Drug Discovery Today  Volume 17, Numbers 19/20  October 2012 REVIEWS

Reviews  POST SCREEN
Silica-based nanoparticles for biomedical
applications
Ahmad Bitar1, Nasir M. Ahmad2, Hatem Fessi1 and Abdelhamid Elaissari1
1
Université de Lyon, F-69622, Lyon, France; Université Lyon 1, Villeurbanne, CNRS, UMR 5007, Laboratoire d’Automatique et de Génie des Procédés, LAGEP-CPE-
308G, 43 bd. 5 du 11 Nov. 1918, F-69622 Villeurbanne, France
2
Department of Materials Engineering, School of Chemical and Materials Engineering (SCME), National University of Sciences and Technology (NUST), NUST H-12
Campus, Islamabad, 44000, Pakistan

In this short review we highlight novel uses of silica-based nanoparticles (NPs) in the biomedical sector.
Silica NPs are widely used in nanotechnology because they are easy to prepare and inexpensive to
produce. Their specific surface characteristics, porosity and capacity for functionalization make them
good tools for biomolecule detection and separation, providing solid media for drug delivery systems
and acting as contrast agent protectors. In addition, they are used as safety and biocompatible
pharmaceutical additives. Here, we focus on novel techniques based on silica NPs for the most important
biomedical applications.

Introduction being widely utilized as an inert solid supporting or entrapping
Considerable efforts are now being devoted to the design and matrix [2].
fabrication of synthetic nanoscale biomaterial structures capable Consequently, intensive research has been performed to use
of functioning at molecular level in accordance to the combined SiNPs in diverse biomedical applications for diagnosing and con-
rules of biology, chemistry and physics. Generally, nanoscale trolling diseases, identifying and correcting genetic disorders and,
materials are defined as solid colloidal particles that include both most importantly, increasing longevity. Thus SiNPs offer consid-
nanospheres and nanocapsules. Because of their unique nano erable advantages and have opened new avenues of biomedical
size-dependent characteristics, these materials are starting to research in numerous leading edge applications, such as biosen-
emerge as undoubtedly the most interesting materials to shape sors [3], enzyme supporters [4], controlled drug release and deliv-
the future of different technologies, and they will have a profound ery [5] and cellular uptake [6].
influence on almost every aspect of our lives. To meet such high In view of the significance of silica-based nanomaterials for
expectations, researchers are trying to develop and employ a biomedical applications, as highlighted above, we review here
variety of nanomaterials, such as semiconductor quantum dots, some of the most specific milestones in ongoing research. We
carbon nanotubes, plasmonic nanoparticles (NPs), magnetic NPs do not consider the environmental aspects of silica NPs. However,
and silica nanoparticles (SiNPs). In comparison to other NPs, we highlight new widespread applications of silica-based nano-
SiNPs may appear mundane at first sight. However, from the materials in protein adsorption and separation, nucleic acid detec-
practical viewpoint, this does not appear to be the case. In tion and purification, drug and gene delivery, imaging and
nanotechnologies, silica-based NPs have a dominant role because pharmaceuticals.
