\r\n\tIn the book the theory and practice of microwave heating are discussed. The intended scope covers the results of recent research related to the generation, transmission and reception of microwave energy, its application in the field of organic and inorganic chemistry, physics of plasma processes, industrial microwave drying and sintering, as well as in medicine for therapeutic effects on internal organs and tissues of the human body and microbiology. Both theoretical and experimental studies are anticipated.
\r\n\r\n\tThe book aims to be of interest not only for specialists in the field of theory and practice of microwave heating but also for readers of non-specialists in the field of microwave technology and those who want to study in general terms the problem of interaction of the electromagnetic field with objects of living and nonliving nature.
",isbn:"978-1-83968-227-8",printIsbn:"978-1-83968-226-1",pdfIsbn:"978-1-83968-228-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8f6a41e4f5ce0e9c48628516d7c92050",bookSignature:"Prof. Gennadiy Churyumov",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10089.jpg",keywords:"Electromagnetic Wave, Microwave Energy Application, Electromagnetic Energy Generation, Intelligent Microwave Heating, Microwave Organic Chemistry, Microwave Reactor, Microwave Discharge, Microwave Plasma, Microwave Drying System, Tissue Microwave Heating, Measurement Automation, Industrial Microwave Process",numberOfDownloads:224,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 3rd 2020",dateEndSecondStepPublish:"July 24th 2020",dateEndThirdStepPublish:"September 22nd 2020",dateEndFourthStepPublish:"December 11th 2020",dateEndFifthStepPublish:"February 9th 2021",remainingDaysToSecondStep:"7 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Prof. Gennadiy I. Churyumov is a professor at two universities: Kharkiv National University of Radio Electronics, and Harbin Institute of Technology and a senior IEEE member.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"216155",title:"Prof.",name:"Gennadiy",middleName:null,surname:"Churyumov",slug:"gennadiy-churyumov",fullName:"Gennadiy Churyumov",profilePictureURL:"https://mts.intechopen.com/storage/users/216155/images/system/216155.jfif",biography:"Gennadiy I. Churyumov (M’96–SM’00) received the Dipl.-Ing. degree in Electronics Engineering and his Ph.D. degree from the Kharkiv Institute of Radio Electronics, Kharkiv, Ukraine, in 1974 and 1981, respectively, as well as the D.Sc. degree from the Institute of Radio Physics and Electronics, National Academy of Sciences of Ukraine, Kharkiv, Ukraine, in 1997. \n\nHe is a professor at two universities: Kharkiv National University of Radio Electronics, and Harbin Institute of Technology. \n\nHe is currently the Head of a Microwave & Optoelectronics Lab at the Department of Electronics Engineering at the Kharkiv National University of Radio Electronics. \n\nHis general research interests lie in the area of 2-D and 3-D computer modeling of electron-wave processes in vacuum tubes (magnetrons and TWTs), simulation techniques of electromagnetic problems and nonlinear phenomena, as well as high-power microwaves, including electromagnetic compatibility and survivability. \n\nHis current activity concentrates on the practical aspects of the application of microwave technologies.",institutionString:"Kharkiv National University of Radio Electronics (NURE)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"24",title:"Technology",slug:"technology"}],chapters:[{id:"74623",title:"Influence of the Microwaves on the Sol-Gel Syntheses and on the Properties of the Resulting Oxide Nanostructures",slug:"influence-of-the-microwaves-on-the-sol-gel-syntheses-and-on-the-properties-of-the-resulting-oxide-na",totalDownloads:94,totalCrossrefCites:0,authors:[null]},{id:"75284",title:"Microwave-Assisted Extraction of Bioactive Compounds (Review)",slug:"microwave-assisted-extraction-of-bioactive-compounds-review",totalDownloads:12,totalCrossrefCites:0,authors:[null]},{id:"75087",title:"Experimental Investigation on the Effect of Microwave Heating on Rock Cracking and Their Mechanical Properties",slug:"experimental-investigation-on-the-effect-of-microwave-heating-on-rock-cracking-and-their-mechanical-",totalDownloads:28,totalCrossrefCites:0,authors:[null]},{id:"74338",title:"Microwave Synthesized Functional Dyes",slug:"microwave-synthesized-functional-dyes",totalDownloads:21,totalCrossrefCites:0,authors:[null]},{id:"74744",title:"Doping of Semiconductors at Nanoscale with Microwave Heating (Overview)",slug:"doping-of-semiconductors-at-nanoscale-with-microwave-heating-overview",totalDownloads:45,totalCrossrefCites:0,authors:[null]},{id:"74664",title:"Microwave-Assisted Solid Extraction from Natural Matrices",slug:"microwave-assisted-solid-extraction-from-natural-matrices",totalDownloads:25,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"252211",firstName:"Sara",lastName:"Debeuc",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/252211/images/7239_n.png",email:"sara.d@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"50142",title:"Non-viral siRNA and shRNA Delivery Systems in Cancer Therapy",doi:"10.5772/62826",slug:"non-viral-sirna-and-shrna-delivery-systems-in-cancer-therapy",body:'RNA interference (RNAi) is a conserved endogenous cellular process for post-transcriptional regulation in sequence-specific gene silencing. The regulatory RNA molecules include small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) provide the specific degradation of target mRNA in mammalian cells [1]. siRNAs are the products of long double-stranded RNA (dsRNA) molecules in cells, which are expressed transgenically or delivered exogenously. Synthetic siRNAs can be transfected into cells that specifically silence the expression of target genes. In the RNAi pathway, dsRNA (over 100 nt) molecules are cleaved into 21- to 23-nucleotide duplexed RNAs, termed as siRNA duplex, by endoribonuclease Dicer or RNAse III-type enzyme. The cleaved siRNA duplexes contain 5′-phosphate and two-base 3′ overhangs. siRNAs are incorporated into the endogenous RNA-induced silencing complex (RISC). One of the two strands of siRNA duplex is guide (antisense) strand, and the other is passenger (sense) strand. siRNA duplex is unwinded by RNA helicase activity. While the guide strand binds to the RISC, the passenger strand is degraded. The activated RISC binds to mRNA with base-pairing for sequence-specific degradation of complementary mRNA. The mRNA fragments cleaved by Argonaute (Ago) proteins are released from RISC and degraded by other endogenous nucleases. After mRNA degradation, the active RISC is rebuilt and can participate in another RNAi pathway [2, 3]. In the event, RNAi process decreases specific mRNA levels, and thus decreases target gene expression.
Among the nucleic acid–based drugs, siRNAs as potential novel drug candidates are offered a highly promising strategy in cancer therapy. The knockdown of abnormal gene overexpression, occuring in cancer by using siRNA, has been used in therapeutic applications [2]. Targets of chemical drugs are limited to certain classes of receptors, ion channels, and enzymes. In the treatment with siRNA, known sequence of any gene of interest is sufficient and its target choice is unlimited [4].
The potential advantages of siRNA treatment compared with other treatment methods are that siRNAs [5–7] (i) provide sequence-specific gene therapy; (ii) can specifically target many undruggable genes or downregulate gene products; (iii) are considered the safe therapeutics; (iv) are potent and efficient molecules and possess high gene silencing activity; and (iv) can be easily designed for any disease.
RNAi might be a promising new pharmaceutical area for treatment of incurable and severe diseases such as cancers and infections. RNAi applications have been recently achieved by using synthetic siRNAs and vector-based siRNA expression systems or short hairpin RNAs (shRNAs) synthesized within the cells by vector-mediated production. The expressed shRNAs from plasmid and viral vectors in nucleus are cleaved by Dicer in cytoplasm and siRNAs are formed. There both strategies have advantages and disadvantages. Vector-based siRNA expression systems have several advantages for applying RNAi compared to synthetic siRNAs. Both permanent and transient transfection with vector-based systems can be achieved, and thus vector-based system increases the period of siRNA-mediated inhibition of gene expression [8]. In addition, shRNA constructs are more stable than siRNAs [9]. Low amount (nM) of siRNA and less than five copies of shRNA are sufficient for stable transfection and for acheiving gene silencing effect [10]. The synthetic siRNAs can be easily synthesized in large amounts and chemically modified to improve stability, permeability, efficacy, and transfection control; however, the modified siRNAs are highly expensive [11]. siRNAs are not integrated into host genome. The modification of vector-based shRNA systems is difficult, but shRNA expression systems can be regulated or induced by appropriate promoters and termination sequences. Choice of promoter, loop structure of shRNA, length and arrangement of sense and antisense strands, and orientation of restriction enzyme regions are important for shRNA expression cassette preparation. Similar to the various RNAi applications for targeted gene silencing, the chimeric expression cassettes of siRNA and shRNA in the same expression unit might also be made [12].
Design of optimal siRNA sequence plays a key role for successful siRNA therapy. The choice of potent and specific siRNA sequences is important for minimization of immune responses and off-target effects. siRNAs are 19–27 base pairs in length, but mostly preferred to be 21 nt of siRNAs with a structure of 19 nt duplex region and two nucleotide overhangs at the 3′ end, usually TT and UU, which are important for recognition by the RNAi machinery. Increasing the length of the dsRNA may enhance its potency, dsRNAs with 27 nucleotides are up to 100 times more potent than the siRNAs containing 21 nucleotides. The longer (25–30 nt) duplexes act as a substrate for Dicer (Dicer-subtrate siRNAs). This Dicer-substrate siRNAs are more efficiently loaded into the RISC over the siRNAs with 21 bp and newly produced siRNAs from the long dsRNAs directly incorporated into the RISC complex. Thus, gene silencing mechanism can be facilitated [13, 14]. On the other hand, dsRNAs longer than about 30 bp can lead to interferon response, which is the defense mechanism against viral infection. The activation of interferon pathway causes non-specific mRNA degradation and apoptosis [15, 16]. The long dsRNAs activates innate immune response by interaction with protein kinase receptor (PKR) and Toll-like receptors (TLR7 and 8 are activated by ssRNA; TLR9 activated by unmethylated CpG; and TLR3 activated by dsRNA). The activation of these receptors induces interferon (IFN) and proinflammatory cytokines [10, 17].
