophobic biodegradable polymer to enhance encapsulation efficiency of a hydrophobic drug. Then, a lipid layer is applied to stabilize core and shell, and to prolong drug release. Finally, hydrophilic polymeric layer, consisting of DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy (polyethylene glycol)2000) was applied to improve pharmacokinetics of LPHN. The three-layer LPHN showed high encapsulation and sustained release of hydrophilic drug [59]. A hydrophilic polymer monolayer may be applied to LPHN to escape phagocytosis and early removal from body. Generally, polyethylene glycol (PEG) is used to provide this stealth property and enhance circulation time of nanoparticles. PEG will attract water to make an aqueous layer which protect LPHN from attachment of opsonin proteins and let it escape the uptake by reticuloendothelial (RES) system. Hydrophilic polymer layer can also enhance colloidal stability of LPHN due to steric hindrance effect [5]. As stealth layer can also hinder interaction with target cells, PEG can be conjugated with other monomers or polymers to form block copolymers that are specific to certain stimuli. This approach enables long circulating LPHN that can shed stealth layer when come in contact with target cells. The stimuli could be intracellular and extracellular protease enzymes, low pH or reducing agents [103].
\nSelection of polymeric matrix plays a major role in drug delivery properties of LPHN. LPHN are commonly used for poor water soluble or hydrophobic drugs. A hydrophobic polymer core can encapsulate higher amount of hydrophobic drug and vice versa. Two or more drugs could also be loaded into the core of LPHN. On the other hand, LPHN with hydrophilic and hydrophobic drug could be made to contain one drug in core and the other in shell. Wong et al. [67] prepared LPHN containing lipid core to encapsulate hydrophobic drug Elacridar (GG918) and hydrophilic shell of hydrolyzed polymer of epoxidized soybean oil (HPESO) to encapsulated doxorubicin. They found that both drugs were released in sustained manner for more than 72 hours (Figure 2). Simultaneous delivery of chemosensitizer GG918 was able to revert multidrug resistance to anticancer drug doxorubicin. These simultaneously loaded LPHN showed better efficacy than free drug solution or LPHN of any of the two drugs.
Drug release from gold nanoparticles containing solid lipid nanoparticles. F1 (5mg diacerein) and F2 (10 mg diacerein) show sustained release of drug for 39 and 48 hours. However, F3 had same composition as F2 but drug release was conducted at 40°C. F5 and F6 contained increasing amount of hydrophilic gold nanoparticles with 5 mg diacerein. F7 contained gold nanoparticles same as F6 but 10 mg diacerein. Finally, F8 contained lipophilic gold nanoparticles with 10 mg diacerein. Drug release was faster at higher temperature (F3) as compared to 37°C. Furthermore, hydrophilic gold nanoparticles containing formulations F5, F6 and F7 released drug in less than 5 hours, whereas hydrophobic gold nanoparticles showed prolonged release up to 25 hours.
As a wide variety of polymers and lipids are available, LPHN can be prepared to theoretically load any therapeutic moiety. Nucleic acid based therapeutics i.e. plasmid DNA, antisense oligonucleotide, small interfering RNA and small hairpin RNA, have shown promise to cure many diseases. LPHN have emerged as nonviral carriers for nucleic acid products with low toxicity, immunogenicity and cost of production. Cationic polymers and lipids have been widely investigated for this purpose. Cationic groups can bind negatively charged nucleic acid molecules and deliver to target cells. Zhong et al. [104] prepared LPHN with biodegradable PLGA and two cationic lipids i.e. 1, 2-dioleoyl-3-trimethyammonium-propane (DOTAP) or 3β-[N-(N′,N′-dimethylaminoethane)-carbamyl]cholesterol (DC-Chol). LPHN were prepared by two either with cationic lipid core so that DNA is loaded inside core or with cationic lipid shell so that DNA is loaded on surface. The in vitro evaluation was done in human embryonic kidney cells. They found that LPHN with DNA on surface showed higher transfection efficiency than those with DNA inside core. Next, they prepared LPHN with polymer both inside core and on the surface which showed efficiency similar to that of LPHN with DNA on surface. This study concluded that LPHN can show transfection efficiency about 600 times higher than unbound DNA. However, cationic lipids and polymers may have some problems on their own. They may interact with biological components, be nonbiodegradable or toxic after systemic administration. These factors are controlled by hydrophobic chain length, nature of cation group and linkage. To solve these problems, Shi et al. [54] prepared novel LPHN with four distinct layers. First is a hollow core i.e. aqueous droplet containing nucleic acid which is coated by an inner lipid layer of cationic lipid ethylphosphocholine.
\nThe cationic lipid orients itself in such a way that cationic group faces inward and its hydrophobic chain faces outward. Third layer is formed by ester terminated PLGA. It is a hydrophobic polymer that intermingles with protruding chains of cationic lipid. Finally, self-assembled lecithin and DSPE-PEG form outer coating to facilitate transfection and to impart stealth property to LPHN. This LPHN system release loaded siRNA in sustained manner up to 6 days and enhanced gene expression in mice.
\nA recent trend in drug delivery research has focused on the development of human-like vesicular drug delivery system. This concept emerged when exosome were found to be responsible for cell to cell communication in tumors and regulate tumor microenvironment. It was believed that exosomes isolated from patients may be filled with antitumor drugs and injected back to the patients for personalized treatment. As isolation of exosomes from patients is complicated and very costly, this dream was realized by synthesizing surface antigens of exosomes by genetic engineering and grafting on the surface of drug containing liposomes or other vesicular systems [5]. In addition to this, many bacterial and viral antigens have been used. These antigens are used for the delivery of vaccine and act as immune adjuvant i.e. enhance immune response to vaccine. Moreover, polymeric core produce better adjuvant effects than lipid core. Bershteyn et al. [105] prepared PLGA core and phospholipid bilayer coated LPHN that were stabilized by PEG for simultaneous loading of antigen and adjuvant. The protein adjuvant was covalently bonded on surface and lipophilic adjuvants, such as monophosphoryl lipid A and α-galactosylceramide, which were loaded in lipid bilayer. Immune response was shown at dose as low as 2.5 ng which was detectable after 100 days. It was also found that α-galactosylceramide shows rapid rise in antibody titer whereas monophosphoryl lipid A produced response in sustained manner. Interestingly, coloading of both adjuvants with antigen further increased antigen titer by 12 fold. These results show that LPHN can reduce dose of antigen to reduce cost and side effects.