of their fundamental characteristics, such as size (generally from 5
to 1000 nm), unique optical properties, high specific surface area, Protein adsorption and separation
low density, adsorption capacity, capacity for encapsulation, Due to their ease and speed of preparation, low cost, high specific
biocompatibility and low toxicity [1]. These features lead to SiNPs surface area and numerous surface functionalization possibilities,
SiNPs provide promising tools for specific protein adsorption and
Corresponding author: Elaissari, A. (elaissari@lagep.univ-lyon1.fr) separation. The interaction between SiNPs and proteins has been

1359-6446/06/$ - see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2012.06.014 www.drugdiscoverytoday.com 1147

c released by MSNs can serve as an active enzyme in aqueous lently with human serum albumin (HSA) protein. Reviews  POST SCREEN diagnostic assays and designing biosensors. Figure 2 branes. and site-spe- nanoparticles (MSNs) to transport cytochrome c through cell mem. was subjected to an activity test. studies have focused transportation and release by MSNs. Taking another direc.4 nm). This suggests that we can use these NPs for visual cytoplasm. REVIEWS Drug Discovery Today  Volume 17. and immediate solution.9] and the orientation of protein adsorption contents in the cytoplasm. Slowing et al. 1148 www. Kim et al. which proved that the cytochrome Ester-functionalized polypyrrole-SiNPs [11] can be bound cova. into the intracellular compartment [12]. Cytochrome c was loaded in on conformational changes [7]. cific protein labeling with multiple fluorophore species. isolation/purification.drugdiscoverytoday. Numbers 19/20  October 2012 studied extensively in the past. the cytochrome c released on SiNPs [10]. the influence of SiNP size on MSNs. [13] prepared dual mode silica-based NPs for specific tion. [12] succeeded in preparing mesoporous silica binding to his-tagged proteins. For example. In addition. Cytochrome c is loaded outside the cell membrane and released. Human cervical cancer cells (HeLa) have been selected flocculation is observed after the incubation of HSA functionalized for the intracellular delivery and release of cytochrome c into the NPs with anti-HSA. Figure 1 shows a presentation of cytochrome c intracellular presents the preparation and the function modes of nitrilotriacetic Mesoporous silica nanoparticle Cell membrane Cytochrome c Mesoporous silica nanoparticle Intracellular controlled release Drug Discovery Today FIGURE 1 Cytochrome c transporting into the cytoplasm using MSNs (particle size is 265–933 nm and pores approximately 5.com . which crossed the cell membrane and then released their enzyme activity [8. under physiological conditions. Abbreviation: MSNs: mesoporous silica nanoparticles.

after removing the Hb template. Depend. orientation. 200 nm in size and interacted with two protein models: C-terminal tion [17–19]. silica/boron-coated face of protein imprinted NPs. it was demonstrated that the protein HRP resisted leach- for protein immobilization. biosensors and bioseparation. Bovine serum albumin (BSA) was used as a His-rich products. [20] reported silica-coated work using NTA-polyethylene glycol (PEG)-modified SiNPs was magnetite NPs using the reverse microemulsion technique [21].com 1149 . acid (NTA)-modified dye-embedded SiNPs. Magnetite-containing spherical NPs were used for bioseparation. He et al. Shiomi et al. biocompatibility and a platform for fulfilling a approximately 30 protein units were captured per particle. due to their magnetic properties that provide an easy 6x his-tag and an internal 6x his-tag.drugdiscoverytoday. auguring well for highly specific biosensors. [16] were able to His-rich proteins were also targeted by silica-coated iron oxide copolymerize functional and cross-linking monomers on the sur. they have protein that presented reversible adsorption on zinc/silica-coated a magnetic core that can be used for fast particle separation by an magnetic NPs. NH4OH OH TFA-DCM-thioanisole. In New techniques have been used to design SiNPs as solid media addition. In addition. A similar wide range of functions. [15] covalently immobi. thereby conserving its peroxidatic activity. magnetite NPs [22] were prepared for specific interactions with Furthermore. to isolate his-tagged proteins and tagging with multiple fluorophore. silica-coated iron oxide NPs have attracted 6x His-tagged proteins. rt Me O H O 12 hrs. The modified NPs were approximately increasing attention as new tools for protein binding and separa. 