Revisão sobre Nanopartículas: Propriedades Únicas e Aplicações em Biologia e Química, Notas de estudo de Engenharia Elétrica

Baixe Revisão sobre Nanopartículas: Propriedades Únicas e Aplicações em Biologia e Química e outras Notas de estudo em PDF para Engenharia Elétrica, somente na Docsity! R E V IE W DOI: 10.1002/adma.200703183 A R T IC L E Applications of Nanoparticles in Biology**By Mrinmoy De, Partha S. Ghosh, and Vincent M. Rotello*The wide variety of core materials available, coupled with tunable surface properties, make nanoparticles an excellent platform for a broad range of biological and biomedical applications. This Review provides an introduc- tion to nanoparticle–biomolecular interactions as well as recent applications of nanoparticles in biological sensing, delivery, and imaging of live cells and tissues.1. Introduction The use of nanomaterials in biotechnology merges the fields of material science and biology. Nanoparticles provide a particularly useful platform, demonstrating unique properties with potentially wide-ranging therapeutic applications.[1] The field of nanoparticles in biology is certainly a burgeoning one, with the estimated number of papers in the area (based onWeb of Science) rising from 11 in 1991 to nearly 10000 in 2007. Clearly, we cannot exhaustively cover the field, so this Review provides a brief overview of recent studies using spherical nanoparticles with metallic, metal oxide, semiconductor, and silica cores. The unique properties and utility of nanoparticles arise from a variety of attributes, including the similar size of nanopar- ticles and biomolecules such as proteins and polynucleic acids. Additionally, nanoparticles can be fashioned with a wide range of metal and semiconductor core materials that impart useful properties such as fluorescence and magnetic behavior.[2] The applicable properties of some well-known core materials and corresponding possible ligands used for surface functionaliza- tion with their possible applications are summarized in Table 1.[*] Prof. Vincent M. Rotello, M. De, P. S. Ghosh Department of Chemistry University of Massachusetts 710 North Pleasant Street Amherst, MA 01003 (USA) E-mail: rotello@chem.umass.edu [**] The NIH (GM077173) and NSF (Center for Hierarchical Manufacturing, DMI-0531171) are acknowledged. Adv. Mater. 2008, 20, 4225–4241
2008 WILEY-VCH Verlag GIn this Review we will discuss general approaches to the integration of nanoparticles with biomolecules. We will then discuss three major areas of nanoparticle application: (i) drug and gene delivery, (ii) biosensing, and (iii) bioimaging.2. Nanoparticle–Biomolecule Interactions Biomacromolecule surface recognition by nanoparticles as artificial receptors provides a potential tool for controlling cellular and extracellular processes for numerous biological appli- cations such as transcription regulation, enzymatic inhibition, delivery and sensing. The size of nanoparticle cores can be tuned from 1.5 nm to more than 10 nm depending on the core material, providing a suitable platform for the interaction of nanoparticles with proteins and other biomolecules (Fig. 1).[3] The conjugation of nanoparticles with biomolecules such as proteins and DNA can be done by using two different approaches, direct covalent linkage and non-covalent interac- tions between the particle and biomolecules.[4–9] The most direct approach to the creation of integrated biomolecule– nanoparticle conjugates is through covalent attachment.[10] This conjugation can be achieved either through chemisorption of the biomolecule to the particle surface or through the use of heterobifunctional linkers. Chemisorption of proteins onto the surface of nanoparticles (usually containing a core of Au, ZnS, CdS, and CdSe/ZnS) can be done through cysteine residues that are present in the protein surface (e.g., oligopeptide, serum albumin),[11] or chemically using 2-iminothiolane (Traut’s reagent).