\nTerm LPHN may also be extended to nanoparticle systems consisting of two or more polymer at least one of which is lipophilic. A hydrophilic shell may be applied to drug containing hydrophobic (or lipophilic) polymeric core to impart mucoadhesion or to make them stealth. For example, PEG or chitosan coating has been widely used to improve circulation life of sustained release solid lipid nanoparticles [106]. On the other hand, a hydrophobic polymer shell may be formed over hydrophilic polymer core to enhance LPHN absorption through biological membranes. This approach is especially useful for oral administration of therapeutic macromolecules [107]. Recently, Liu et al. has synthesized supramolecular vectors for gene delivery. First, adamantyl-terminated polyethyleneimine was admixed with β-cyclodextrin to encapsulate nucleic acid, i.e., DNA or siRNA which was further coated with adamantyl-PEG. The supramolecular vector was stabilized by host-guest interaction. This LPHN system showed low toxicity and high transfection efficiency during in vitro experiments. Graphene is another two-dimensional framework of carbon atoms that is investigated for hybrid applications. When treated with suitable reagents, it can be oxidized, hydroxylated, carboxylated or halogenated. These functional groups can be conjugated with different materials desired for biomedical applications [108].
IOHN are synthesized from organic and inorganic materials. Most commonly, core is made of inorganic materials and the shell of an organic material is applied to improve its pharmacokinetic parameters. On the other hand, inorganic shell may be applied to the core of organic materials to impart different properties. IOHN are interesting because they offer properties of both materials. Like organic polymer, they can be functionalized with different groups. Like metallic nanoparticles, inorganic shell provides physical and chemical stability to polymeric core. Generally, the inorganic portion is developed by reduction of metal ions to zerovalent state. Inorganic core is synthesized by mixing metal ions solution with a reducing agent with or without heating. However, inorganic shell may be synthesized either by reduction of metal ions on polymeric core or by deposition of preformed metal colloids on organic core.
\nMethods for synthesis of organic core and shell have already been discussed in detail in a chapter. We have prepared IOHN consisting of gold core with fatty acid shell. First, gold nanoparticles were synthesized with lecithin bilayer (hydrophilic surface) and lecithin monolayer by acid treatment (hydrophobic surface). The gold nanoparticles were added to molten fatty acids and emulsified with aqueous surfactant solution. Upon cooling, we found that gold nanoparticles with hydrophobic surface are more stable as compared to gold nanoparticles with hydrophilic surface [109]. The presence of gold nanoparticles in core enhanced drug release rate from lipid nanoparticles. This can be attributed to the presence of gold nanoparticles that push drug toward periphery and reduce diffusion path length (Figure 1). In another study, we prepared an organic core of lecithin and inorganic shell of gold nanoparticles. First, lecithin nanoparticles were prepared and loaded with drug. Next, preformed gold nanoparticles were adsorbed on its surface. We found that drug release was controlled by both gold nanoparticles. Gold nanoparticles retard release of drug due to physical barrier. Lecithin controlled release of anti-inflammatory drug from core in pH-dependent manner [110]. Gold is also known to possess anti-inflammatory effect. In this study, gold shell was found to synergize anti-inflammatory effect of encapsulated drug diacerein by many folds (Figure 3).
Efficacy of anti-inflammatory drug encapsulated in lecithin core-gold shell hybrid nanoparticles; (A) Anti-inflammatory effect of diacerein is synergized in the presence of gold as compared to pure drug, diacerein. PEG-AuNP = PEG coated gold nanoparticles, LD-NP = diacerein loaded lecithin nano[articles, L PEG-AuNP = Lecithin nanoparticles surface coated with PEG coated gold nanoparticles, L Cit-AuNP = Lecithin nanoparticles surface coated with citrate coated gold nanoparticles, L B-AuNP = Lecithin nanoparticles surface coated with sodium borohydrate coated gold nanoparticles, LD PEG-AuNP = L PEG-AuNP loaded with diacerein, LD Cit-AuNP = L Cit-AuNP loaded with diacerein, LD B-AuNP = L B-AuNP loaded with diacerein. (B) represents decrease in swelling as measured by Vernier caliper before (a, b, c, d, e, f, g) and 3 h after (b´,c´, d´, e´, f´, g´) from untreated (b), diacerein (c), PEG-Au NPs (d), LD PEG-Au NPs (e), LD Cit-Au NPs (f), and LD B-Au NPs (g) treatments groups, while a is normal rat paw.
Various organic materials have been used to prepare IOHN to improve their performance. The materials that are used to synthesize or stabilize nanoparticles may impart specific function. The most pronounced function is enhanced penetration inside target cells which in turn controls toxicity of IOHN. Freese et al. [47] studied toxicity of gold nanoparticles with different organic coatings with neutral, positive and negative charge. The results showed that IOHN with positive charge coating shows more internalization in cells, and thus, higher toxicity. The cell membrane has a negative charge, whereas the IOHN are positively charged particles. This charge difference triggers the rapid binding to the cell surface and internalization of these IOHNs. As gold can cause toxicity at higher dose, higher internalization in cell will lead to high toxicity [111].
\nMetallic nanoparticles smaller than 100 nm are usually responsive to different stimuli, a technique that has been widely employed in diagnosis and therapy. IOHN with metallic core can be used for thermotherapy of cancer whereby IOHN produces heat when exposed to external magnetic field. Similarly, metallic moieties, i.e., nanoparticles or tagged polymers, can be bound to core of organic materials. These nanoparticles will be targeted to cancerous tissues and magnetic moieties will produce hyperthermia under external stimuli. When core of organic material is loaded with drug, inorganic part can release the drug by hyperthermia-mediated degradation of core after reaching the target site [5]. In addition to magnetic field, inorganic nanoparticles are also responsive to infrared and ultrasound waves. This makes IOHN interesting candidates for biomedical imaging of targeted tissues. More recently, multimodal IOHN have ensured imaging and drug release from the same system after systemic administration. This target can be achieved in two ways. First, magnetic field of low frequency or intensity is applied for imaging of IOHN. Once in cancer tissue, intensity or frequency is increased to produce hyperthermia-based cell killing or drug release [112]. Secondly, inorganic materials responsive to more than one stimulus can be used. One stimulus aids in imaging, whereas second stimulus will lead to drug release or thermotherapy [113].