100% Me O H O t-Bu Me O t-Bu N C N N C O + H2N Me O Si N O O t-Bu Me O Si N H O O t-Bu Me O Me O O 2 3 O 4 O O O (MeO)3SiPr(MPEG)6~9. immunoassays. HRP was distance between immobilized proteins and solid substrate are entrapped in the silica pores with entrapment efficiency in the controllable. The combination of two depended on the adsorption of zinc NPs on silica-coated magnetic materials makes it possible to enhance the properties of final NPs [23]. lized on prepared SiNPs. 23 nm. rt. ing from NPs for a period of more than 60 days. The SiNPs obtained external magnetic field. published [14]. and colloidal stability. range of 85–90%. ing on the type of vinyl-modified SiNP. Numbers 19/20  October 2012 REVIEWS O t-Bu O t-Bu O O DCM. Another preparation and fast method for NP separation. Abbreviation: his: histidine. NPs. His6-GFP and his6-biotin were specifically immobi. EtOH. In the case of silica coated iron oxide NPs. and a silica shell that provides greater showed high specific interaction with his-tagged proteins. areal density and and horseradish peroxidase (HRP) was used as a protein. Yang et al. Finally. have been suggested for various uses such as enzyme immobiliza- SiNPs functionalized for Hb recognition were obtained. Silica nanoparticles surface is modified by nickel ions Ni2+ for specific interaction with 6x his-tagged proteins [13]. Thus these structures can be used as purification www. and then NiCl2 6H2O Me O Si N C N N OH OH Reviews  POST SCREEN H Me O SiO2 5 O O TMR O OH2 O H O H O OH2 SiO2 H Ni 2+ H SiO2 O Si N C N N TMR Ni O H H TMR H O H r H O H Other H m H O O n H H proteins ER PEG x 1 His6-ER Cell lysate SiO2 Ni2+ TMR SiO2 SiO2 Em TMR Acceptor Donor TMR Ni2+ Ni2+ HHHHHH HHHHHH or Cy5 or FI ER ER L Em L FI SRC SRC Cy5 Drug Discovery Today FIGURE 2 Dual-mode functional preparation of modified silica nanoparticles. These biomole- lized the hemoglobin (Hb) on SiNPs and a second layer of silica was cular nanostructures entrapped in silica-coated magnetite NPs created on the surface.Drug Discovery Today  Volume 17. tion. and nitrilotriacetic acid/Co2+-linked.

magnetic NPs have become preferential tools for biomedical which is totally degraded by DNase I. plasmid DNA takes a non-compact form and through the employment of silica-based NPs for DNA detection. photostable signals was obtained. with Ru(bpy)32+-doped gold NPs on a gold electrode [32]. REVIEWS Drug Discovery Today  Volume 17. purification and analysis.75–0. On the contrary.drugdiscoverytoday. capacity and facility for DNA molecule tion. 60 nm silica particles were obtained and Amino-functionalization is one of the applications used in this silanized with 3-mercaptopropyltrimethoxysilane (MPTS). In a divalent salt with Ca2+ ions formation [25]. [29] presence of 0. and adsorption to silica is reversible. is 0.5 mM. then field. In a monovalent salt solution with Na+ ions having functionalized surfaces have enhanced biomedical research low ionic strength. Furthermore.7 M NaCl. Through such efforts. Mesoporous silica and/ lar DNA. interact with the nucleic acid molecules. Through significantly reduces the intramolecular electrostatic repulsion of understanding the nature of such interactions. and for more specific interaction between DNA and tion of oligonucleotides onto SiNPs using disulfide-coupling silica. Zhou et al. degradation by DNase I. functional groups were created onto the particle surface. Employing SiNPs in this technology has almost tripled detection sensitivity and has also increased selectivity. [33] studied the separation and purification. with only a small with separation properties while the functional shell is charged to fraction of supercoiled DNA being transformed into nicked circu. researchers have the DNA molecule. Nguyen et al. These dye-doped silica-coated gold NPs were used for efficiency and specificity. Interestingly.87 and adsorption is fast and irreversible. [27] synthesized amino-modified SiNPs. 