[12] Bifunctional linkers provide a versatilembH & Co. KGaA, Weinheim 4225 R E V IE W A R T IC L E M. De et al./Applications of Nanoparticles in Biology Table 1. Characteristics, ligands and representative applications for various metal and semiconductor materials. Core material Characteristics Ligand(s) Applications Au Optical absorption, fluorescence and fluorescence quenching, stability Thiol, disulfide, phosphine, amine Biomolecular recognition, delivery, sensing Ag Surface-enhanced fluorescence Thiol Sensing Pt Catalytic property Thiol, phosphine, amine, isocyanide Bio-catalyst, sensing CdSe Luminescence, photo-stability Thiol, phosphine, pyridine Imaging, sensing Fe2O3 Magnetic property Diol, dopamine derivative, amine MR imaging and biomolecule purification SiO2 Biocompatibility Alkoxysilane Biocompatible by surface coating 4226means of bioconjugation. Biomolecules are often covalently linked to ligands on the nanoparticle surface via traditional coupling strategies such as carbodiimide-mediated amidation and esterification.[13] For biological applications oligoethylene glycol (OEG) or polyethylene glycol (PEG) is used in the linker to enhance the stability of the attached biomolecules and minimize non-specific adsorption of other materials. Non-covalent assembly provides a highly modular approach to the biofunctionalization of nanoparticles. DNA–NP binding can be effected through electrostatic interactions, groove binding, intercalation, and complementary single-strand DNAMrinmoyDe received his B.Sc. in C Organic Chemistry from the Indian pursuing a Ph.D. at the Departme under the guidance of Prof. Vinc nanoparticles for biomolecular rec biomaterials. Partha S. Ghosh received his B.Sc Belur, India in 2002. He received hi 2004. He is currently a graduate stud at Amherst, USA under the guida focused on the use of nanoparticle Vincent M. Rotello received his B. Ph.D. in 1990 from Yale University 1990–1993. Since 1993, he has been currently the Charles A. Goessmann of synthetic chemistry to polymers www.advmat.de
2008 WILEY-VCH Verlag GmbH &binding.[14] Nanoparticles provide an attractive receptor for nucleic acids, providing a direct analogy to protein–DNA interactions.[15,16] One approach to particle–DNA assembly uses complementary electrostatic interactions to promote high affinity of nanoparticle–DNA binding. The use of cationic ligands on the nanoparticle surface provides a complementary surface for binding the negatively charged backbone of DNA, for example the use ofNP1 to recognize a 37-mer DNA duplex (Fig. 2a and b) by Rotello.[17] The binding of the DNA inhibited transcription by T7 RNA polymerase, indicating the high affinity of the NP–DNA complex, and pointing out ahemistry fromVidyasagar University, India in 2000 andM.Sc. in Institute of Technology-Bombay, India in 2002. He is currently nt of Chemistry, University of Massachusetts at Amherst, USA ent M. Rotello. His current research is focused on the use of ognition, their applications in biology, and the development of . in Chemistry from Ramamkrishna Mission Vidyamandira at sM.Sc. from the Indian Institute of Technology-Kanpur, India in ent at the Department of Chemistry, University ofMassachusetts nce of Professor Vincent M. Rotello. His current research is s for delivery applications. Sc. from the Illinois Institute of Technology, USA in 1985, his , USA and was an NSF postdoctoral fellow at M.I.T., USA from at the University of Massachusetts at Amherst,USA where he is Professor of Chemistry. His research focuses on the application , nanotechnology, and biological systems. Co. KGaA, Weinheim Adv. Mater. 2008, 20, 4225–4241 R E V IE W A R T IC L E M. De et al./Applications of Nanoparticles in Biology Figure 4. Schematic illustration of a) DNA-induced nanoparticle aggrega- tion, and b) sensing of DNA triplex binder using DNA-directed AuNP assembly. Figure 5. a) Cleavage of the substrate strand of DNAzyme in the presence of Pb2þ. DNAzyme mediated assembly of gold nanoparticles in b) a head-to-tail or c) a tail-to-tail manner.composed of a catalytic and a substrate strand. In the presence of Pb2þ, the substrate strand cleaves into two pieces (Fig. 5a), resulting in head-to-tail (Fig. 5b) or tail-to-tail (Fig. 5c) aggregation with a concomitant red to blue color shift with a sensing limit of 100 nM, which is unaffected by other divalent metal ions. Another attractive sensor approachuses apta- mers, single-stranded oligonucleic acid-based binding molecules that can bind a wide range of targets with high affinity and specificity.[61] An example is cocaine sensing, using a cocaine- specific aptamer (Fig. 6).[62] The sensor features a particle functionalized with two different sequences of single-stranded DNA, one for conjugation and anotherwith the cocaine aptamer. In the presence of cocaine the nanoparticles are deaggregated, with a concomitant blue-to-red color change. This method has been extended to mixed-aptamer systems that respond to combi- nations of analytes,[63,64] as well as the detection of other biomolecular systems such as plate- let-derived growth factors (PDGFs)[65] and thrombin.[66] Nanoparticles featuring ligands targeted at specific biomolecules provide another avenueAdv. Mater. 2008, 20, 4225–4241