In addition to immune responses, another important problem for efficient RNAi therapy is off-target effects of these molecules. The cause of off-target effects are the suppression of undesired or unpredicted genes other than the desired target genes. The absence of homolog sequences between siRNA and its target mRNA can cause cleavage of non-targeted mRNA regions. Off-target effects of siRNA can lead to problems in the interpretation of gene silencing studies, serious and unwanted side effects such as potential toxicity and even cell death [18]. There are many factors and mechanisms leading to occurence of off-target effects. These factors are the length of dsRNA or siRNA, the length and position of siRNA-target sequence mismatch, and coding sequences and untranslated regions in genes [19]. The mechanisms leading to off-target effects of siRNAs are (i) the regulation of unwanted transcripts by seed sequence homology to the 3′ UTR of cellular mRNAs, (ii) the saturation of RISC by affecting cellular miRNA activity of siRNAs in large amounts, (iii) the function of miRNAs as siRNAs or shRNAs because of similarities in gene silencing pathway, (iv) non-specific distribution by non-targeting systemic delivery, and (v) immunostimulatory motifs in siRNA sequences [14, 17, 20].
Many preclinical studies with siRNA indicated that it is a hopeful molecule for clinical research of various diseases. Up to date, at least 22 RNAi-based drugs have been evaluated in clinical trials [21]. The first clinical trial with siRNA was made in 2004 by Opko Health. The clinical studies of Bevasiranib, that is, siRNA targeting vascular endothelial growth factor (VEGF) to suppress ocular neovascularization in patients with age-related macular degeneration (AMD), continued to the phase III trial, but the clinical trials was terminated in 2009 because of its poor efficacy and causing vision loss. Allergan company has terminated the phase II clinical trials of siRNA AGN-745, targeting VEGF because of its off-target effects [21]. The clinical translation of RNAi can be possible with development of safe and efficient RNAi delivery systems that lack of off-target effects [7, 21].
Although siRNAs are used as the potential therapeutic molecules in cancer and other diseases, the most important challenge in the development of RNAi-based drugs is efficient and safe delivery of appropriate doses to target cells and tissues. Therefore, the development of siRNA-based viral and non-viral delivery systems are required to have an enhanced efficacy, improved stability, and minimized non-specific gene silencing such as off-target effects and immune responses. This chapter focuses on recent improvements in the non-viral siRNA delivery systems in cancer therapy.
Cancer is a multistep genetic disease, which develops as a consequence of changes in the control of cell proliferation and differentiation. In the transformation of normal cells to tumor cells, the affected cells undergo mutations such as downregulation of tumor suppressor genes and overexpression of oncogenes. RNAi-based therapeutics have been extensively used for knockdown of cancer-associated genes. The in vitro and in vivo studies with siRNA and shRNA have shown that silencing of genes related to tumor cell growth, invasion, angiogenesis, metastasis, and chemoresistance in various types of cancer [17]. RNAi technology, as a new approach for cancer therapeutics, offers many advantages over conventional cancer treatment strategies. Advantages of gene silencing by siRNA and shRNA are the high degree of specificity to target tumor cells and tissues, a capacity to inhibit target gene expression, a simple and rapid design, and synthesis [22]. While non-specific chemotherapy leads to death of cancer cells, it significantly damages the surrounding healthy tissues and organs, causing extensive systemic toxicity. The side-effects of chemotherapeutic drugs can be minimized with siRNA treatment.
Cancer cells have the ability to develop a resistance to chemotherapeutic drugs. RNAi-based therapeutics can simultaneously target multiple genes in cancer signaling pathway. The simultaneous silencing of multiple genes in cancer therapy have importance in terms of minimizing the multiple drug resistance caused by small chemical molecules given in high dose [23, 24]. This therapy inhibits survival signals and pathways that take part in the development of multi-drug resistance in cancer cells.
Oncogenes, mutated tumor supressor genes, survival and apoptotic genes, causing tumor initiation and progression, are major targets for RNAi-based therapy. Simultaneous suppression of one target gene or multiple genes has provided a significant advantage in cancer therapy. siRNAs can be designed for effective gene knockdown by targeting any gene or multiple genes in cells [25]. siRNAs are likely to be more effective than other antisense approaches because of many properties such as a highly specific mRNA degradation, cell-to-cell spreading of gene silencing effect, long silencing activity, improved stability in vivo, and their efficiency in lower concentrations [26, 27]. A single therapeutic strategy is insufficient for the inhibition of cancer growth and progression; RNAi as a new therapeutic strategy may be used as well as with chemotherapy, immunotherapy, anti-hormone therapy, and radiotherapy for achieving synergistic therapeutic effect.
In clinical trials, the most of siRNAs have been given by local administration. When siRNAs are delivered to target tissue locally, lower siRNA doses can be used for pharmacologic effect (e.g., saline-based formulation, or excipiants such as 5% dextrose) and any drug delivery approaches (e.g., liposome, nanoparticle, and complexes) [28]. However, systemic drug administration by intravenous injection is required for cancer diseases [7]. In systemic effect, siRNAs must encounter several extra- and intra-cellular barriers until it reaches the target cell and tissue. siRNAs cannot freely cross physiological and cellular barriers because of their high molecular weight and negative charge. The significant challenges of using siRNA are their poor cellular uptake, degradation by serum nucleases, and rapid elimination. These factors and barriers reduce therapeutic effect of siRNA. Therefore, efficient in vitro and in vivo delivery of siRNA-based therapeutics in cancer is dependent on the development of appropriate delivery systems. siRNA delivery systems should (a) protect siRNAs against degradation enzymes and serum proteins, (b) prolong the circulation time of siRNA, (c) provide siRNA stability in blood serum, (d) avoid sequestration in the reticuloendothelial system (RES), (e) avoid aggregation in serum, (f) minimize non-specific tissue and cellular uptake, (g) achieve target-specific siRNA delivery, (h) allow for immune evasion, (i) resist rapid renal clearance, (j) enhance vascular permeability to reach cancer tissues, (k) promote trafficking to the cytoplasm and uptake into RISC, and (l) have low or non-toxicity [7, 29, 30].
siRNAs have large molecular weight (~13 kDa) and are polyanionic nature (~40 negative phosphate charge) and are easily degraded by enzymes in cells, tissues, and bloodstream. In addition, siRNAs cannot easily cross the cell membrane [29]. The naked siRNAs are readily degraded by serum endonucleases. The half-life of circulating naked siRNA is less than 10 minutes because of its rapid clearance by the kidneys, so that they cannot reach to target cell efficiently. The gene silencing activity of unmodified or uncomplexed siRNAs is little or absent [31]. To solve this problem, two strategies are used: chemical modifications and conjugation of siRNA molecules or use of gene delivery systems for increasing efficiency of RNAi-based therapeutics.
Chemical modification is the major approach to overcome in vivo siRNA delivery problems. Chemical modifications of naked siRNAs have been performed to (i) enhance siRNA stability, (ii) protect siRNA from degradation, (iii) avoid recognition by the innate immune system and minimize immunostimulatory responses, (iv) minimize off-target effects, (v) reduce required dose for gene silencing, (vi) improve pharmacodynamic properties, (vii) increase delivery to target cells, and (viii) allow the delivery by systemic administration. The sugar, backbone and nucleobase modifications of siRNA, can significantly protect siRNA in both serum and cytoplasm. The commonly used chemical siRNA modifications are the incorporation of locked nucleic acids (LNA), phosphorothioate linkages, and 2′-o-methyl, 2′-amine, 2′-fluoro groups [7, 32, 33]. Chemical modifications must increase the stability of siRNA without affecting its gene silencing activity [23]. However, these substitutions may lead to off-target effects, cytotoxicity, reduced RNAi activity, and impaired biological activity [17, 34].
Other chemical strategies for siRNA are cholesterol, folate, and aptamer conjugation and peptide modification. siRNAs can associate with aptamers, ligands, and antibodies by electrostatic interaction or direct conjugation. The conjugation of these functional groups provides cell- or tissue-specific targeting and efficient delivery. As a result, the efficacy of silencing can be increased [1].
Viral and non-viral vectors have been extensively used in the siRNA-based therapy. Viral vectors encoding shRNA have a high gene transduction and gene silencing effects. Adeno-associated viral vectors, lentiviral vectors, and adenoviral vectors have been extensively used in gene knockdown studies [35]. The transfering of shRNA-encoding vectors into the nucleus of cells have obtained high and long-term shRNA expression. In addition, viral vectors can integrate the host genome [14]. Although viral vectors have a high gene transfection efficiency, the challenges such as inflammatory reactions, strong immunogenicity, insertional mutagenesis, and oncogenic transformation of viral vectors can cause important safety concerns. In addition, some viral vectors have low capacity for transgene insertion. To overcome these problems, non-viral vectors have been developed and used in siRNA delivery. Compared to viral vectors, non-viral vectors have several advantages such as lack of immunogenicity, low or no integration into genome, large-scale production, and use of wide variety of nucleic acids size [36]. However, the transfection efficiency of non-viral vectors is not as high as the viral vectors.