300 mM NaCl is 0. In another work. The adsorption efficiency of these particles was four to five observed at an emission wavelength of 520 nm to evaluate the times higher compared to silica-coated magnetic NPs in the efficiency of hybridization. nopropyltrimethoxysilane (AHAPS). the attachment coefficient observed in the presence of interactions. kinetics and conformational changes of plasmid DNA adsorption on silica in monovalent and divalent salts. Kang et al. cules [36]. Nowadays. Non- SiNP uses for specific DNA detection porous silica-coated iron oxide NPs were prepared to isolate SiNPs are also employed to design DNA biosensors through their plasmid DNA from a bacterial cell lysate [37] and genomic functionalization with oligonucleotides by hybridization with DNA from plant cells [38]. The numerous options for preparing NPs with multi. although 30 parts of SiNPs completely or magnetic particles were prepared as adsorbents of DNA mole- protects the DNA. To do this. The magnetic core of such structures endows them SiNPs almost totally protects the plasmid DNA.01–0. conformation. this interaction Fourier transform infrared (FTIR) spectroscopy [26]. Increased sensitivity with specific regarding their targets. cost-effective and robust isolation method for DNA extrac- increased the competence. while a detection limit of 1  10 12 mol l 1 was achieved Reviews  POST SCREEN for diagnostics. and platinum [31]. They found that two DNA adsorption onto silica surface kinds of electrostatic interactions should be considered: interac- In line with this direction. chemistry. separation and purification. but without a functional surface these particles were not highly specific and DNA load depends on pore size. Numbers 19/20  October 2012 tools for this kind of protein. dehydration and hydrogen bond static repulsion is not effective. the addition of ten parts of applications. electrochemiluminescence DNA achieved. Nucleic acid detection and purification 1  10 13 mol l 1 of the target DNA was detected using a Significant information can be obtained from DNA molecules used Ru(bpy)32+-doped silica NP DNA probe on a platinum electrode [31].35]. DNA was successfully separated. The new techniques developed have fast. Due to their fast and easy separation. unlike free plasmid DNA. Furthermore. SiNPs are becoming more labeling in microarray-based detection. and oligonucleotide signaling probes were also silica-coated magnetic NPs. the interaction of DNA with silica that form complexes with the oxygen atoms of the phosphate surfaces through hydrogen bonds was studied by Raman and groups of double-strand oligonucleotides [34. The fluorescent signal was 25 nm. 1150 www. Thus the latter has become the foundation of molecular biology. [28] reported the immobiliza. and interaction as one of the most important techniques applied to the field of between subunits of the plasmid DNA that control molecule genetics. in the presence of 1 mM Ca2+ the attachment coefficient nopropyltrimethoxysilane (AEAPS) or N-(6-aminohexyl)-3-ami. Specific detection and quantifica. The average size of particles was from 10 to 100 nm with a surface charge potential from +7 to DNA extraction by silica-coated magnetic NPs +31 mV at pH 7. The adsorption of DNA onto the when increasing ionic strength. [39] reported the synthesis of amino-functiona- oligonucleotide probes were immobilized onto the SiNPs. it is difficult to separate the latter at this ratio. from saliva and blood with high immobilized. using amino-functionalized coated gold NPs. Conse- been able to develop silica surfaces for more specific and efficient quently.03. tion of lysozyme by aptamer-functionalized SiNPs [24] has been In another interesting work. fluorescent intensity. For example. Hilliard et al. Kneuer et al. with the concentration of lysozyme detected in the detection electrodes were developed based on SiNPs and gold [30] range of 0–22. SiNPs also have an important role in building and developing a genetic therapy and genetics. thus it adopts a highly compact form. intramolecular electrostatic repulsion is effective.4. Plasmid DNA was also used to study the Silica-coated magnetic NPs are commonly used to extract DNA interaction with prepared SiNPs to form a complex protected from from biological samples. This depends on the adsorption of target complementary DNA or RNA probes to attain variable plasmid DNA on the silica surface under a high salt concentration. nanotechnology has started to emerge tion between plasmid DNA and the silica surface. the plasmid DNA molecule takes a surface of SiNPs is generally controlled by three effects: weak more compact form. contrast. By based on the modification of SiNPs with N-(2-aminoethyl)-3-ami.com . which means that intramolecular electro- electrostatic repulsion forces. human genomic developed new core shell nanostructures based on silica/dye. which lized silica-coated magnetic NPs with an average particle size of were incubated for DNA hybridization. genetic investigations and therapy. DNA extrac- tion and purification is an important step of DNA manipulation.