\nIOHN have also been prepared with hollow core enclosed inside a hybrid shell. Hollow core IOHN can be prepared by many ways. First strategy is to make layer of inorganic or organic material which is then stabilized by other component of IOHN system. Similarly, it can consist of a mixed shell of inorganic and organic materials enclosing hollow core. Metal-tagged polymers with amphiphilic nature self-assemble to form micelles in aqueous solution or after reaching the target microenvironment [114]. Whole virus or virus capsid has been investigated as drug delivery systems by many researchers due to its inherent high penetration in cells.
\nPortney et al. [115] hybridized virus capsid with quantum dots and single-wall carbon nanotubes to yield hybrid structures that can find various applications. These hybrid structures are very stable to chemical and mechanical stress. IOHN with metallic core and organic shells have been widely investigated for diagnostic application. Although, organic shell usually employed to improve the pharmacokinetics and targeting properties of the metallic nanoparticles but may be beneficial by enhancing the diagnostic efficiency of the system. The most prominent example is nucleic acid-based biosensors with metallic core. When metallic nanoparticles aggregate, they show blue shift due to increase in size. Metallic core is coated with single-stranded DNA (ssDNA) that can identify specific sequence on target DNA and bind it. In bioassay, when metallic nanoparticle conjugated ssDNA start bind target DNA, they come close to each other and test solution color changes from red to blue. This indicates the presence of target DNA as visualized by naked eye or through UV-visible spectrophotometer [116].
Although MPHN can be categorized as inorganic-organic hybrid NP, they are discussed here separately due to difference in structure and many fold increased surface area. The flower-like structure of MPHN is due to the presence of proteins that stabilize metallic crystals in the structure. Proteins act as glue and hold metallic crystals in a pattern which mimics flower petals. Unlike inorganic-organic hybrids, synthesis of MPHN occurs in three stages. First stage is the growth stage in which metal ions bond with proteins through amide bond. This acts as nucleation site leading to growth of primary crystals. In the second stage, metalloprotein crystals aggregate to form larger structures bearing primary petals like structures. Finally, anisotropic growth on metalloprotein aggregates leads to formation of complete petals. Generally, their size lies in the range of 2–30 μm which is another reason to differentiate MPHN from OIHN. MPHN is mostly used for bioassay whereby desired enzyme is conjugated with metallic part. Encapsulation efficiency of enzymes in MPHN has been achieved up to 66%. Enzyme loading above or below this limit decreases encapsulation efficiency. Nevertheless, enzyme efficiency of MPHN varies between 85% and 1000%. Enzyme efficiency higher than free enzyme is due to many reasons. MPHN shows high surface area due to petal-like projections. The petals also have hole-like spaces between them that may be up to 100 nm in diameter. It is also observed that immobilized enzyme shows cooperative interaction to enhance enzyme efficiency. Similarly, metal ions, such as copper, calcium and manganese, may also help enzyme in catalysis. Copper (Cu2+) is the most widely used metal with different enzymes. Cu2+ and laccase enzyme MPHN have been developed for detection of phenols. The prepared MPHN was adsorbed on filter, and a mixture of phenol and 4-aminoantipyrine was added to it. Laccase-assisted reaction of both compounds produced red antipyrine dyes in 5 minutes. The changes in color will be visible with the naked eye, and UV-visible spectrophotometer can be used for quantitative detection. The MPHN-coated filters are reusable and are much faster than chromatography and mass spectrometry based methods. Likewise, MPHN of Cu2+ and horseradish peroxidase was prepared for detection of phenol and hydrogen peroxide. This MPHN was able to detect very low amounts of phenol (1 μM) and hydrogen peroxide (0.5 μM) as change in color was observed with the naked eye. It has been found that hydrogen peroxide induces cell death at concentration higher than 50 μM and the limit of detection of free enzyme is around 20 μM. Thus, these MPHNs will be very efficient to detect slight changes in hydrogen peroxide efficiently even below its threshold level. Cu2+ and trypsin MPHN have been used to carry out proteolysis which is an important step in protein identification. The enzyme efficiency of proteolytic MPHN is similar or superior to free enzyme but are fast and reusable.
\nAnother form of nanoflowers is synthesized using deoxyribonucleic acid (DNA) which, like proteins, possesses high number of nitrogen molecules and serves as a template for nanoflowers. In one study, a drug and a dye molecule was bonded to DNA that was used to synthesize nanoflowers. These nanoflowers showed multimodel property of drug delivery and imaging by using FRET technology. More recently, capsular MPHNs have been prepared with improved characteristics. This technique involved coating of MPHN with protamine and silica. Then, metallic core is removed from capsular MPHN system. Capsular nanoflowers show higher enzyme efficiency and improved stability in harsh environmental conditions.
Silica has been widely used in drug delivery due to its nontoxic and biocompatible nature. Silica shell has been applied to metallic nanoparticles to reduce their toxicity in various biomedical applications. Mesoporous silica nanoparticles (MSNPs) are silica materials with mesopores of up to 50 nm. They are also termed as hollow mesoporous silica nanoparticles due to the fact that mesopores are hollow. The advantages of MSNP are enhanced surface area and that hollow mesopores can be loaded with therapeutic molecules. First, MSNPs were loaded with drugs. Later, MSNPs were used for the delivery of different dyes and macromolecules such as enzymes. MSNP hybrids have been prepared with both organic and inorganic materials. One problem with the use of MSNP is the leakage of drugs from pores. Sreejith et al. [117] used graphene oxide (GO) coating on MSNP to prevent leakage of drugs. After drug loading, GO coating is applied which acts as blanket to physically block the pores. GO coating also prevents encapsulated drug from environmental degradation. In addition to applications in drug delivery, MSNPs are also used for diagnosis and imaging.