The non-viral delivery of siRNA and shRNA therapeutics to target tumor cells is a multistep process. To achieve efficient delivery and therapeutic gene silencing, siRNAs should be stable in biological fluids and must have above mentioned properties [37, 38]. The circulating siRNAs after systemic administration must be evaded from the reticuloendothelial system (RES). Negatively charged siRNAs gain the positive charge after complexed with cationic charged polymers. This positive charge facilitates cellular internalization of siRNAs; however, the cationic charge increase non-specific interactions by non-target cells, negatively charged serum proteins, and extracellular matrix. As a consequence of these non-specific interactions, clot-like accumulations or aggregations are formed. Complexes are entrapped in the endothelial capillary bed or taken up by RES recognition. While RES organs such as spleen, liver, and bone marrow uptake the major part of injected dose, the minor part of this reaches to tumors [25, 37, 39].
Non-viral delivery vectors prolong the biological half-life and mean residence time of siRNA, and they enhance accumulation of siRNA molecules in tumor tissues. siRNA therapeutics can be accumulated into cancer tissue by enhanced permeability and retention (EPR) effect as a result of discontinuous vasculature (permeation) and poor lymphatic drainage (retention) in the abnormal tumor blood vessels compared to the normal blood vessels. Tumor endothelium allows penetration of macromolecules [37, 38].
The other challanges of RNAi-based therapeutics delivery to the tumor tissues after systemic circulation are crossing of cellular membrane, intracellular traffic into the cells with endosomal/lysosomal compartments, release of siRNA or shRNA from carriers, and nuclear transport for vector-based siRNA/shRNA therapeutics and entry to cytoplasm for siRNA-based therapeutics. The cell membrane is an important extracellular barrier for siRNA uptake. The average size of a single siRNA molecule is less than 10 nm. Despite their small size, polyanionic nature and hydrophilicity of siRNA make crossing of biological membranes difficult [18]. To overcome this problem, the complexation of negatively charged siRNA with cationic polymers or lipids are performed. The net positive charge of this formulations facilitates binding to negatively charged cell membranes, following internalization by adsorptive pinocytosis. For cell-type specific delivery, targeting ligands, antibodies, and aptamer-binding non-viral vectors pass through the cell membrane by receptor-mediated endocytosis [1]. After crossing from the cell membrane, siRNAs and vector-based siRNAs/shRNAs encounter several intracellular barriers that include the endosomal trafficking, unpackaging of siRNA, and nuclear traffic. The intracellular traffic of endosomal content is important for succesful siRNA delivery. When siRNA released from the carrier reaches cytosol, RNAi mechanism is induced inside the cells. However, for the onset of RNAi effect, transfer of vector-based siRNA/shRNA to the nucleus is required. In the delivery process, early release of siRNA from endosome is required. If siRNA remains inside the endosome for long time, it will be degraded. Therefore, different agents (fusogenic protein) conjugated with polymers disrupt the endosomal membrane. In addition, polymers possess proton-sponge effect (polyethyleneimine, PEI), which have been used to induce osmotic swelling and subsequent disruption of the endosome [15].
Negatively charged siRNAs or shRNAs can readily bind to cationic polymers or load to the nanocarriers by ionic interactions. Nanosized complexes or polyplexes by electrostatic interactions and nanoparticle formulations by encapsulation have been developed for efficient siRNA/shRNA delivery. Thus, siRNAs can be protected from nuclease attack and cellular uptake of siRNAs via endocytic pathway faciliated. Many natural and synthetic polymers are used for gene delivery, such as polyethyleneimine (PEI), poly-l-lysine (PLL), chitosan, protamine, gelatin, atelocollagen, cationic polypeptides, cyclodextran polymers, dendrimers, poly-lactide-co-glycolide (PLGA), and polydimethylaminoethylmethacrylate (PDMAEMA) [34]. In addition, polyethyleneglycol (PEG) is widely used as a linker between polymer and ligand or nucleic acid or for binding of siRNA onto nanocarrier surface [40].
Among the non-viral vectors, chitosan or its derivatives are attractive where chitosan has been shown to be biodegradable, biocompatible, non-toxic, mucoadhesive, and non-inflammatory and has low cost of production. Chitosan is a cationic polysaccharide, consisting of N-acetyl-d-glucosamine and d-glucosamine units. In addition, chitosan has been designated as “Generally Recognized As Safe (GRAS)” by the FDA [41]. It has been widely used in in vivo siRNA and shRNA delivery applications because of positively charged amines, allowing electrostatic interactions with negatively charged nucleic acids to form stable complexes. The protonated amine groups allow transportation to cellular membranes and subsequent endocytosis into cells. Moreover, the high amounts of chitosan in siRNA complexes may lead to increase cellular accumulation of siRNA molecules and facilitate release of siRNA from endosomes to cytosol under high osmotic pressure in the endosomes of cells [42].
Chitosan-based nanocarriers are prepared by three different methods. These include simple complexation, ionic gelation (siRNA entrapment), and adsorption of siRNA onto the surface of chitosan nanoparticles [42]. The molecular weight and degree of deacetylation of chitosan influence its solubility, hydrophobicity, charge density, and thus the interaction ability with nucleic acids. The N/P ratio (ratio between chitosan nitrogen per siRNA phosphate) of chitosan/siRNA nanoplexes is an important factor for optimization of complex properties (size and zeta potential), transfection, and gene silencing efficiency. Increasing the N/P ratio not only helps to obtain a high transfection efficiency but also enhances toxicity. The excess of free chitosan in the formulations can interact with cell membrane and cellular process, and thus, may reduce cell viability [41].
Chitosan has a great potential in siRNA-based cancer therapy studies, because it can be safely and efficiently delivered to cancer cells. It is reported that chitosan or modified chitosan nanoplexes and nanoparticles as delivery system exerted antitumoral effects in different cancers [43–48].
Studies with chitosan formulations in different cancers
Howard et al. [43] developed chitosan nanoparticles using polyelectrolyte complexation method. The size of nanoparticles was between 40 and 600 nm. The endogenous enhanced green fluorescent protein (EGFP) silencing efficiency with nanoparticles was found to be 77.9 and 89.3% in human lung carcinoma cells (H1299) and murine peritoneal macrophages. The siRNA/chitosan nanoparticles reduced EGFP expression (43%) compared to untreated control in transgenic EGFP mice. They suggested that this chitosan-based system can be used in the treatment of systemic and mucosal diseases.
Salva and Akbuga [44] studied silencing effect of chitosan/VEGF shRNA nanoplexes in breast cancer cell lines. A significant VEGF gene silencing (60%) was obtained after nanoplexes application in MCF-7 cells. Salva et al. [44, 45] demonstrated the successful application of chitosan/siRNA or shRNA VEGF nanoplexes in in vivo breast cancer models. After intratumoral and intraperitoneal injection, comparison was made and higher tumor inhibition was obtained with intratumoral injection. qRT-PCR and Western Blot analysis showed that VEGF mRNA and protein expression was significantly reduced by chitosan nanoplexes.
Salva et al. [46] also studied the IL-4 encoded plasmid (pIL-4) to improve the therapeutic efficacy of siRNA targeting VEGF because of the anti-angiogenic effect of IL-4 molecule. Researchers prepared chitosan nanoparticles containing shRNA VEGF and pIL-4, and they have reported that co-delivery of shRNA VEGF and pIL-4 into chitosan nanoparticles caused additive effect on breast tumor cell growth in rat model (97% inhibition) [46].
In another study, Salva et al. [47] obtained enhanced silencing effect by using siRNAs targeting to VEGF and HIF-1α in different breast cancer cell lines such as MCF-7, MDA-MB-231, and MDA-MB-435. Two siRNAs were encapsulated into liposome coated with chitosan, and the co-delivery of siRNA VEGF and HIF-1α into liposomal form have significantly inhibited VEGF (89%) and the HIF-1α (62%) [47].
Yang et al. [48] reported that chitosan/siRNA VEGF nanoparticles prepared by complex coacervation method showed spherical morphology with a mean diameter of 110–200 nm and positively charged surface (20 mV). Chitosan nanoparticles were effectively transfected to mouse melanoma cells (B16-F10), and they have investigated 40% of the VEGF gene silencing efficiency in cells without any cytotoxicity.
Wang et al. [49] prepared the chitosan-TPP (tripolyphosphate) nanoparticles by ionic gelation method for the delivery of shRNA expressing vector to the human rhabdomyosarcoma (RD) cell line and for the inhibition of TGF-β1 expression. Suppression of TGF-β1 gene by chitosan nanoparticles containing shRNA has resulted in decrease of RD cell growth in vitro and tumorigenicity in nude mice.
Huang et al. [50] studied the effect of chitosan/shRNA VEGF nanocomplexes on angiogenesis and tumor growth in hepatocellular carcinoma (HCC). The administration of low molecular weight chitosan/shRNA VEGF complexes by intratumoral or intravenous injection demonstrated more effective suppression of tumor angiogenesis and tumor growth in the different HCC models. They showed that LMWC could effectively deliver shRNA into tumor tissue. shRNA VEGF concentrations in tumor tissue dramatically increased after intravenous administration of chitosan/shRNA VEGF complexes.