thus researchers try to prepare posi. expression. example. They found that hydrophobic silica is silica surface functionalization. iron was considered as an optimum concentration for maximum sta- oxide [46]. In another work.drugdiscoverytoday. Bakalova et al. first condition is the gene loading. The outer silica shell provides compacted hydrophilic and hydrophobic SiNPs as pharmaceuti- an additional choice for targeting specific cells or tissues through cal excipients (glidants). Numbers 19/20  October 2012 REVIEWS Drugs and gene delivery delivery due to their small size and highly positively charged SiNPs used as carrier systems for drugs and genes have two different surface. Fe3O4-MSN NPs were accumulated at the tumor site.com 1151 . antitumor activity at the tumor site was Functionalized silica nanoparticles (FSN) should have two differ. and release mechanism. essentially nontoxic and nonirritant excipient in oral and topical cules are negatively charged. In this case weak interactions are pre. SiNPs are bilization. [54] applied this technique and reported mesoporous the drug in the pores. The investigated. gold NPs [40]. cellular These kinds of systems are highly efficient for drug delivery.1 to 10 [55]. plasmid DNA-bind. what is capability of Fe3O4-MSN to accumulate at the tumor site and more. To release the drug. They studied the moisture adsorption properties of silica and its stabilizing Imaging effect for a model aspirin tablet.Drug Discovery Today  Volume 17. a disulfide bond. doxorubicin nol (ME). such as amino groups [27]. confirming the drug delivery function of the NPs ent states in two different conditions for use for gene delivery. and viscosity increasing agents. only plasmid DNA-binding SiNPs produced robust gene Silica has a high surface area covered with polar silanol groups. as adsorbents. Multi-constituent kept in the pores of NPs. due to their low cytotoxicity. contrast agent protection and a large number of improve disintegration. functionalized SiNPs in gene delivery. silica was added to magnesium stea- generally used and applied in medical imaging because of char. However. Figure 3 illustrates the uptake bifunctional NPs suitable for both MRI and photothermal therapy. [50] reported the the most efficient glidant as it only requires gentle mixing con- intracellular localization of amino functionalized silica-shelled ditions to achieve high flowability. By contrast. in this case mice were used to test the ifications of the drug needed for loading in the pores and. the mesoporous silica ensure it stays inside them. Covalent interaction between the CdS NPs and silica-coated dye NPs associated with iron oxide NPs (Fe3O4-MSN). such as dithiothreitol (DTT) or mercaptoetha. However. Gore and Banker [56] used and transferred into the cell nuclei. This concept demonstrating the potential of multifunctional particles. imaging. ulomas. These are used to encap. Consequently. controllable size and was found to induce negative effects on lubrication and did not size distribution. The experimental results demon- SiNPs are used in medical imaging and its applications as contrast strated the water adsorption characteristics of silica and their agents have an important auxiliary role. the pore surface takes place after loading the drug inside the pores to with iron oxide as a contrast agent for MRI. In this condition. SiNPs are widely used in pharmaceutical 30 nm. pharmaceutical products. NPs can be forms. Jonat et al. dependence on surface area and pore size. they allow the transfer of a large number of drugs. The second neous injections may produce local tissue reactions and/or gran- condition is gene release. [49] prepared highly fluor. for from the NPs into the target. which requires good affinity between the genes and NPs. no additional mod. for nanostructures are widely used in imaging techniques. SiNPs. Bharali et al. Reviews  POST SCREEN is called gatekeeping [41]. In addition. These reducing