2008 WILEY-VCH Verlfor the colorimetric detection of proteins. The bivalent lectin agglutinin specifically recognizes b-D-galactose, inducing the aggregation of galactose-functionalized nanoparticles at 1 ppm.[67] Other glyconanoparticles have been used for sensing various proteins such as Concanavalin A and cholera toxin.[68,69] Dithiols such as C- and N-terminal cysteinyl peptides can serve as bridging agents to assemble nanoparticles, and have been used for the colorimetric detection of proteases. In a representative study, Stevens et al. reported a two-stage approach by using Fmoc-protected peptides (substrate of thermolysin) with a cysteine amino acid attached to gold nanoparticles.[70] In presence of thermolysin the peptides are fragmented and the assembly changes color from blue to red with a sensitivity of 90 zg mL1 (i.e., less than 380 molecules of protease).[71] This approach has been extended to kinases[72] and phosphatases[73,74] at low concentration.3.2. Fluorescence Sensing The exceptional quenching ability of metallic nanoparticles makes them excellent materials for Förster resonance energy transfer (FRET)-based biosensors,[47] for example, for the fabrication of molecular beacons for sensing DNA.[75] In this approach, the dye molecule is close to the nanoparticle surface in the absence of the target DNA strand due to hairpin structure of the attached DNA, resulting in fluorescence quenching (Fig. 7a). Hybridization of the target DNAopens up the hairpin structure, resulting in a significant increase inag GmbH & Co. KGaA, Weinheim www.advmat.de 4229 R E V IE W A R T IC L E M. De et al./Applications of Nanoparticles in Biology Figure 6. Schematic depiction of the aptamer-based colorimetric detec- tion of cocaine by disassembling the nanoparticles. 4230fluorescence. A range of single-strand DNA and DNA cleavage processes have been monitored using this molecular beacon approach.[76,77] Semiconductor QDs have also been used for the sensing of DNAand proteins.Melvin et al. have developed a fluorescence competition assay for DNA detection using QDs and gold nanoparticles as a FRET donor–acceptor couple.[78] In presence of complementary oligonucleotides, the gold particle is released from the QD, regenerating QD fluorescenceFigure 7. Schematic representation of a) molecular beacon for the detec- tion of target DNA, b) quenching and reestablishment of emission from QDs by using gold nanoparticle and unlabelled complementary oligonu- cleotides and c) competitive inhibition assay for the detection of avidin by using QD-gold nanoparticle couple. www.advmat.de
2008 WILEY-VCH Verlag GmbH &(Fig. 7b). Kim and co-workers have used the similar method for sensing the avidin (Fig. 7c),[79] and glycoproteins.[80] Another paradigm for sensing relies on array-based sensing using selective recognition elements, that is, the ‘‘chemical nose approach’’. Rotello and collaborators have fabricated a sensor array by using cationic nanoparticles with various head groups and anionic poly(p-phenyleneethynylene) (PPE) fluorescent polymer.[81,82] In this sensor design, the cationic nanoparticles quench the fluorescence of the PPE polymer. Competitive binding of analyte proteins then release the PPE polymer, resulting in fluorescence restoration (Fig. 8a). Depending on the protein-nanoparticle interactions, different fluorescence response patterns were generated for individual proteins (Fig. 8b). Linear discrimination analysis (LDA) provided identification of unknown proteins which are iden- tified with 94.2% accuracy on the basis of 52 samples. The application of the AuNP-conjugated polymer systems have also been expanded to the detection of bacteria.