\nMaji et al. [118] prepared MSNP-GNP (gold nanoparticle) hybrids for detection of hydrogen peroxide. They coated MSNP with graphene oxide, and GNPs were coated on this surface. The hybrids were first used for electrochemical detection of hydrogen peroxide in the presence of other biological molecules. Later, MSNP-GNPs were successfully used for in vivo imaging in mice. MSNP surface can be modified with different functional groups that provide opportunities to form hybrid with different materials [118].
Hybrid nanocarriers provide a novel platform that synergizes the effects of therapeutic and diagnostic agents through tunable properties such as particle size, structure, composition, preparatory method and easy surface and charge modifications. Here, we describe the different parameters related to development, optimization as well as characterization to obtain a robust platform for the drug delivery and other biomedical applications. We can still try to focus some unmet challenges of this novel drug delivery system. These challenges include development and optimization of the application of target ligands in appropriate ligand density that will improve the pharmacokinetics as well as pharmacodynamics profiles of all the drugs loaded in these hybrid nanoparticles either single or in combination with other therapeutic and diagnostic agents. Similarly, development of these hybrid nanocarriers at large scale has received less attention. So it is a key parameter to translate the system for large-scale applications by using the different methods mentioned in the section of method of preparation especially the one-step self-assembly method that is likely to improve the production in a facile and economic manner.
Water is an important resource that supports life on earth. Its availability plays key roles for attaining socio-economic developments globally [1]. It is also a priority toward meeting the United Nations Sustainable Development Goal (SDG) 6 that seeks to ensure access to water and sanitation for all [2]. This requires an adequate enabling environment and strong systems at country level. The United Nations General Assembly has called for country-led, coordinated efforts to provide financial resources and build capacity and technology transfer to help countries yield stronger and sustainable services [3]. Water is thus an essential resource for balancing the well-being of humans and healthy ecosystems.
The survival of humans and continuing social-economic developments depend on the supply of appropriate water quality and quantity. The relationship between humans and ecosystems is core as people strive to improve their well-being. Ecosystem services are beneficial to all living creatures including humans in a number of ways [4]. Water, for instance, contributes to ecological functions through the provisioning of habitat for aquatic life, including fish that is food for humans.
Water also provides ecosystem services that include freshwater supply, regulatory functions such as dilution and water purification, and fulfilling cultural necessities (e.g., water for traditional, esthetic, or medicinal and spiritual purposes). The benefits derived from ecosystem services are available to humans, regardless of where they live or where the services are generated. For example, urban dwellers enjoy river ecosystem service benefits including fishing for food or growing trees along the river banks, which can be used as timber to build houses or as firewood for cooking.
Ensuring sustainable management of aquatic ecosystems for improved food security is therefore important [5]. This is especially true in urban areas where human activities may pollute distant ecosystems through effluent discharges caused by industrial and domestic or mining activities [6]. Human activities can pollute water bodies and impact socio-economic developments negatively. Any changes in water quality can affect short- or long-term food security goals if aquatic resources are not properly managed.
This chapter discusses the effects of water quality and scarcity with respect to food security on the African continent. A comprehensive synthetic evaluation of various published and technical reports was conducted in order to draw the relationship between the potential of water and food security in the African region. The use, distribution, and requirement for food systems that promote water conservation to create sustainable food production are explored. Lastly, issues concerning water pollution and food safety are discussed to identify knowledge gaps that impede food security in Africa toward the attainment of the United Nations Sustainable Development Goals.
This section seeks to highlight the basic human need for water and track the global water distribution and its importance in food security. Water is a basic unit of life and an essential nutrient that is required in amounts that exceed the body’s ability to produce it [7]. Like all nutrients, water performs different functions in the body [8]. Water is an essential component of cells, tissues, and organs required for digestion, absorption, and dissolution and as a carrier for nutrients, eliminating waste products; temperature regulation; and as a lubricant and shock absorber [9, 10, 11].
To achieve all these functions, total body water must be approximately 60% of body weight in males and 50% of body weight in females [12]. The water distribution is up to 60% intracellular (this amount is lower in females due to larger amounts of subcutaneous tissue and smaller muscle mass) and 20% in extracellular space [13]. The extracellular fluid compartment comprises fluid in blood, interstitial fluid, bone, connective tissue, and transcellular fluid. Variation in water intake depends on human health, weight, and human physical performance.
Human survival can be achieved with minimum water requirement where water lost through normal activities gets replenished [14]. The average adult body naturally loses almost 2–3 L of water daily which must be replenished to function on a day-to-day basis. This loss occurs mainly via urine, perspiration, feces, and exhaled air.
The amount of body water that gets lost depends on individual and environmental factors. These factors are affected by the climate a person lives in, his or her age, physical activity level, and kidney function [8]. To regulate the body’s water levels, the water input must balance water output through metabolic processes (0.3 L/day), fluid intake triggered by thirst (1.5 L/day), and solid foods triggered by appetite (approximates 0.7 L/day). Too little or too much water in the body can lead to less-than-optimal body function.
Early stages of decreased water intake in the form of dehydration can lead to difficulty in concentrating, headache, and sleepiness. Decreased water intake has also been associated with bladder and lower urinary tract cancer and increased risk of colorectal cancer as well as kidney stone formation [15]. Taking too much water can also put an unnecessary burden on the cardiovascular system and the kidneys and can cause a drop in the concentration of electrolytes in cells causing harm in the long run.
While water may be a renewable resource, it is unfortunate that there is only a finite amount and there are no substitutes. Without clean and safe water, human survival cannot be achieved. This has a great impact on the global burden of disease, health, education, and economic productivity of populations.
Water is an important component in a number of human functions, hygiene, and the overall maintenance of health. At the most basic level, water service must meet consumption and hygiene needs and sustain good health at household level [16]. Millions of the world’s poorest people, however, die each year from preventable diseases due to poor hygiene, lack of clean drinking water, and lack of proper sanitation facilities [17].
The reality is that water and sanitation are weakly integrated into countries’ poverty reduction strategies. Many national governments are failing to put in place the policies and finances needed to accelerate progress toward achieving clean water and adequate sanitation.
