Fluorescence; Fluorescence resonance energy transfer (FRET); Metal-ion sensing; Molecular wire effect

pradipta behera

doi:10.1016/J.TRAC.2011.04.017

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Fluorescence; Fluorescence resonance energy transfer (FRET); Metal-ion sensing; Molecular wire effect

pradipta behera

https://doi.org/10.1016/J.TRAC.2011.04.017

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13 pages

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This review deals with the emerging field of fluorescent conjugated polymers for the development of chemical and/or biochemical sensors. As a result of their amplified physical properties due to a ''molecular wire effect'', these materials offer excellent characteristics to develop different sensing schemes (e.g., employing direct superquenching or relying on development of fluorescence-resonance-energy-transfer formats). The versatility of their synthesis procedures allows us to introduce the desired functional groups to achieve analytically useful interactions with analytes [e.g., from transition-metal ions to explosives, or even, in recent years, relevant biomolecules (e.g., proteins or DNA, where conformational changes play a decisive role in detection)].

Fluorescent conjugated polymers for chemical and biochemical sensing Adrian Alvarez, Alfonso Salinas-Castillo, Jose ´ M. Costa-Ferna ´ndez, Rosario Pereiro, Alfredo Sanz-Medel This review deals with the emerging ﬁeld of ﬂuorescent conjugated polymers for the development of chemical and/or bio- chemical sensors. As a result of their ampliﬁed physical properties due to a ‘‘molecular wire effect’’, these materials offer excellent characteristics to develop different sensing schemes (e.g., employing direct superquenching or relying on development of ﬂuor- escence-resonance-energy-transfer formats). The versatility of their synthesis procedures allows us to introduce the desired functional groups to achieve analytically useful interactions with analytes [e.g., from transition-metal ions to explosives, or even, in recent years, relevant biomolecules (e.g., proteins or DNA, where conformational changes play a decisive role in detection)]. ª 2011 Elsevier Ltd. All rights reserved. Keywords: Biochemical sensing; Chemical sensing; Conjugated polymer; Conjugated polyelectrolyte; DNA sensing; Explosives sensing; Fluorescence; Fluorescence resonance energy transfer (FRET); Metal-ion sensing; Molecular wire effect 1. Introduction Synthetic polymeric materials are widely used today in a great variety of applica- tions, including packaging, adhesives and lubricants, electrical insulators for micro- electronics, and implantable devices in biomedical applications. A particular type of polymer of emerging potential in ana- lytical chemistry is the so-called conju- gated polymer (CP). CPs, which are conducting polymers, are polyunsaturated compounds with alternating single and double bonds along the polymer chain, in which all backbone atoms are sp or sp 2 hybridized. The resulting interaction be- tween orbitals creates a semiconductor- band structure having a valence band (ﬁlled with electrons) and a conduction band (devoid of electrons). The electronic conjugation between each repeating unit creates a semicon- ductive ‘‘molecular wire’’, providing very useful optical and electronic properties. It is the presence of such a conjugated elec- tronic structure that gives CPs their name, and Fig. 1 shows some of the most common basic structures. Also, CPs incorporating pendant ionic functional groups in the polymeric back- bones (Fig. 2) are named ‘‘conjugated polyelectrolytes’’ (CPEs). The discovery in 1977 of the ﬁrst con- ducting polymer, a halogenated derivative of poly(acetylene), by Shirakawa et al. [1], opened a growing ﬁeld of exciting new applications. The delocalized (conjugated) electronic structure of poly(acetylene) is responsible of the good mobility of the charge carriers (which can be created through doping) and of the strong light absorption in the UV–visible region. Unfortunately, poly(acetylene) is difﬁcult to process and is unstable in the presence of oxygen or water, making it useless for many applications. Nevertheless, further research led chemists to develop much more stable aromatic CPs. Such polymeric materials today offer a combination of the best fea- tures of metals and typical semiconductors with those of synthetic polymers. They have been successfully employed (e.g., as transparent antistatic coatings, transis- tors, light-emitting diodes, photovoltaic cells, modiﬁed electrodes, and biosensors). A general characteristic of neutral CPs is that they are wide band-gap semicon- ductors usually showing efﬁcient UV-Vis- ible absorption or emission at the band Adrian Alvarez, Jose ´ M. Costa-Ferna ´ndez, Rosario Pereiro, Alfredo Sanz-Medel* Department of Physical and Analytical Chemistry, University of Oviedo, Avda. Julian Claveria 8, E-33006 Oviedo, Spain Alfonso Salinas-Castillo* Department of Analytical Chemistry, Faculty of Sciences, University of Granada, Granada, Spain * Corresponding author. Tel./Fax: +34 985 103 474; E-mail: asm@uniovi.es Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 Trends 0165-9936/$ - see front matter ª 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2011.04.017 1513