[83] Similar to the protein detection, in presence of various bacteria, the initially quenched PPE polymers regain their fluorescence depending on the relative affinity between the bacteria and nanoparticles. The sensor array successfully identifies 12 micro-organisms with more than 95% detection accuracy.3.3. Electrochemical Sensing The conductivity and catalytic properties of metallic and semiconductor nanoparticles have been applied to electro- analytical sensing.[84] The attachment of nanoparticles onto electrodes drastically enhances the conductivity and electron transfer from the redox analytes.[85] Based on this concept, Willner et al. reported several systems using nanoparticle– enzyme hybrids as electrochemical sensors. In one example, a bioelectrocatalytic system was constructed by connecting the redox enzyme glucose oxidase (apo-GOx) onto a gold nanoparticle that was functionalized with N6-(2-aminoethyl) flavin adenine (FAD) (Fig. 9a).[86] This enzyme–nanoparticle hybrid system was linked to the electrode through dithiols, or alternatively the FAD-functionalized nanoparticle was assembled onto the electrode followed by the addition of apo-GOx. This system exhibited a highly efficient electrical communication with the enhanced turnover rates as compared to native Gox, and provided an effective sensor for glucose in the physiolo- gical concentration regime. An analogous electron transfer from protein to nanoparticles was used for monitoring hydrogen evolution from zinc-substituted cytochrome c immobilized TiO2 nanoparticles, as reported by Yeni Astuti et al. [87] Mirkin et al. have developed a method for the detection of DNA by selective deposition of oligonucleotide-functionalized nanoparticles between two electrodes.[88] In this approach short-chain oligonucleotides were deposited onto a SiO2 surface between two electrodes. In the presence of target DNA, oligonucleotide-functionalized gold nanoparticles hybridize on the the surface. Deposition of silver by usingCo. KGaA, Weinheim Adv. Mater. 2008, 20, 4225–4241 R E V IE W A R T IC L E M. De et al./Applications of Nanoparticles in Biology Figure 8. Schematic drawing of a ‘‘chemical nose’’ sensor array based on nanoparticle and fluorescence assay. a) The competitive binding between protein and quenched polymer leads to the fluorescence light-up. b) The combination of an array of sensors generates fingerprint response patterns for individual proteins. Figure 9. a) Fabrication of a GOx electrode by the reconstitution of apo-enzyme on a FAD-functional by the reconstituted GOx electrode in the presence of different concentrations of glucose. c) E hybridization with DNA-functionalized AuNPs followed by silver deposition. Adv. Mater. 2008, 20, 4225–4241
2008 WILEY-VCH Verlag GmbH & Co. KGaA,Agþ salt and hydroquinone on the gold nanoparticle enhances the conductivity pro- viding sensitivity down to 500 fMwith a point mutation selectivity factor of about 100000:1 (Fig. 9c).[88] A similar antigen–antibody- based protein sensor was designed by Velev and Kaler, detecting human IgG at 0.2 pM.[89]3.4. Other Sensing Methods Surface enhanced Raman scattering (SERS) has been successfully exploited in biological sensing using nanoparticles.[90,91] Mirkin et al. used gold nanoparticles labeled with oligonucleotides and Raman-active dyes to achieve multiplexed detection of different DNA targets.[92] The SERSmethod was also employed for the detection of the protein–small molecule and protein–protein interactions by fabricating the nanoparticles with proteins and Raman dyes.[93] Another ultrasensitive ‘‘bio-barcode’’ bio- sensor for proteins and nucleic acids has been developed by Mirkin’s group, where the oligonucleotide is amplified and then detected either by surface hybridization or by PCR amplification, providing a means forized gold nanoparticle. b) Plot of the current developed lectrical detection of DNA based on the ‘‘sandwich’’ Weinheim www.advmat.de 4231 R E V IE W A R T IC L E M. De et al./Applications of Nanoparticles in Biology Figure 13. a) Structures of nanoparticles used for transfection by Rotello. b) b-Galactosidase transfection using various nanoparticle-DNA complexes at 2200:1. c) Transfection efficiency of nanoparticles 9, 10, 11 (2200:1 nanoparticle/DNA ratio) and PEI (60 kDa). All transfections were performed in the presence of 100mM chloroquine and 10% serum. d)NP 12 fabricated by Klibanov with branched 2 kDa polyethylenimine (PEI2) conjugated to a gold core. e) Incorporation of PEI2 onto nanoparticles increases the transfection efficiency. Further addition of dodecyl-PEI2 to NP 12 increases the transfection efficiency. The numbers in the parentheses indicate the ratio of PEI nitrogen to DNA phosphate. 