In many rural communities, lakes, dams, and stream that are the main sources of water run dry for long periods, forcing people to use unsafe water sources [18]. For the 2.1 billion people who lack access to clean water, they can only afford to get a measly 5 L a day and fail to meet the recommended basic minimum of 20 L a day required for human health, economic, and social development [19]. This is a far cry from the 200 L a day per person that people from rich countries consume on average in a day.
A report on global distribution of the global drinking water services in 2015 found that 71% of the global population (5.2 billion people) had access to a safely managed drinking water service [19]. The report further found that sub-Saharan Africa was the region with the lowest number of people with access to safe drinking water located on their premises. Only Australia and New Zealand had 100% access, where all of the population had basic services (including basic drinking water, sanitation, and hygiene) in their households.
The same report estimated that two-third of the total global population was living in water-stressed areas that experience water scarcity for at least 1 month in a year in 2015 [2]. Of the two-third, 844 million people lacked basic drinking water service and 263 million people were reported to be spending over 30 minutes per round trip to collect water from an improved water source [19].
Still, 159 million people were reported to collect drinking water directly from surface water sources and over half of these people were living in sub-Saharan Africa. These people share their domestic water sources with animals. A large fraction of the people that live in extremely vulnerable situations of water scarcity all year-round are found in Libya, Somalia, Pakistan, Morocco, Niger, and Jordan where 50–90% of the country’s population lives under those circumstances [20].
An estimated three fifth of the earth’s surface is covered by water, which makes up a total volume of almost 35 million km3 [2]. Of the available amount, only 200,000 km3 (1%) of this is fresh water that is usable by humans. This is the water that is expected to fulfill the demands of the increasing global population, meet the food production needs using the limited amount of arable land, and sustain industrialization.
Historically, people looked for location to set up their livelihoods near water supplies such as river bases that could provide drinking water and carry off waste. Over time, areas close to water sources became populated by industries and agricultural holdings which use water for irrigation and also to power industries [21].
Distribution of piped water is realized as a sign of progress toward achieving the SDGs. Industrialized countries (20%) have managed to achieve piped water coverage in 85% of their entire household. The poor countries, however, have only managed limited piped water coverage with only 25% of all their households having access [19]. Industrialized countries have been better able to achieve water security compared to poor countries and this is evident from the average water usage data of 200 L per person per day in rich countries compared to the 5 L per person per day in poor countries [18].
Factors that contribute to high water scarcity levels include areas with a high population density, areas with irrigated agriculture, and areas with very low natural water availability [20]. Geographically, water scarcity can be found in in the world’s arid areas with low water availability like the Sahara, Taklamakan, Gobi, and central Australian deserts.
Water scarcity has also been found to be intense in areas with high population density and irrigation intensity. Globally, these areas are found near river basins and include the Ganges basin in India, the Limpopo basin in Southern Africa, and the Murray-Darling basin in Australia [20].
Distribution by sectors shows that water use is spread between domestic, agriculture, and industry sectors. Agriculture accounts for over 70% of freshwater use [16, 22] and industry water use accounts for 20% globally. In spite of this, it is believed that there is enough water in the world for domestic, agriculture, and industry purposes; the only problem is how this water is distributed especially to the poor who are systematically excluded from the distribution.
Water use varies significantly by sector across the world. How do these three sectors use fresh water?
As discussed above, water use varies considerably across the world especially between the poor and rich. Agriculture is the biggest user of fresh water with Africa and Asia, accounting for the largest users under this sector with an estimated 85–90% of all freshwater [23]. Future demands for water for agriculture are threatened by climate change, technological development, and urbanization. The challenge is to produce more food to meet the growing population demands using less water and other resource inputs in an environmentally friendly manner [24]. Low-income countries’ average agriculture usage is estimated at 90%; 79% for middle income and only 41% in high incomes countries [22].
Industrial water use includes all the water used for manufacturing, energy generation, and other industrial activities such as dilution, steam generation, washing, and cooling of manufacturing equipment [25]. Globally, an estimated 20% of total available fresh water is used for industrial purposes. Within the industrial sector, hydropower and nuclear power generation uses 57–69% and the thermal power generation uses 0.5–3% [23]. Industries also pose a threat to fresh water because of the amount of wastewater it produces, its mobility, and loading of industrial pollutants and their potential impacts on water resources, human health, and the environment. High-income countries tend to use the largest portion of water on industries (17%), with low-income countries using the least with an average 2% [26].
Domestic water is the most visible form of water and it shows the problem that exists in the distribution of fresh water between the rich and the poor. People in developed countries consume almost up to 10 times more water daily than those in developing countries. In developed countries, where large cities have centralized water supply and an efficient canal system, domestic consumption averages 200 L per person per day [23].
In developing countries within Asia, Africa, and Latin America regions, consumption in cities and towns is between 50 and 100 L per person per day, and in the water scarce areas within these regions, the amounts can be as low as 5 L per person per day [23]. Countries with the largest population, China followed by India, have the highest water use globally [26].
The change in water distribution will have a serious implication on people’s health and well-being, especially for people living in high population density areas, areas with irrigated agriculture, and areas with very low natural water availability. These are the estimated 1.8–2.9 billion people who experience severe water scarcity for at least 4–6 months per year and the 500 million people face severe water scarcity all year round [20].
The distribution of water between sectors is expected to change over the coming years as a result of population growth, increased water scarcity, and drought due to climate change. Water use for irrigation and other water using sectors of the economy are expected to experience extreme competition which will place more burden on food security.
Water forms an essential part in national food security. To attain food security, there must be an acceptable quantity and quality of water for health, livelihoods, ecosystems, and production [27, 28]. Any sustainable attainment of food safety and security for a fast-growing population requires thoughtful decisions to develop and manage water resources.
Food security and safety are key development agenda items in most developing regions (Global Panel on Agriculture and Food Systems for Nutrition, 2016). Global research and funding have been prioritized and channeled toward fighting against food insecurity. Although substantial progress globally is evident [29], the same cannot be said for some of the African regions. Sub-Saharan Africa continues to have less access to sufficient quantity and quality food for proper health and growth. The report also classified the sub-Saharan countries as food insecure, with limited access to safe food within their population.