Studies with chitosan derivatives and conjugation with other polymers and ligands in different cancers
In order to increase the transfection efficiency of chitosan, different modifications are made on the structure of chitosan. Modified forms of chitosan such as carboxymethyl or trimethyl chitosan, trisaccharide-substituted chitosan oligomers, and succinated or galactosylated chitosan are formed. Chitosan is also conjugated with folic acid or PEG [51].
Jere et al. [52] used chitosan-graft-polyethylenimine (CHI-g-PEI) copolymer for delivery of shRNA Akt1 expressing plasmid in lung cancer cells. The formed complexes were silenced Akt1 onco-protein and significantly reduced the survival, proliferation, and growth progression of lung cancer cell. Akt1 silencing induced apoptosis in cancer cells. The suppression of Akt1 oncoprotein decreased A549 cell malignancy and metastasis. The therapeutic efficiency of CHI-g-PEI-shRNA Akt was found higher than PEI25K-shRNA Akt compared to carrier.
Noh et al. [53] prepared a copolymer containing additional cationic moieties linked with chitosan to enhance the cationic charge of chitosan. Therefore, chitosan derivation with poly-l-arginine (PLR) and polyethyleneglycol (PEG) (PLR-grafted CS) polyplexes were used for in vitro and in vivo delivery of siRNA RFP. PLR alone can be cytotoxic, thus conjugation of PLR to chitosan both decreased cytotoxicity of PLR and enhanced siRNA delivery efficiency. The pegylation of cationic polymers reduces the charge of polymers and limits the interaction with cell membranes. PEG-CS-PLR did not significantly reduce the cellular delivery of siRNA. Three intratumoral injections of 120 μg of PEG-CS-PLR/siRNA RFP complexes to B16F10-RFP tumor-bearing mice had decreased RFP expression at 90% level in tumor tissues. It is indicated that PEG-CS-PLR can be a useful carrier for delivery of oncogene-specific siRNAs.
Fernandes et al. [54] investigated folate conjugation to improve gene transfection efficiency of chitosan. When chitosan was conjugated with folate, the folate-chitosan-siRNA complexes have increased gene silencing efficiency because of promoted uptake in HeLa and OV-3 cell lines, which are known to have high folate receptor expression. Higher transfection efficiency and lower toxicity of folate-chitosan complexes are reported in folate receptor–positive cells.
Cell penetrating peptide-based systems may improve cellular uptake and gene silencing efficiency of siRNAs without side effects. Protamine is a cationic, non-toxic polypeptide that has membrane translocation and nuclear localization activities because of its arginine-rich amino acid sequences. In addition to its stabilization enhancing properties, protamine is known to exhibit cell penetrating activity and is an important compound for several cancer targeting systems [55].
Salva et al. [46] have developed ternary nanoplexes of chitosan/protamine/siRNA targeting VEGF in breast cancer cell lines for efficient siRNA uptake and inhibition effect. Ternary nanoplexes showed the highest cellular uptake than binary nanoplexes.
Erdem-Cakmak et al. [56] reported that addition of protamine to chitosan complexes increased the silencing of VEGF genes after using chitosan/shRNA/protamine nanoplexes. In terms of the gene silencing and transfection, when the molecular weight of chitosans were compared at the different cell lines including HEK293, HeLa, and MCF-7, low molecular weight chitosan (70 kDa) proved more efficient than medium molecular weight chitosan. Gene inhibition values in cell lines after transfection of binary and ternary complexes followed the rank HEK293>HeLa>MCF-7. In addition, any cytotoxicity was not found after the complexes.
Song et al. [57] used protamine/antibody fusion protein to deliver siRNAs targeting c-my, MDM2, and VEGF specifically to HIV envelope-expressing B16 melanoma cells and envelope-expressing subcutaneous B16 tumors. The positively charged protamine served as binding partner for negatively charged siRNA and showed cell internalization and release of the siRNA cargo. The antibody-protamine delivery system can target siRNA specifically to cells.
Choi et al. [58] reported that complexes prepared with low molecular weight protamine (LMWP) inhibited cell growth by suppressing VEGF expression in hepatocarcinoma cancer cells. In tumor tissues, the expression of VEGF was inhibited through the systemic application of peptide complex, thereby suppressing tumor growth.
Polyethylenimines (PEIs) are water-soluble cationic synthetic polymers. They can be synthesized in different lengths and different molecular weights such as branched (bPEI) or linear (lPEI) and low molecular weight (<1000 Da) or high molecular weight (>1000 kDa). PEI has a high cationic charge density because of the protonation of its primary, secondary, and tertiary amine groups positioned at every third nitrogen [59]. While in linear PEI all nitrogen atoms are protonable, in the branched form, two-thirds of nitrogens can be charged. PEI can lead to proton accumulation in endosome, which was brought in by endosomal ATPase with an influx of chloride anion. Proton accumulation in endolysosome counteracts pH decrease, inhibits nucleases and unbalances endosome osmolarity depend on CI concentration and results in osmotic swelling of endosome. This effect of PEI is named as “proton sponge effect”. PEI may enhance intracellular delivery by facilitating endosomal escape and induce lysosomal distruption, endosomal release, and DNA/siRNA protection from lysosomal degradation by buffering endosomes [60].
The molecular weight of PEI is important in the development of gene delivery and level of cytotoxicity in cells. The high molecular weight PEI has higher transfection efficiency than low molecular weight PEIs. PEI has a high electrostatic capacity, which can provide strong electrostatic interactions with the siRNA and contribute to cell membrane binding and internalization. Especially, the 25 kDa bPEI is one of the most effective non-viral vectors in gene silencing because of efficient endosomal escape. However, the high positive charge of bPEI leads to severe cytotoxicity and non-specific interactions with serum proteins [61, 62]. The cytotoxicity of PEIs can be decreased with modification of free amine groups or conjugation of cell binding and targeting ligands. Therefore, graft copolymers have been usually preferred as a delivery system.
Schiffelers et al. [63] prepared PEGylated PEI nanoplexes with Arg-Gly-Asp (RGD) peptide ligand containing siRNA targeting VEGFR-2 and investigated the effect of angiogenesis and tumor growth in tumor-bearing mice. This study indicated that nanoplexes containing siRNA VEGFR-2 reached tumor tissues after systemic administration. This delivery system has sequence-specific inhibition effect and reduced the tumor growth.
Jiang et al. [64] studied anti-VEGF siRNA/PEI-HA complex prepared by PEI-hyaluronic acid (PEI-HA). Complexes at the dose of 4.5 μg of siRNA/mouse were applied intratumorally to C57BL/6 mice by daily injection for 3 days. At 24 hours post-injection, the siRNA VEGF formulations were distributed mainly in the tumor, spleen, lung, heart, liver, and kidney. This study suggested that siRNA VEGF/PEI-HA complexes can be used for the treatment of cancer in the tissues having HA receptors such as the liver and kidney.
Park et al. [61] synthesized siRNA/(PEI-SS)-b-HA complexes and, after characterization, applied to in vitro and in vivo gene silencing for target-specific tumor treatment. This delivery system demonstrated an excellent in vitro gene silencing efficiency (50–80%). siRNA VEGF/(PEI-SS)-b-HA complexes were administrated intratumorally to colorectal tumor bearing mice every 3 days. After the treatment of tumor, VEGF gene silencing and reduction in tumor growth were seen.
Among cationic polymers, poly (l-Lysine) (PLL) is one of the mostly studied polymers used for nucleic acid delivery. It formed complexes with DNA smaller than 100 nm. Its complexes can target different cells after binding suitable ligands. PLL can be easily produced in large scale and is physiologically stable and biosafe [65]. PLL may protect siRNA from degradation effect of nucleases. However, PLL has some hurdless that impade its clinical application. PLL does not have the proton buffering ability to enhance lysosomal release of transported siRNA. It can be modified also by addition of ligands [66].
The ternary copolymer mPEG-b-PLL-g(ss-IPEI) was used for siRNA delivery to SKOV-3 ovarian cancer treatment. Nanocomplexes were administered to SKOV-3-implated Balb/c mice and tumor growth inhibition was observed [67].
Dendrimers are highly branched spherical and synthetic multifunctional macromolecules. The surface functional groups of dendrimers can be modified to enhance biocompatibility and decrease toxicity. Polycationic dendrimers such as poly(amidoamine) (PAMAM) and poly(propyleneimine) (PPI) dendrimers, because of the high density of positive charges on the surface, are highly attractive for delivery of negatively charged pDNA, antisense oligonucleotide (AsODN), and siRNAs. PAMAM dendrimers have primary amine groups on their surface and tertiary amine groups inside. Their amine groups are complexed with siRNAs. Thus, compact structure promote cellular uptake of siRNA and tertiary amine groups initiate the proton sponge effect to enhance endosomal release of siRNA [68, 69].
Waite et al. [70] conjugated cationic PAMAM dendrimers with RGD targeting peptides to enhance the delivery efficiency of siRNA to glioma cells. They suggested a promising strategy of RGD-conjugated dendrimers for siRNA delivery to solid tumors.
Liu et al. [71] investigated in vitro characterization and anticancer effect of PAMAM dendrimer-mediated shRNA against human telomerase reverse transcriptase (hTERT) in oral cancer. Dendriplexes had 110 nm size and +30 mV zeta potential which were favorable parameters for escape from the vasculature and intracellular delivery. shRNA hTERT dendriplexes were applied by intratumoral administration to tumors. Dendrimer-mediated shRNA TERT resulted in cell growth inhibition and apoptosis in vitro and tumor growth inhibition in vivo in the xenograft model. In addition, expression of HTERT and PCNA proteins was reduced in tumors.