4234in facilitating transfection. Lin et al. have recently reported mesoporus silica nanoparticles (MSNs)-mediated delivery of DNA into plants.[108] In contrast to polycation-mediated transfection, cellular internalization of oligonucleotide-functionalized gold nano- particles carrying high negative surface potential has emerged as a new approach to gene therapy.[109] Antisense nanopar- ticles (ASNP) were effective in low concentration to suppress EGFP signal in C166 cells. Investigation on mechanism of cellular uptake of ASNP revealed that the endocytosis is initiated by adsorption of a large number of serum proteins onto the particle surface.[110] Rotello et al. have functionalized the monolayer of gold nanoparticle with a photo-cleavable o-nitrobenzyl ester moiety that dissociates upon light irradiation to alter the surface potential from positive to negative, thereby releasing adsorbed DNA (Fig. 14a),[111] as established in-cuvette by a T7 RNA polymerase assay (Fig. 14b). A FITC-labeled DNA was successfully delivered into mammalian cells with nuclear localization of the released DNA observed (Fig. 14c and d), an important requirement for genetic therapy.www.advmat.de
2008 WILEY-VCH Verlag GmbH &RNA technology has emerged as a potential tool for curing disease at an early stage. A small interfering RNA (siRNA), generally consisting of 19–21 base pairs, can efficiently slice the gene of interest. For in vitro delivery, siRNA has been conjugated by a thiol linker with variety of nanoparticles, such as gold,[112] quantum dots,[113] or iron oxide.[114] Moore et al. have designed a multifunctional superparamagnetic nanopar- ticle that can: (i) carry the siRNA, (ii) deliver it in a site-specific manner, and (iii) probe the delivery by magnetic resonance imaging as well as optical imaging.[114] The multifunctional nanoparticles were effective for in vitro and in vivo gene silencing via a specific pathway. Protein delivery is complementary to nucleic acid therapies in the field of biomedicine. Nanoparticles can efficiently bind protein, and hence be used as protein delivery systems. Lin et al. have fabricated MCM-41 type mesoporous silica nanoparticles (MSNs) as protein carriers (Fig. 15).[115] These MSNs can incorporate cytochrome c, a membrane-impermeable protein, into their large pores (diameter¼ 5.4 nm), and slowly release the proteins in active form under physiological conditions.Co. KGaA, Weinheim Adv. Mater. 2008, 20, 4225–4241 R E V IE W A R T IC L E M. De et al./Applications of Nanoparticles in Biology Figure 14. a) Depiction of photo-triggered release of DNA inside living cells. b) Illustration of light-induced surface transformation of nanoparticles. c) Fluorescence and bright field micrographs of cells after photo irradiation. To clarify the overlap of F-DNA and nuclei stain DAPI; green (Fluorescein) and blue (DAPI) channel are depicted with red and yellow color, respectively. d) Confocal microscopy images illustrating that the photo-released DNA accumulates inside the nucleus. Panels 1, 2, 3, and 4 show four consecutive slices of middle sections of z-series confocal images (interval¼ 1.0mm). Figure 15. Schematic illustration of cellular delivery of cytochrome c using mesoporous silica nanoparticles. Adv. Mater. 2008, 20, 4225–4241
2008 WILEY-VCH Verl4.2. In vivo Targeting of Nanoparticles A key goal of delivery systems is to discharge their payloads specifically at the diseased tissue. Two approaches to serve this purpose are ‘‘passive’’ and ‘‘active’’ targeting.[116] Passive targeting relies on the homing of the carriers to infected tissues. In tumor tissues, the blood vessels are frequently leaky, facilitating accumulation of nanosized carriers. On the other hand, active targeting relies on specific recognition of the ligands that are displayed on delivery vehicles by cell surface receptors. The ligand used for active targeting can be a small molecule, or a peptide or protein. Weissleder et al. have reported cell-specific targeting of fluorescent magnetic nanoparticles through multivalent attachment of small molecules.