Despite the global food security achievements realized in recent years, food security and limited access to food safety still remain as challenges in Africa. Water scarcity and irregular rainfall distribution are proving to be an impediment to Africa’s efforts to ensure food security. Agriculture production systems, which are the backbone of food security, are also adjusting to tightening water availability by reducing freshwater use especially in the African region. This has resulted in the emergence of new diets that are sensitive to the significant influences of water and land use [30].
As the water challenge for agricultural production in Africa increases, it is expected that the share of irrigated agriculture in global water use could rise by over 30% by 2030 [30]. Total global water demand could double by 2050. The increased competition for scarce water and land resources increases concerns about where the additional food will come from. The challenges are further exacerbated by climatic changes that cause irregularities in water availability across the African landscape [31].
Water requirements in agriculture vary significantly not only in terms of quantity, but also in terms of quality and timing depending on food type. This is very significant especially when it comes to staple foods such as maize, rice, and wheat that are critical in food security of many countries in Africa. Some of these countries have increased awareness toward conserving their national water supply by opting for virtual water trade—importing food from outside the country in the effort to conserve water resources and maintain food security [32]. Other countries have shifted food production within the agriculture sector focusing more on planting water-efficient crops.
Apart from water being important in production, it also plays a huge role in food processing, transformation, and preparation adding to the competition against industrial and domestic water use [33]. Even though food processing uses much less water than primary production, this part of the food system requires water that is of high-quality standards and that does not pose any health and safety risks on both human and ecosystem health.
There is also a drive toward introducing water-use efficiency, reducing pollution impacts from processing industries [34]. Poor quality water used in food processing can lead to food-borne disease such as diarrhea and other diseases that contribute to malnutrition. The unsafe food creates a vicious circle of diseases affecting particularly the more vulnerable populations that include children, the elderly, and the sick [33].
Priority must be given to encouraging greater efficiency of water use and the development of integrated water management plans [30]. The shortage of food production due to water scarcity calls the need to manage every water drop to attain food security and food safety in Africa. This raises awareness that water for agricultural production is a pressing issue.
It has been noted that agricultural developments require a consistent and sustainable provision of large quantities of good quality water for food security [35]. The present situation is a clear sign that previous potential solutions to solving Africa’s food insecurity have not received the most needed attention when defining development goals on the continent. Societies depend on water availability to meet a wide range of needs including water for irrigation, domestic, and industrial use.
Poverty and water are inextricably intertwined. Food security cannot be achieved without tackling water issues since lack of safe water underpins food insecurity. Countries continue to invest in the protection and management of water resources to continue deriving benefits for improved living standards. Undoubtedly, major water investments in agriculture are necessary toward meeting food production needs [35]. Crucial role players are needed to put together efforts to conserve water for a food secure world.
Many Africans depend on aquatic and riparian plants and animals as an important source of food for both humans and livestock. These include fish, shellfish, bait, edible plants, and grazing. In addition, some areas such as wetlands and floodplains across Africa may be used for the cultivation of food crops. In this way, these riparian areas contribute to food security and livelihoods. These services are of particular importance to poor communities [36].
Nonetheless, the provision of reliable sources of water whether for small-scale water for food processing or large-scale water for irrigation is necessary to move beyond subsistence farming toward a more food secure continent [37]. The availability of water allows farmers to continue growing crops of high value such as vegetables, which are highly sensitive to water stress periods [38].
Although quality of water is crucial for peoples’ nutrition and water availability for food security in developing countries [39], water investments have been rapidly declining. While irrigation has a high potential for environmental damages or disturbances, it has contributed positively to poverty eradication [39]. Irrigated agriculture has benefited both rural and urban poor by lowering food prices [39]. The availability of water for irrigation means less people fall below the poverty line, and that poor communities, women in particular, also benefit greatly from irrigation as a major source of water for most of their domestic uses, fishing, small and/or informal businesses [39].
Nonetheless, small-scale water availability can impact on food security positively. The availability of water for small-scale harvesting has a huge effect on incomes and food security in developing and poorest communities. Major water investments will have more drastic and positive impacts on the poorest communities, where the majority of people live on less than US$1 on a daily basis [39].
Existing challenges between water availability, quality, and sustainable agriculture linkages must be explored and be made explicit in planning potential agriculture-based strategies for improving food security. The need for fresh clean water is, however, threatened by the changing quantity and quality of the freshwater resources on which people depend for survival. The need for clean water is also linked to adequate sanitation and improved health [14]. Proper sanitation helps to protect water sources from bacterial, viral, and protozoal agents that cause water-related diseases. The concern for many is how can water quality be attained?
As much as water is an essential component of life, it is a hotbed for carriers of many diseases caused by consuming unclean water. Access to safe drinking-water, sanitation, and hygiene (WASH) services is an important element of food security and has a positive impact on nutrition [40]. A number of approaches are used to assess water pollution effects on the ecosystems which have a direct contribution to food security and nutrition.
A common approach is to use chemical indicators to measure the concentration of chemicals or toxicants within a water body using either water samples or direct in-stream measurement of the water source using water samples as (chemical indicators). If the chemicals within the water are in exceedance with acceptable limits, that water system is regarded as polluted and not fit for human consumption. Biomonitoring can also be used to assess water quality by examining the presence or absence of certain species or organisms in a water body [41].
Another approach that is used to assess water pollution is ecotoxicology. An investigation is conducted to examine responses of insects, fish, and other invertebrates to a chemical or stressor as biological indicators of water quality [42]. Thus, polluted aquatic systems may not adequately support the provision of fish and insects as food for humans. Similarly, necessary microbes that support plant growth in soils may not thrive in polluted environments, thereby affecting food security.
Without good quality water, the lives of millions of people especially young children are at risk of dying from preventable diseases caused by poor water, and a lack of sanitation and hygiene. There is a growing interest to better understand and measure the effect of programs and approaches not only directed toward improving water management in agriculture and food production but also to include integrated approach to implementing safe water and adequate sanitation [40]. Approaches and practices for ongoing efforts to better link WASH and nutrition programs integrating WASH into food security and nutrition programs are discussed in the following section.