molecule. intraperitoneal and subcuta- tively charged NPs. tablet segregates. these properties of silica to stabilize aspirin tablets. shell for drug delivery and dye NPs for fluorescence imaging. organic dyes [47] and quantum dots [48]. anticaking agents. deliver a drug. However. at low glidant www. (DOX). which was verified by MRI and orange RITC Functionalized silica nanoparticles for gene delivery applications fluorescence. [59] investigated the use of than their constituent fluorophores. and tested in two cases: (i) in vitro. suspending agents. thermal stabilizers. is needed to break the covalent bond and open the pores. [43] reported in vivo applications of amino-surface glidants. These NPs demonstrated good intracellular strongly depends on mixing conditions. meaning that it cannot be administered parenterally. The coated dye NPS for constructing dual imaging probes to perform uptake and release mechanism is dependent on the drug being both fluorescence and MRI functions [52]. rate [57]. The NPs prepared were photostable and 20 times brighter applications as glidants. as caps to close the pores. Iron oxide-doped SiNPs are used for Mesoporous SiNPs for drug delivery applications MRI cell labeling [51] and grafting has been performed on silica- Mesoporous SiNPs are used as carrier systems for drug delivery. which suggests that the gene was very well protected which is favorable for water adsorption. DNA mole. used as multifunctional tools such as contrast agents and drug/ gene/protein delivery systems. 0. on B16-F10 cells. mesoporous NPs and surface functionalized NPs. trifunctional NPs were loaded by an anticancer drug. Ow et al. the uptake and Pharmaceutical applications storage of the gene molecules by the NPs and the interactive nature Colloidal anhydrous silicon dioxide is generally regarded as an between them depends on electrostatic interaction. by using additional molecules. with a percent ratio varying from ing SiNPs and free plasmid were injected into mouse brains. ferable between the gene and FSN to assist the release of the genes because silica excipients are used for several functionalities. The effect of adding silica as an excipient possible surface functions. In addition. silver [45]. hydrophilic silica quantum dot micelles. because uptake of NPs was confirmed by both MRI and fluorescence they have efficient stimuli-controlled release. In addition. such as gold [44]. Lai et al. emulsion stabilizers. CdS NPs have the role of caps that keep Lee et al. (ii) in vivo. thus example. It was noticed that tablet strength was improved but it acteristics such as higher biocompatibility. also observed. 3% silica sulate contrast agent particles. [42] reported the synthesis of The technique of a core and multilayer shell was applied to mesoporous SiNPs with chemically removable CdS NP caps as synthesize gold coated and/or silica-coated iron oxide NPs [53] as carrier systems for drug delivery. taking amox- escent silica-coated fluorophore NPs with sizes ranging from 20 to icillin as an example [58]. on the bioavailability of the drug was investigated.

REVIEWS Drug Discovery Today  Volume 17.3 nm) [42]. Numbers 19/20  October 2012 OH Drug O Drug CdS S Drug Drug Drug Drug Drug Drug Drug CdS NH2 Drug Drug Drug Reviews  POST SCREEN S Drug Drug S Drug Drug CdS Mesoporous silica nanosphere Drug CdS Si Drug CdS nanoparticle Amidation CdS S Disulfide Linker O Drug Drug Drug CdS HN CdS CdS Drug Drug S Drug MSN S Drug CdS Drug CdS Drug Drug Mesoporous silica nanosphere Si OO O MSN Disulfide cleavage SH Dithiothreitol OH (DTT) HS OH SH Drug Drug Drug CdS CdS CdS Drug Drug SH SH Drug CdS Drug SH S Drug Drug Mesoporous silica nanosphere Drug Drug Discovery Today FIGURE 3 CdS nanoparticle-capped MSN-based drug delivery system. 1152 www.drugdiscoverytoday. CdS (2 nm) link to MSN (200 nm) by a disulfide bond that can be chemically reduced to release the drug from MSN pores (2.com .

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