Atelocollagen, which is produced from bovine type I collagen, has biomaterial properties such as high biocompatibility, biodegredability, and low immunogenicity. Atelocollagen forms a helix of three polypeptide chains and has positive charge, which enable its binding to nucleic acid molecules [72]. At low temperature, atelocollagen exists in liquid form (2–10°C), therefore, it can be easily mixed with nucleic acid solutions [72, 73]. Thus, atelocollagen can increase cellular uptake, nuclease resistance, and prolong release of nucleic acids. The size, charge, and sustained release of atelocollagen/siRNA complexes can be altered by ratio of siRNA to atelocollagen [74, 75].
Takei et al. [76] first studied anti-tumoral effect of atelocollagen complexes containing siRNA VEGF in vitro and in vivo. They showed that siRNA VEGF with atelocollagen inhibited tumor angiogenesis and tumor growth in PC-3 cell lines in vitro and xenograft tumor in vivo model.
Koyanagi et al. [77] reported that siRNA targeting vasohibin-2 (VASH-2) using atelocollagen complexes siginificantly inhibited ovarian tumor growth and angiogenesis in ovarian cancer xenograft model. The knockdown of VASH2 with atelocollagen/siRNA VASH2 complexes exerted a significant antitumor effect and helped in tumor vascularization.
PLGA has been widely used as gene delivery system because of its biodegredability, biocompatibility, and non-toxic properties. FDA has approved PLGA as a pharmaceutical excipient. PLGA nanoparticles enter the cells efficiently by specific and non-specific endocytosis. Nanoparticles can release the encapsulated drug slowly leading to sustained drug effect [25].
Murata et al. [78] investigated anti-tumor effect of long-term sustained release of PLGA microspheres encapsulating anti-VEGF siRNA. The release of siRNA from microspheres was sustained for over one month. Intratumoral injection of PLGA microspheres containing siRNA VEGF inhibited tumor growth.
Su et al. [79] prepared PEI-coated PLGA nanoparticles loaded with paclitaxel and Stat3 siRNA. PLGA-PEI nanoparticles more rapidly released Stat3 siRNA than paclitaxel. Thus, decrease of Stat3 expression by siRNA in human lung cancer cells (A549) and A549-derived paclitaxel-resistant A549/T12 cell lines reduced resistance of cell to paclitaxel. The released paclitaxel from nanoparticles killed the cancer cells that induce microtubule aggregation. In summary, inhibition of Stat3 expression decreased cell viability, increased apoptosis, and reduced cellular resistance to paclitaxel.
Cationic lipids are used as carrier for siRNA delivery. Liposomes and lipoplexes, as lipid-based delivery systems, have been widely used in local and systemic siRNA or shRNA delivery. Liposomes are microscopic vesicles that consist of single or multiple lipid bilayer, form in a sphere with an aqueous core. Nucleic acids can either be entrapped in the aqueous core of liposomes or attached to the lipid surface for delivery. The advantages of liposomes as delivery system include a high gene transfection efficiency, enhanced stabilization, easy penetration into cell membranes, efficient in vivo delivery, and flexible and versatile physicochemical properties. The disadvantages of liposomes are the short half-life in serum, lack of tissue specificity, rapid liver clearence, and cell toxicity [17]. Three different liposomes, such as neutral, anionic, and cationic liposomes, are used in the siRNA delivery studies [22]. Cationic liposomes for siRNA delivery can easily cross the cell membrane, promote escape from the endosomal compartment, and reach the target genes with good biocompatibility. However, cationic lipids can induce an interferon response and cause unwanted interactions with negatively charged serum proteins because of its high cationic charge density [32, 67]. Interferon responses can lead to not only change in gene expression but also show dose-dependent cytotoxicity and pulmonary inflammation [80, 81]. The toxicity and transfection efficiency of cationic lipids depend on length and structure of hydrocarbon chains of lipids [82].
Neutral lipids lead to less cellular toxicity and do not induce immune responses without the down-regulation of gene expression. However, neutral liposomes have shown low transfection efficiency because of their lack of surface charges [17]. The commonly used cationic lipids for siRNA delivery include 1,2-dioleoyloxy-3-trimethylammonium propane (DOTAP) and 1,2-di-o-octadecenyl-2-trimethylammonium propane (DOTMA) have combined with neutral lipids such as 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). This combination can enhance transfection efficiency. Because neutral lipids facilitate fusion to the host cell’s membrane, cationic lipids can facilitate electrostatically complexation with siRNA to obtain more stable formulation and entry to cells more easily [18]. Liposomes are usually more stable than lipoplex in biological fluids [5].
Lipid-based siRNA delivery strategies have shown as promising in cancer therapy. Tumor-targeting approaches have been used to enhance antitumor efficacy of these delivery systems. Specific delivery to target cells can be achieved by conjugation of ligands or molecules such as transferin or PEG on the surface of liposomes [20]. The targeting and prolonged circulation half-life of liposomes allow for the enhanced permeability of tumor vasculature, increased delivery to tumor tissue, and reduced side effects [34, 82]. Cationic liposomes containing siRNA targeting tumor-associated genes have been used to inhibit tumor growth and proliferation, induce apoptosis, and enhance the radiosensitivity of tumor cells [83–85].
Cationic lipids can interact with negatively charged siRNA by ionic interactions. Thus, self-assembly formed lipoplexes protect siRNA from enzymatic degradation, enhance cellular uptake of siRNA by endocytosis, enhance the release of siRNA from endosomal/lysosomal entrapment, and thus, promote siRNA accumulation in the cytosol [16]. Commercially available cationic lipid formulations such as Lipofectin®, Lipofectamine® (Invitrogen), Dharmafect® (Dharmacon), RNAifect® (Qiagen), and TransIT TKO® (Mirus) have been studied as tranfection reagents for siRNA delivery in vitro [86]. The ratio of lipid and siRNA (lipid/siRNA ratio) affects the colloidal properties of the lipoplexes (particle size and zeta potential). Lipid/siRNA or shRNA ratio is important to facilitate the cellular internalization of lipoplexes and to dissociate the nucleic acids in the cytosol. Lipid/siRNA ratio can be optimized in terms of biological activity [16]. Developing a lipid-based delivery system, choice of lipids, and appropriate formulations are essential to decrease cytotoxicity and increase the transfection efficiency of formulation.
To overcome the drawbacks of lipoplexes and liposomes, different nanostructures such as neutral lipid-based nanoliposomes, stable nucleic acid lipid particles (SNALP), and solid lipid nanoparticles (SLN) have been developed as siRNA delivery system. SNALPs are composed of cationic, neutral, and fusogenic lipid mixture. SNALPs increase cellular uptake and endosomal release of siRNA [4]. PEG-conjugated SNALPs represent exciting lipid-based systemic RNAi. The PEG-lipid conjugate improves the retention time to >10 hours [87]. Recently, Tekmira Pharmaceuticals [88] has developed siRNA-based drugs that are encapsulated in the SNALPs for delivery of siRNAs to target tissue by intravenous injection. SNALP-encapsulated siRNA targeting PLK1 initiated phase I trial in December 2010. Alnylam Pharmaceuticals [89] has developed first dual-targeted siRNA drug, SNALP-encapsulated siRNAs targeting VEGF, and kinesin spindle protein (KSP) for the treatment of hepatocellular carinoma. Phase I trial was initiated in April 2009 [90].
Tekedereli et al. [91] indicated that knockdown of Bcl-2 by intravenously administered nanoliposomal-siRNA Bcl2 (150 μg siRNA/kg) twice a week lead to antitumoral activity in breast tumors of orthotopic xenograft models. In addition, nanoliposomal-siRNAs have enhanced the efficacy of chemotherapeutic agents in the breast cancer therapy.
Landen et al. [92] studied neutral nanoliposomes incorporating siRNA targeting EphA2 in orthotopic mouse model of ovarian cancer. Three weeks of treatment with EphA2-targeting siRNA nanoliposomes (150 μg/kg twice weekly) reduced tumor growth. The combination therapy with paclitaxel reduced tumor growth.
Salva et al. [47] investigated the effect of co-delivery of siRNA HIF1-α and VEGF in liposomal form in the breast cancer cell lines. Chitosan-coated liposomal formulation for co-delivery of siRNA VEGF and HIF1-α were developed. The co-delivery of siRNA VEGF and HIF1-α was greatly enhanced in vitro gene silencing efficiency in the breast camcer cell lines (95%). In addition, chitosan-coated liposomes showed 96% cell viability. Salva et al. has suggested that siRNA-based therapies with chitosan-coated liposomes may have some promises in cancer therapy [47].
In conclusion, siRNA-based therapeutics are new and potential targets in cancer studies. In cancer, different mechanisms including angiogenesis, and cell growth were studied as target pathways. However, siRNAs have different hurdles in treatment because of their short biological life in blood, instability, and poor cellular internalization. In order to overcome these hurdles two solutions are present: one is modification of siRNA and the other is use of suitable siRNA delivery system. In cancer treatment, viral and non-viral delivery systems are evaluated as siRNA delivery. Although limited information is available related to in vivo delivery, more papers are present in literature. Viral delivery systems have serious problems. Therefore, non-viral systems are more attractable than viral systems for siRNAs. Cationic lipids, liposomes, and polymers such as chitosan, PEI, PLL, and PLGA are used as non-viral siRNA delivery system. However, more suitable carriers are needed for siRNA delivery systems.