The World Health Organization [43] report defines drinking water as water with acceptable quality in terms of its chemical, bacteriological, and physical parameters for safe human consumption. Estimates indicate that about 80% of all sicknesses and diseases on a global scale are linked to consumption of unclean and unsafe water and poor sanitation.
However, the quality of any water is influenced by both natural and human factors [44]. Without human influences, water quality would be determined by natural factors and/or processes such as bedrock minerals, deposition of dust, natural leaching of soil minerals and organic matter, and biological processes, among others. Water quality is determined by using water quality guidelines or standards to make a comparison between the physical and chemical characteristics of water samples. The guidelines and standards are developed to ensure the safe consumption of water and protection of ecosystems.
Africa with its soaring human population continues to experience a decline in water quality [43, 44]. Adequate water, sanitation, and hygiene are essential components for reducing poverty, illness, and death and bring about an improved socio-economic development. Poor WASH programs expose people to water-borne diseases, resulting in death and disabilities in certain cases [44]. The United Nations International Children’s Emergency Fund (UNICEF) report revealed that the absence of toilets results in the contamination of water resources, while a lack of clean water impedes on basic hygiene [45]. However, increasing WASH programs have led to increased access to adequate drinking water sources and improved sanitation globally since 1990 [43].
To explore how WASH programs could improve the water and sanitation conditions for poor and developing countries across Africa, it is important to define hygiene and sanitation. Peal et al. [46] defined “sanitation” as the treatment and management of human excreta from coming into contact with humans, while “hygiene” is a required action to avoid the transmission of diseases within and between different communities. WASH programs are vital for helping people avoid contaminating water sources, which in turn improves their access and the overall food safety and security.
WASH programs also help to improve water quality for adequate food production due to their design nature, whereby communities work together to disseminate WASH information for a more collaborative program and implementation [46]. Here, practitioners work together with communities and local authorities to deliver the components of the WASH program on-site. This is complemented by practitioners revisiting the communities or distributing surveys for monitoring and evaluation purpose. Therefore, WASH program approaches have the potential to improve food security within the poor and developing African countries.
Water pollution is the building up of one or more substances in water to an extent that they cause water-related problems for people and animals [47]. It is a complex problem that is underpinned by many causes, which makes it difficult to solve. Increasing human population continues to exert immense pressure on the world’s water resources [29]. Both urbanization and industrial revolutions have exacerbated water pollution through effluent and untreated wastewater discharges.
Irrigated agriculture has resulted in increased salinity of freshwater bodies as salts are flushed out from soils [48]. When farmers fertilize their fields or control insects using herbicides, the chemicals used get washed away as salts through surface run-off into nearby water systems. Toxic chemicals released into the atmosphere by industries can also enter into water systems as acid rain [49].
An increase in water salinity negatively impacts on the survival of aquatic macroinvertebrates, while some crops become intolerant to high soil salinities if thresholds are exceeded [50]. As a consequence, soil productivity is affected and can lead to low crop production and food insecurity. It is therefore clear that low crop production is not only an issue in semi-arid regions but also areas that receive plenteous rainfall.
Thompson and Darwish [49] argued that the poor quality of water has a direct impact on food security, with metals detected in some edible food in China, posing a high health-related risk to consumers. If pollution effects are properly monitored using the approaches outlined above, Africa can produce quality food for its citizens. However, the UNICEF [45] report outlines the importance of educating people on water quality issues as another approach to solving water pollution.
Further, strict environmental laws are necessary to minimize water pollution. For example, environmental reports indicate that the “polluter pays” principle is effective in tackling pollution [49]. The polluter principle makes it less expensive for humans to behave in an environmental cautious and/or responsible manner. It is sad, to note, however, that some countries considered to have the best water laws in Africa and beyond, such as South Africa [51], are still struggling to deal with historical water quality issues that subsequently impact on their food security. Further, unstable countries due to political reasons such as Libya would greatly be affected by food insecurities considering their dry nature. The water quality of both countries is discussed in the following sections.
South Africa has sufficient water to meet all the needs of the country until the year 2025 and beyond [37]. However, the country is faced with challenges related to water quality, which impedes on food production to meet people’s demand for food. Poor water quality renders water unusable. Changes in agricultural practices and the expansion of urban settlements have a serious effect on the quality of water [37]. Furthermore, acid mine drainage (AMD), pesticides from agricultural practices, unmonitored sewerage systems, domestic water usage like washing clothes on the river and dumping waste in water sources in some areas of the country, and salinization from the weathering of minerals all pollute water [42, 52, 53]. Once water is polluted, it may be difficult and extremely expensive to redress, particularly in the case of underground water, which may affect agricultural production in terms of excessive salts on the soil and usable water for food production. It is thus important to note that good water quality would be suitable for food production to ensure food security.
Libya has a rapid growing demand for freshwater availability while the water supply is limited [54]. The issue of severe water deficits as a result of nonending water demands in Libya has become more problematic for the increasing population under low rainfall, which is a result of climate change. Furthermore, the country has been experiencing high rates of pollution and depletion due to water resource unavailability. This has had major impacts on Libya’s economy and social and environmental resistance capacity.
Considering that Libya is one of the driest countries on a global scale with high temperatures, meeting and maintaining acceptable living standards for the future is extremely difficult, especially in relation to food security. Food sufficiency remains uncertain in Libya due to its political instability coupled with poor water quality and soaring human population [54]. The country is likely to experience severe and most devastating situations and high risks of food insecurity and malnutrition with current political instabilities.
This section discusses the relationship between water and food safety. Water is seen as an essential component in the food chain, starting from production, processing, and eventually consumption. In addition, water pollution has historically impacted on food safety, which constitutes an important threat to human health, food, and nutritional security. In most sub-Sahara African countries, food safety problems vary in nature, severity, and extent. These challenges are often exacerbated by the effect of climate change and natural disasters such as floods and hurricanes, whereby food may become contaminated by surface water that has itself been contaminated by sewage and wastewaters. It is well documented that flood waters often pick up large quantities of wastes and pathogenic bacteria from farms, sewer systems, latrines, and septic tanks. Overcrowding of the survivors after disasters may aggravate the situation, particularly if sanitary conditions are poor.