[117] For cancer therapy, folic acid (FA) or methotrexate (MTX) can be anchored onto nanoparticles for recognition by folate recep- tors, which are overexpressed on surfaces of many cancer cells. FA-grafted gold nanoparticles[118] or iron oxide[119] nanopar- ticles are specifically uptake by folate receptor-positive KB cells. Methotrexate provides an additional advantage as it can serve as a targeting ligand as well as a chemotherapeutic drug.ag GmbH & Co. KGaA, Weinheim www.advmat.de 4235 R E V IE W A R T IC L E M. De et al./Applications of Nanoparticles in Biology 4236Zhang et al. have shown that cells expressing human folate receptor (MCF-7 and HeLa) internalize MTX-conjugated superparamagnetic nanoparticles, killing the cells.[120] Many cancer cells overexpress receptors for the protein transferrin on their surface. He et al. have reported transferrin- mediated uptake of gold nanoparticles by tumor cells.[121] Nanoparticles have also been tagged with peptides or antibodies for targeting tumors in vivo.[122] Ruoslahti et al. have fabricated quantum dots coupled to different peptides, targeting nanocrystals to specific organs.[123] Paciotti et al. created a potential for cancer therapy based on colloidal gold (cAu-PEG-TNF) was decorated with PEG and protein tumor necrosis factor (TNFa).[124] Following intravenous injection into mice, cAu-PEG-TNF accumulated preferentially in MC-38 colon carcinoma tumors compared to other healthy organs, diminishing tumor mass more effectively than free TNF. The efficacy of this approach was further improved by grafting an anticancer drug, paclitaxel, onto colloidal gold.[125]5. Nanoparticles for Bioimaging A number of molecular imaging techniques, such as optical imaging (OI), magnetic resonance imaging (MRI), ultrasound imaging (USI), positron emission tomography (PET), and others have been reported for imaging of in vitro and in vivo biological specimens.[126,127] The current development of luminescent and magnetic nanoparticles advances bioimaging technologies.[128,129] Two different type of nanoparticles have been widely used for imaging: luminescent nanoprobes for OI andmagnetic nanoparticles forMRI. There are also dual-mode nanoparticles for simultaneous imaging by OI andMRI.[130,131]Figure 16. a) Size- and material-dependent emission spectra of several surfact CdSe/ZnS or CdS QDs. Adapted with permission from [134]. Copyright 1998 ZnS-capped CdSe QD that is covalently coupled to a protein by mercaptoac www.advmat.de
2008 WILEY-VCH Verlag GmbH &5.1. Optical Imaging Most nanoparticle-based optical imaging agents can be subdivided into two categories: quantum dots (QDs) [132] and dye-doped nanoparticle QDs. The use of QDs for cell imaging was first reported by Nie’s[133] (Fig. 16c) and Alivisatos’ groups in 1998.[134] Compared to conventional fluorophores, QDs are photochemically stable,[135] brighter, have a narrow, tun- able[136] and symmetric emission spectrum (Fig. 16a and b), and are metabolically stable.[137,138] There are, however, issues of toxicity, photo-oxidation, and water solubility associated with these materials.[139,140] The problem of acute toxicity and photo-oxidation can be overcome by capping with a protective shell of insulating material or semiconductor, for example, ZnS-coated CdSe core/shell QDs.[141] As water solubility is key to their applications in imaging, there are a range of methods reported tomake the QDs water soluble and biocompatible for biological imaging, such as fabricating the surface with suitable thiolated ligand,[142] over-coating with silica,[143,144] and encapsulating with amine-modified polymer.[145] Likewise, there are a number of strategies for their functionalization.[146,147] Taking the advantage of the size dependent emission of QDs Choi et al. determined the size- and charge-dependent renal clearance of QDs, a very important issue for the design of biologically targeted nanoparticles for medical applica- tions.[148] Their study revealed that zwitterionic or neutral QDs with hydrodynamic diameter >15 nm prevent renal extraction. whereas rapid and efficient elimination was observed for QDs <5.5 nm in diameter. 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