Despite the renewed interest in safeguarding research output, the changing storage carriers due to the fragility of storage carriers, lifespan, and handling practices are a cause of concern for the university libraries [1]. University libraries cannot avoid working in the cloud as they have become adaptive to inevitable and unpredictable changes occurring within the digital environment [1]. The university community places much emphasis on research and publication not only because it is presumed that research enriches teaching and the learning process, contributing to the body of knowledge, but also because it is a major determinant of institutional prestige and that of the nation at large [2].
\nIrrespective of the technological changes, stored research output in universities must be secured for future availability and accessibility [3]. Cloud storage has become an alternative for the storage of research output. According to Yuvaraj [4], university libraries have continued not only as only new technology adopters but rather cutting-edge IT users. Clearly, cloud computing as a cutting-edge IT platform proves to be a lasting technological innovation that continues to rise in usage [5].
\nHowever, owing to the technological age, university libraries are faced with new opportunities for innovative educational practices, hence providing electronic library services. Almost all university libraries are primarily concerned with enhancing teaching, learning, and research through the provision of timely information resources. On that basis, researches by Gabridge [6], Gold [7] and Jones [8] revealed the need for libraries to provide research data services. In providing timely information resources, modern libraries’ digital collections must be stored for future use and as backups to ensure continuous accessibility by library users.
\nWitten and Bainbridge [9] explained that a digital library is a focused “collection of various forms of digital objects” such as text, audio, and video, as well as their methods for access, retrieval, selection, organization, and maintenance. Rosenberg [10] also reiterated that a digital library can refer to information resources which are accessed by and delivered to users electronically or via a network [11]. Primarily, in developing countries, microfilms, databases, CD-ROMS, hard disks, external drives have been the existing platforms for storing library digital information, though these come with major drawbacks. For instance, these storage devices are exposed to threats such as theft, inadequate storage space, virus attacks and unauthorized accessibility among others. These drawbacks have been a major concern for academic libraries’ thus an ongoing debate and discussion on the new technology “cloud storage” as an alternative storage media.
\nTo a large extent, studies confirm that modern university libraries have greatly shifted from traditional roles (paper-based services) to digital library services. This paradigm shift has paved the way for library services to be accessed and delivered via the web [12]. For university libraries, the issue of using cloud services to store digital collections is particularly important as technological changes have paved the way for library services to be accessed and delivered via the web [12]. As more data and information is generated and stored in the cloud, either by design or default, university libraries need to be confident of the security of the digital collections. There is a growing interest in the implementation of cloud storage services which exposes university libraries to a new set of threats and vulnerabilities. McLeod and Gormly [13] concluded that if cloud service providers are to be used, their security, viability, sustainability, and trustworthiness must be paramount.
\nStudies have demonstrated that that cloud computing in libraries has widely examined the rise of data-intensive services in academic libraries with less emphasis on cloud storage security [14, 15]. Most of these studies were based on individual or small-scale survey data concentrated in one country. Owing to the extant gap in wide-scale exploratory studies, the present paper explored the risks associated with cloud storage services and how university libraries can ensure safe research output. In this light, the paper contributes significantly to the body of literature by unraveling new evidence from universities located in Ghana and Uganda on how academic libraries can secure research output with cloud services.
\nThe following sections include research questions, related literature, theoretical framework, research methodology, results, a summary of key findings, conclusion and recommendation.
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What are the existing storage carriers/media for storing research output in university libraries?
What are the reasons for university libraries moving research output into a cloud infrastructure?
What risks are associated with cloud storage services for university libraries?
In university libraries, how can research output store on the cloud service be secured?
Libraries use several types of media in storing digitized content or information (audio, video, text, images etc.). Each of the media suffers disadvantages with regard to reliability, high lifespan, ease of access and validation plus various costs. Enakrire and Baro [16] argued that these media include;
Magnetic disk drives are disk drives which are mostly mounted on computers. They are inexpensive, of very high-density, fast to use, and multiple user connectivities to the server are possible.
Magnetic tape, which comes in various formats and can only be effective for duplicate or backup copies. However, they are not recommended for primary storage.
Optical disks, for example, CD-R and DVD-R cost less, use low energy but exert high labor costs, poor accessibility, a periodic verification is not cost-effective and low density by today’s standards. Others are CD-RW and DVD-RW these are recommended for individual and day-to-day use but are not recommended for data preservation [17].
Until recently, evidence from the pool of literature shows that the concept of cloud is of the growing research area. Indeed, a lot more storage capabilities exist in the cloud. According to Mavodza [18], cloud computing is the delivering of hosted electronic services over the internet. Scale [19], opines that it is: “the sharing and use of applications and resources of a network environment to get work done without concerns about ownership and management of the network’s resources and applications, data are no longer stored on one’s personal computer, but are hosted elsewhere to be made accessible in any location and at any time”. Gosavi et al. [20] iterated that cloud computing harnesses the capabilities of resources like storage, scalability, and availability, which are accessible to university libraries as clients. Hence, depending on the needs of the clients, the infrastructure can be scaled up or down.
\nIn developed or developing countries, cloud storage provides promising advantages to university libraries. According to Li [21], cloud storage reduces the cost of hardware and software, and it makes the storage and management of data on the internet possible. It also reduces the work of Information Technology (IT) professionals as most of the system’s work is performed by the hosting company. Payment for the cloud storage service is by pay-as-you-go, which is convenient for organizations such as academic libraries which have budget restraints. Han [22] enumerates cost-effectiveness, flexibility, and data safety as a rationale for cloud storage in academic libraries. Han [23] alludes the advantages that cloud storage has over traditional storage to “availability, scalability, off-site storage, on-demand, and multi-tenancy” which allows different applications or different users to access the same resources to fit their needs. Han further states that data stored in the cloud can be easily transferred and duplicated globally to minimize data loss due to natural disasters.
\nHaris [24] also gives an analysis of the benefits of cloud storage especially for libraries and these include high performance, an avenue for collaboration, less “need for in-house technical expertise, cost savings, and more timely access” to the latest IT functionality. Haris further states that the cloud also provides a better workflow, “automated software updates, redundancy”, and backups. Cloud storage provides collaboration, particularly for academic and research libraries. Through the use of cloud technology, a collaboration between libraries, researchers, and students is promoted. The cloud also enables remote access to a wide range of research materials.
\nIn this section, the role of cloud computing in university libraries, specific cloud storage platforms and the risks associated with cloud storage are reviewed.
\nKaushik and Kumar [25] contend that cloud computing can offer many interesting possibilities for institutions such as libraries. Cloud computing is quite significant as it reduces technology cost, increases capacity reliability, and storage performance for some type of automation activities like library services. In recent times, cloud computing has made strong inroads into other commercial sectors and is now beginning to find more of its applications in the library and information environment.
\nAfter the personal computer and the internet, cloud computing also known as the third revolution is completely new in terms of technology. Potentially, cloud computing is an unraveled technology in university libraries as digital content can be stored in the cloud. Mobile devices are enabled using cloud computing by taking out an item or scanning a barcode [26]. Gosavi et al. [20] argued that when using cloud computing, users can be able to browse a physical shelf of books located in the library, choose an item or scan a barcode into his mobile device. More so, heritage materials or documents can be digitized, searched and accessed by library patrons. The new concept of cloud libraries includes OCLC, Library of Congress (LC), Exlibris, Polaris, Scribd, Discovery Service, Google Docs/Google Scholar, WorldCat and Encore [27].
\nNowadays, studies appear to be emerging in cloud computing. For instance, a paper presented by Saleem et al. [27] indicated that university libraries have adopted cloud computing technology to enhance library services by adding more values, attracting users and cost-effectiveness. In the cloud computing environment, clouds have vast resource pools with on-demand resource allocation and a collection of networked features. The new concept of cloud and libraries has generated a new model called cloud libraries.
\nIn the work of Zainab et al. [28], it was reported that the first reason of shifting research report into cloud computing is to reduce the total cost of ownership and maintenance of the cloud infrastructure. Secondly, scalability of the cloud service system is another objective, so that it is able to handle increased traffic. Due to the rapid expansion of the user group, we need to redesign the back-end web server with scalability in mind, such that it is able to accommodate an increasing number of concurrent users.
\nBased on the web traffic statistic, the average visit per month for the year 2012 is approximately 87,000 users and we expect the numbers will grow in the coming years as resources in the repository also grew. The high volume of transaction is causing The server to behave extremely sluggish and crashes frequently [28]. On the hand, migration is necessary in order to meet the increasing demand for storage space for full-text digital resources. File sizes of some digital resources are extremely large especially audio, video and images. Besides, as more users’ access and upload articles to the magnetic hard drives, university libraries face problems in fulfilling the storage space demand. The cloud storage service which promises and contributes to about 13 terabytes of storage space, can store over 12 million digital files of research output. Thus, it is very obvious that without a long-term plan, university libraries would not able to sustain the present storage demand from users in the future until alternative storage is assessed.
\nIt is expected that migration of digital files would reduce downtime when scheduled backup and indexing, as well as site traffic, occur simultaneously. The previous system backup was very laborious and time-consuming. Often scheduled jobs would cause unnecessary downtime of the magnetic and optical systems. System downtime is unavoidable because the system was hosted without a redundant server.
\n\n
Amazon S3: Amazon Simple Storage Services (Amazon S3) provides a secure, durable, highly-scalable object storage (Amazon, 2015). It uses a web service interface to store and retrieve any amount of data. It is a pay as you use service. There are different storage classes designed for different uses; Amazon S3 standard, Glacier for long-term archive. The services include backup and archiving, disaster recovery, and big data analytics [29].