Any breakdown in vital services, such as water supply or electricity, also adversely affects the quality of food. In the absence of electricity, cold storage may be more difficult, if not impossible, and foods may be subject to bacterial growth. This may be obtained at any stage of the food chain, from production to consumption. Lack of safe drinking water and sanitation hampers the hygienic preparation of food and increases the risk of food contamination.
Food safety has become a constant global concern apart from affecting human health; factors such as international trade and food security are also influenced. Consequently, most research institutions, healthcare institutions, and governments of several African countries have conducted comprehensive studies on the effect of water on food safety in various production chains. According to a recent study, the main water issues that affect food safety in low income countries include bacterial pathogens, followed by pesticide residues and healthy diet [40]. Although the reported evidence of food-borne disease is still limited, the known incidences of food borne disease in low income countries such as sub-Saharan African largely emanate from three major sources, namely biological hazards and chemical and physical contamination.
Water and food contaminated by microorganisms are major contributing factors for the emerging diarrheal diseases in the developing countries, and over 1 billion children under the age of 5 years are affected worldwide [26]. The high prevalence of deaths related to food and water contamination in developing countries could be attributed to several factors. For example, in many African countries, milk and dairy production constitute an important source of livelihoods for most peasant and smallholder farmers. Furthermore, animal production has become part of agricultural diversification strategy for most African countries in an attempt to ensure food security. The intensification of animal production has also generated a considerable impact on the environment considering the fact that milk provides suitable condition for the growth of different kinds of microorganisms, and microbial hazards are the most important concern within the dairy industry.
Biological agents associated with water contamination that have an impact on food safety include enteric pathogens such as bacteria, viruses, and protozoa. A study conducted in North-West Province of South Africa reported that multi-drug resistant Staphylococcus aureus strains were detected in samples of raw, bulk, and pasteurized milk [43]. Other common biological contaminants are Escherichia coli. The E. coli bacteria belong to the intestinal microbiota of humans and animals and are generally not harmful. Certain E. coli strains, however, harbor virulence factors and can cause intestinal and extra-intestinal diseases. For example, Shiga toxin-producing Escherichia coli zoonotic bacteria have globally been associated with various foods of animal origin, especially beef and sheep meat [40].
Apart from animal product contamination, biological contaminants may also occur in crop products. Foodborne outbreaks from fruit and vegetable produce have caused economic loss, food wastage and loss confidence regarding the safety of fresh produce from most African countries. Studies on the safety of fresh produce have identified water as one of the key risk factors that contribute to contamination of the farm produce. Indeed, studies have shown that most foodborne diseases are caused by consumption of fresh, perishable foods sold in informal markets [44].
Generally, mycotoxins, heavy metals, and over-application of fertilizers and pesticides are considered to be the most important chemical factors impacting on food safety in most developing countries including the African region [45]. In nature, thousands of mycotoxins occur but only a few of them present significant food safety challenges.
Mycotoxins are secondary metabolites mainly produced by fungal species from the Aspergillus, Penicillium, and Fusarium genera. They often develop during production, harvest, and storage of grains and nuts in the presence of water [45]. In the food production process, mycotoxins are among the most potent mutagenic and carcinogenic substances known. Ingestion of mycotoxins poses chronic health risks such as hepatotoxicity, genotoxicity, suppression of immunity, estrogenicity, nephrotoxicity, teratogenicity, and carcinogenic effects [44].
The adverse health effects of mycotoxins are compounded by the fact that they are not completely eliminated during food processing operations and can contaminate finished processed food products [55]. The presence of mycotoxins, particularly the aflatoxins, has generated a lot of interest in the food products from African countries. The work by Maxwell (1998) evaluated the presence of aflatoxins in human body fluids and tissues in relation to child health in the tropics. The findings showed that in Ghana, Kenya, Nigeria, and Sierra Leone, 25% of cord blood samples contained aflatoxins, ranging from 7 ng/L to 65 μg/L. The major classes of aflatoxins that were identified in the African countries include B1 and M1. Figure 1 shows the chemical structures of the most prevalent aflatoxins in African countries.
Chemical structures of aflatoxins prevalent in African countries.
Heavy metals have also contributed negatively to the food safety status in most African countries. As such, human exposure to heavy metals in Africa has become a major health risk and has received the attention of national and international environmentalists [47]. Rapid population growth, increasing urbanization, and the increasing appearance of slums and townships as a consequence of poor planning coupled with increasing industrial activities are some of the major factors that have contributed to the accumulation of heavy metals in food products. Africa has large deposits of mineral resources, and mining activities have increased with poor environmental regulations and compliance. Thus, heavy metals have constituted agents of toxic pollution of water, air, soil, and food products.
An environmental assessment report by the United Nations Environment Programme (UNEP) released in 2011, showed that drinking water, air, and agricultural soil in 10 communities from southeastern Nigeria contained over 900 times permissible levels of hydrocarbon and heavy metals [47]. The report further indicated that heavy metal pollution is a continental public health challenge in the sub-Saharan African region. Another study conducted in the Democratic Republic of Congo showed a 43-fold increase in the urinary concentration of cadmium, cobalt, lead, and uranium in human subjects including children living in mining areas compared to controls [56]. The increase in the levels of the heavy metals was largely attributed to ingestion of contaminated food products and water with toxic chemical compounds. The increasing negative effects on food safety from water and soil pollution have, therefore, potentially put more people at risk of carcinogenic diseases, particularly in food producing areas.
Water is the most vital natural resource on the planet that many life forms depend on for survival. This chapter has shown how population growth, competition for water across sectors, and the exposure to infectious agents or toxic chemicals pose a serious threat to water security, food security, and human existence. There is increased pressure on all sectors to minimize water use by considering more efficient use of water and alternative sources of water. This is only possible if the normative criteria of the human right to safe drinking water which are accessibility, availability, and quality are enforced to ensure that all current and foreseeable water demands highlighted under SDG 6 are met. Little promising progress has been achieved, but much work still has to be done to make water sustainability a reality before the SDG target date of 2030. The present status of water potential in Africa suggests that synergies that adopt sharing of expertise, experiences, knowledge, analytical capabilities, and optimizing mechanisms for greater food safety assurance and awareness by looking at both chemical and microbial hazards in foods should be promoted in the continent.
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