Google cloud storage: Allows storage and retrieval of any amount of data at any time. It facilitates the storage of data on Google’s infrastructure with high-reliability performance and availability (Google, 2015) [29]. The services include data storage, large unstructured data objects, uploading data, and managing data. The lowest storage class is $0.01 GB/month.
Microsoft Azure: Azure supports the selection of wide services including operating systems, frameworks, tools, and databases. It’s typically a platform-as-a-service and software-as-a-service. It provides secure private connections, storage solutions, and data residency and encryption features (Microsoft, 2015). It provides scale-as-you-need, pay-as-you-go service plan, and strong data protection security.
Other cloud storage platforms include Dropbox, SkyDrive, Box, Google Drive, Flickr, Google music, Apple iCloud, and Amazon cloud player.
Lili and Buer [30], highlighted that advancement in technology may not necessarily transform the cloud services into mainstream technology in academic libraries. A scan of literature [31, 32, 33], revealed that cloud security, interoperability, and regulatory perspectives are worrying. In addition, academic libraries may or may not completely lose control over IT and data. Sometimes, trust in the service provider, data portability, migration, copyright issues, and privacy is a big risk when it comes to adopting cloud computing technology.
\nPolicies guide institutions and operations on what to do and not to do. Cloud storage and applications are valuable resources that allow academic libraries to store large amounts of information and perform collaborative tasks more effectively. However, there are risks associated and that must be mitigated in order to properly secure the research assets placed into the cloud [32]. In this light, it is purposeful for the policy to provide the framework within which the libraries will be expected to operate for storage and process information in cloud environments. Basically, the policy should encompass the scope of work, software, research information, human resource, users, copyright and many more.
\nOnce a digital collection (scholarly works, publications/collections, and historical documents) is put on the cloud, it becomes available for all groups of users and this can be exposed to unauthorized access to data centers. “Cloud operators can dictate the manner in which users can access, use and reuse content or information via specific online services or applications. That is, the user interface ultimately dictates what can or cannot be done by end-users, regardless of what they are theoretically entitled to under the law” [34]. So, the question is whether academic libraries can allow such law to be overridden on as it has already fallen in the public domain. This indeed is likely to impact on copyright law in the context of online applications.
\nCloud storage service providers are not guided by standard regulations. As a result, some service providers are tempted to offer low-quality services to developing countries in Africa thus creating loopholes for cybercriminals to take advantage. As an emerging trend, this issue of no interoperability is of concern, if research assets can be secured on the cloud. Interoperability refers to the ability of a collection of communicating entities to share specific information and operate on it according to agreed-on operational semantics [35]. Even though the clients (academic libraries) desire standards for cloud interoperability, the reality currently is that standard efforts only focus on portability, which is the ability to migrate workloads and data from one provider to another.
\nLibrarians cannot sit unconcerned in this matter since the open access (OA) repositories are also part of collections of the library [36]. Though the OA repositories facilitate sharing of resources in educational research through portals that are modeled as gates to several repositories, it is a challenge because data synchronization is an issue when components in different clouds or internal resources work together, whether or not they are identical. Communication between clouds typically has a high latency, which makes synchronization difficult. Also, the two clouds may have different access control regimes, complicating the task of moving data between them [37].
\nThus, interoperability is required, not just between different components, but between identical components running in different clouds [38]. Such components often keep copies of the same data, and these copies must be maintained in a consistent state. The design approach must address management of “system of record” sources, management of data at rest and data in transit across domains that may be under control of a cloud service consumer or provider and data visibility and transparency.
\nNurnberg et al. [39] argued that full interoperability includes dynamic discovery and composition: the ability to discover instances of application components and combine them with other application component instances, at runtime. Application interoperability requires more than communications protocols. It requires that interoperating applications share common processes and data models. These are not appropriate subjects for generic standards, although there are specific standards for some particular applications and business areas.
\nObviously, the cost is a challenge for academic libraries. More especially, enterprise cloud storage platforms such as Amazon S3 and Microsoft Azure are paid for as you use the cloud services. Unfortunately, libraries that find it difficult to fund basic services will see that as an extra cost inhibiting them to withdraw from the cloud service. The cost comes with human resource and sometimes maintenance of servers.
\nThe paper adopts the development of a Cloud Storage Security Framework (CSSF) to support an integrative approach to understanding and evaluating security in cloud storage in university libraries. The framework enables understanding of the makeup of cloud storage security and its associated measures. Drawing upon CSSF, it indicates that security in cloud storage can be determined by seven factors: (1) security policies implementation in cloud storage, security measure that relates to (2) protecting the data accessed in cloud storage; (3) modifications of data stored; (4) accessibility of data stored in cloud storage; (5) non-repudiation to the data stored; (6) authenticity of the original data; (7) reliability of the cloud storage services.
\nThe framework is summarized in Figure 1.
\nCSSF. Source: Yahya [40].
In applying the framework to the current research, security of research output in the cloud infrastructure can be determined by ensuring that all the seven factors are met by the university library.
\nThis study aimed to explore security issues considered in migrating research output to the cloud service as input into the development of preservation or storage systems within the library environment. This section described an approach followed in the study. This included the research approach, purpose, instrumentation, and sources of data. Our paper adopted the qualitative approach to explore cloud computing in university libraries in the sub-Saharan Africa. Using a wide range of evidence and discovering new issues, the purpose of the paper was to explore the risks associated with cloud storage and security implications. The exploratory design was significant as the authors became more familiar with basic facts, settings, concerns, and generating new ideas. In this study, interviews were conducted with respective librarians in charge of research output within the (4) universities. Hence, the research sites were purposefully selected to ensure that they provided sufficient opportunities to test available infrastructure for storing research output. Again, since the paper was interested in only libraries with repositories, the institutions without OA repositories were excluded.
\nAn interview schedule on the research questions was presented to 4 librarians from the universities. Thus, participants for the investigation were made up of librarians in charge of institutional repositories. These four university libraries selected were; Balme Library, (University of Ghana—Legon), Kwame Nkrumah University of Science and Technology—KNUST library (Ghana), HamuMukasa Library, (Uganda Christian University), and The Iddi Basajjabalaba Memorial Library, (Kampala International University—Uganda). The thematic content analysis was used to analyze the qualitative data. The authors further reviewed scholarly research articles, explored in the context of research data storage in and outside Africa.
\nThis section draws reference from respective university libraries in the context of cloud storage security for research data.
\nThe University of Ghana (UG), the premier university and the largest university in Ghana was founded as the University College of the Gold Coast by Ordinance on August 11, 1948, for the purpose of providing and promoting university education, learning and research. The vision of the university is “to become a world-class research-intensive University over the next decade”. To achieve the vision, it “will create an enabling environment that makes the University of Ghana increasingly relevant to national and global development through cutting-edge research as well as high quality teaching and learning” (
Established in 1948, the Balme Library is the main library of the University of Ghana. In addition to the Balme Library, there are other libraries in the various Schools, Institutes, Departments, Halls of Residence and the Accra City Campus which form the University of Ghana Library System (
In UG, research assets (theses, journals, newspapers) in the form of PDFs, word files, conference papers, videos, and audio have been generated. In the context of this study, the existing storage media for storing research data include CDs, DVDs, external drives, servers, hard drives, microfiche, and microfilms. Others include networked drives, Google drive and Dropbox used by researchers and the library in storing research assets.
\nThe interviewee indicated that digital storage and backup is important because;
\n“Data may need to be accessed in the future to explain or augment subsequent research. Other researchers might wish to evaluate or use the results of previous research outputs as precedence to conduct other similar or extended studies”.
\nAgrawal and Nyamful [41] corroborated the findings in the present study. Accordingly, they reported that storage devices which stores and maintains large sets of data over time play an important role in mitigating big data challenges. Factors such as capacity, reliability, performance, throughput, cost, and scalability are involved in any ideal storage solution system. They argued that reliability is basically the retrieval of data in its original form without any loss. The issue of reliability takes into account both internal and external system failures and vulnerabilities. With the scale of data, the probability of losing some data during retrieval can be very high. In order to ensure continuous accessibility of data, storage is very necessary.
\nIt was revealed by the interviewee that
\n“there is no robust or enough backup plan when the primary server goes down. With an average of 3000 visits per day on the Institutional Repository (IR), we wish to keep The website availability as high as possible. To solve the problem, the IR team decided to move digital files to a cloud environment using virtualization technology”.
\nA study by Ji et al. [42], revealed a compelling need for storage and management of research output. Given the current development of data (text, audio, video, images, etc.), university libraries are employing techniques such as data compression, deduplication, object storage, and cloud storage.
\nThe Librarian in charge of research data opined that
\n“Unauthorized accessibility, physical damage, theft, and hacking are particular concerns with electronic data. Many research projects involve the collection and maintenance of human subject’s data and other confidential records that could become the target of hackers and thus integrity must be maintained. The costs of reproducing, restoring, or replacing stolen data and the length of recovery time in the event of a theft highlight the need for protecting the computer system and the integrity of the data”.
\nThe Librarian iterated that several issues are associated with storing research data on the cloud.
\nOne interviewee pointed out that;
\n“Risks associated with cloud storage are crucial for the Balme Library. Storing research assets online via the Dropbox, mozy.com, Box.net, Adrive.com, Carbonite.com have proven the best alternative. However, a few associated risks include issues regarding property rights, copyright, data protection licenses or privacy. Other issues to consider is the fact that in the event of restoring data, it may be a bit slow and the service provider (Google Reader) could go out of service”.
\nKNUST Library has realized the need to digitize and store documents and research data generated by staff and students of the University, hence the decision to create the online Institutional Repository. The online repository showcases the intellectual output from the KNUST. In the earlier 2010, a server and scanners were acquired to support digitization processes. Since then, postgraduate thesis, reports, and few research articles have been uploaded unto the repository. Increasingly, the project has continued to receive acclamation internationally due to robust IT infrastructure in the library.
\nThe librarian for KNUST responded in this manner,
\n“Currently, the KNUST uses non-web based storage media to store data. There are two servers; one for the Library’s catalogue and another for the Institutional Repository. The library also uses an external hard drive as a backup, but both media are located in-house”.
\nReed et al. [43] asserted that “data backup plays an indispensable role in the computing system. Backup is one way to ensure data protection. By keeping copies of production data, backup protects data from a potential loss such as hardware and software loss, human errors, and natural disasters. The huge amount of data needing backup and archiving has reached several petabytes and may soon reach tens, or even hundreds of petabytes. The massive amount of data in today’s library environment may consume much storage.”
\nFurthermore, it was reported by the interviewee that
\n“The challenge faced with this kind of storage media is frequent memory crash, lack of expertise to manage the storage media, lack of space – the servers have low memory space, an interrupted power supply which uninterruptible power supply (UPS) is not even able to solve. Then finally, remote access to the information is denied because data is not online”. Thus, the need to seek cloud storage.
\nIt was evident from the interviewees that cloud computing environments are easily scalable and backup recovery is very easy in Infrastructure as a Service (IaaS) Providers, hence there is efficient incident response whenever data needs to be recovered.
\nThe authors sought to find what risks were associated with cloud storage. Cost and data security were concerns raised by the managers of the repositories. Agrawal and Nyamful [41] argued that the state of preventing a system from vulnerable attacks is considered as the system’s security. Security risks involved with the use of cloud computing have various risk factors for the library environment. Seven important identity factors for risk in a cloud computing model are access, availability, network load, integrity, data security, data location, and data segregation.
\nUganda Christian University has been in existence for 11 years having only one library which uses traditional devices. In the year 2015, the library launched its institutional repository. The storage media for storing research data in Uganda Christian University library is examined as follows:
\nUganda Christian University has both traditional and modern storage devices. Traditional storage includes CDs, flash disks, card catalog and later introduced modern storage like creating an institutional repository where dissertations and research papers are kept safely for future use.
\nThe Librarian in charge of the research data output of the Uganda Christian University observed that;
\n“For modern storage devices, Google drive is currently used to store documents such as student Theses works, proposals, and the day to day statistics. This started early last year when the learning commons was opened. This is used because it is cheap and can be accessed easily by staff and students while doing their work”.
\nIn this twenty-first century, information is not just in print but digitally created and reused by researchers and patrons within academic institutions. There is a need for digital information storage at Uganda Christian University because of the advantages. Prior to cloud storage, institutions invested heavily in data centers and servers even though they may not have used its storage space. The cloud storage allows institutions’ (academic libraries) only pay for computing resources they use. By using cloud storage one can achieve a lower variable cost than can be gotten on the traditional storage devices.
\nHowever, using cloud storage by Uganda Christian University academic library has some risks. Lack of internet access or less bandwidth is a major issue. Specifically, when the internet is down its difficult for data to be retrieved thus inconveniencing the patrons. Secondly, sensitive information for the institution can be disclosed accidentally or deliberately in cloud services if not handled well especially when demand grows. Thus, the inappropriate accessibility of the institution data can be compromised.
\nFor an institution like Uganda Christian University Library to ensure the safety of its research information in the cloud, the following must be considered.
avoid unauthorized accessibility of research data using strong passwords.
Privacy policy services settings must always be checked by appropriate management.
The Iddi Basajjabalaba Memorial Library (The IBML) is an integral part of Kampala International University (KIU). It is the intellectual hub of the university that supports the study, teaching, research and social information needs of the university. The IBML has grown over the years from one small room in 2001 manned by one member of staff and serving 700 users to an eight ultra-modern building serving over 20,000 users. The IBML system has evolved over time from the manual system providing print information resources to automated circulation services and digital information resources. In 2014, The IBML set up a digital repository to capture, store, and disseminate the intellectual content of the university. The digital content includes research articles, papers written by university staff, PhD theses, and other university publications. DSpace software was used for this project and it is hosted locally on a networked server. The repository data is backed up on an external hard drive with several terabytes of storage capacity.
\nThe IBML has not ventured much into cloud storage because data is still stored locally. Researchers, academic staff, and students typically use external hard drives, flash disks, CDs, DVDs, emails and Google Drive to store their data. Not many use Dropbox, OneDrive, and other Cloud storage media. However, this trend is risky because the library faces several challenges especially power outages that lead to a computer crash, theft of computer hard drives, and other storage media. There is also a danger of data breaches by unauthorized persons since the repository server is not within the confines of the library. Therefore, cloud storage is an important choice for the library to use in order to mitigate the danger of data loss.
\nFigure 2 depicts how university libraries provide library services via cloud services. Due to the unreliability of non-web based storage media, university libraries have refocused attention to an alternative; cloud service which is web-based. In providing library services to university faculty, students and researchers; research assets in the form of electronic theses/dissertation, articles, research datasets, research reports are stored in the cloud. It is important to note that cloud services provide advantages like large storage space, data back-up among others which non-web based media does not have. However, alternative storage media (cloud computing) appears to accommodate the concerns of university libraries. Putting in place, security of content, defining accessibility levels, adherence to copyright and legal issues, cloud storage policy, among others, safety of research assets on the cloud service is safer.
\nCloud computing in university libraries.
The paper discovered pertinent and important findings which were very vital for drawing a conclusion and informing policy makers.
\nFrom the study, it can be concluded that all the sampled academic libraries used magnetic disk drives (hard disk drives) for storing research outputs and assets and optical disks (CD-R and DVD-R).
\nFrom the empirical evidence, it is concluded that information enhances knowledge, which affects behavior, and leads to development warranting its preservation. University libraries have the digital format as text, audio, video, and image which facilitates easy sharing of information. Storage is needed for current and future generation of researchers and academia as a whole. In addition, digital storage makes information easily accessible to users as compared to “analog items”. This is due to the ability to easily copy the information on storage devices and carry around. Furthermore, digital storage facilitates the easy sharing of information.
\nSpecifically, copyright law infringement, unauthorized data accessibility, policy issues, the security of content, no interoperable cloud standards were identified as the risks associated with cloud storage in academic libraries.
\nCloud computing offers university libraries improved storage solutions. In the era of IT, the library and information environment face numerous challenges including constant change of storage platforms. Notably, the storage of research output is primary to the functions of university libraries. Thus, there is a need for storage security; as it is a reality in the current technological environment.
\nIn the developed world, some university libraries have already built and managed their own research data centers comparable to the developing world. Indeed, to avoid loss of data integrity, large digital storage in the cloud must be backed up, maintained and re-produced to avoid stress on the local server infrastructure. In conclusion, the opportunities offered by cloud computing via its storage services could ensure that university libraries gain more control over research output.
\nUniversity libraries must consider investing in cloud infrastructure as it assures large savings or cost effectiveness in operational cost and tech-start-ups [44], paying for what you use and risk transfer and availability [45], scalability, accessibility [4], on-demand service, access to a large network, rapid elasticity and resource sharing [46]. Above all, Gosavi et al. [20] pointed out that libraries are likely to benefit from cloud storage in the area of self-healing, multi-tenancy, linearly scalable, service-oriented, SLA driven, virtualized and flexibility of services.
\nThe paper contributes to knowledge by protecting research data in cloud storage systems. Furthermore, the implication of the findings gives significant input to policymakers, information professionals and future researchers. Finally, with qualitative data, the adopted framework indicates how the security of cloud storage can be implemented successfully.
\nThe authors recommends the following; security/confidentiality of content, the resilience of librarians, determining access levels and enterprise cloud storage platforms if research output can be secured on the cloud;
\nContent concerns raised by Cave et al. [47] and Genoni [48] require consultation with legislation or the legal office of the academic institution. This is to say that the type of records and length of time for keeping research output must be determined, and policy put in place. In a fast-changing library environment, the technology for storage of research output suffers from obsolescence hence the need for regular back-ups to avoid data loss. Whichever way one considers the issue, storage and access concerns are central, leading to the consideration to make the cloud a viable option.
\nThere is a need for university librarians to maintain the character of resilience and also be adaptive to inevitable and unpredictable changes that occur at an accelerated pace. It is therefore required of librarians to provide a wide variety of information from an equally varied selection of sources and formats through teams (working together) and particularly with the prevalence of cloud use. Since cloud computing enables almost a new streamlined workflow, cooperation through team building or network can be very laudable.
\nTo overcome the enumerated challenge of unauthorized access to data centers, academic libraries must be concerned with the levels of accessibility; ranging from completely open access to highly private. In securing the content of the research assets on the cloud, different levels of accessibility or privileges must be assigned to the different users within the network. For instance, students, researchers, librarians, users outside the university community must be assigned roles as such.
\nThe authors highly recommends the enterprise cloud storage platforms such as Amazon Simple Storage Services (Amazon S3), Google cloud storage and Microsoft Azure. This is because they provide secure, durable, highly-scalable object storage, allows retrieval of any amount of data at any time and high-reliability performance and wide services including operating systems, frameworks, tools, and databases.
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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. 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