edge. Moreover, they can emit strong luminescence, but its efﬁciency is affected by delocalization and polarization of the electronic structure. Although CPs generally exhibit low conductivities, these can be signiﬁcantly increased by means of doping. (When talking about doping in a CP, we are not referring to the replacement of atoms in its structure, as happens in a common semiconducting material, but to the oxi- dation or the reduction of the conjugated electronic system: p-doping and n-doping, respectively). This can be carried out chemically or electrochemically, and a counterion is needed to keep electroneutrality. The intrinsic physico-chemical properties of CPs make them highly attractive for the development of novel chemical and biochemical sensors [2]. One of their most remarkable advantages for sensing applications, compared to devices based on conventional organic molecules, is the ability of CPs to exhibit enhanced col- lective properties, resulting in ampliﬁed sensitivity to very small perturbations or interactions, (particularly as a result of their enhanced transport properties, electrical conductivity or rate of energy migration). Moreover, another function of polymers when used in sensory devices is to act as structural materials to ensure stability. Such CP-based sensors can provide analyte recognition as a result of an appropriate covalent or physical inte- gration of the appropriate receptor, imprinting, and/or due to the intrinsic electrostatic and chemical charac- Figure 1. Basic repeating units of some of the most common conjugated polymers. Figure 2. Common functionalizations leading to conjugated polyelectrolytes. (MPS-PPV): [poly (2-methoxy-5-propyloxy sulfonate phenylene vinylene] (Reproduced from [58] with permission). Trends Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 1514 http://www.elsevier.com/locate/trac

teristics of the CP. As usual, such recognition results in a measurable change (analytical signal). As a consequence of their advantageous properties of CPs, CP-based sensors have been developed with a variety of transducing schemes, those employing changes in electrochemical or optical properties being particularly relevant. Although CPs have been used for the construction of very diverse chemical-sensing platforms, growing interest has been focused in recent years on biomolecular recognition, with DNA molecules being remarkable targets, both for electrochemical and optical CP-based sensors. CP-based electrochemical sensors mainly rely on conductometric and potentiometric measurements. At a ﬁxed potential, CP conductivity can change by several orders of magnitude even with a small amount of charge injection. CPs have also been employed in the development of potentiometric sensors, just by immobilizing the CP on a single electrode. The reversible nature of the redox pro- cesses taking place in CPs, as well as their sensitivity to conformation and electrostatics in the medium, is the basis for potentiometric measurements with CPs. As alternatives, optical sensors can also be developed by taking advantage of the excellent optical properties of CPs. Many colorimetric sensing systems have been successful, based on changes in the absorption properties of CPs. However, in this review, we review and discuss the exploitation of the intrinsic ﬂuorescence of CPs, of increasing analytical importance. Fluorescent CPs have the structure of a conjugated molecular wire, for which a minor disturbance caused by the analyte can be ampli- ﬁed in not only the molecular chains of the system but also the entire polymer system. This determines the ability of CPs to detect analytes at ultra-low content, due to their improved sensitivity, typically better than that of conventional, small molecule-based ﬂuorescent sensors. After reviewing the sensing mechanisms of ﬂuorescent CPs, we review their use as optical sensors for ions and small molecules, as well as biosensing of proteins. Finally, we discuss future prospects for the use of ﬂuor- escent CPs in bioanalysis. 2. Optical properties of conjugated polymers As mentioned above, due to electronic delocalization, CPs exhibit interesting optical properties, especially related to the absorption of radiation and the relaxation of their electronic excited states via ﬂuorescent emission. Development of ﬂuorescence sensors with CPs is partic- ularly interesting because of the expected enhanced sensitivity, as discussed above, as a consequence of the delocalization of the charge carriers in the polymeric structure. As a result, they have been referred to as ‘‘amplifying ﬂuorescent polymers’’. Fluorescence-quenching processes can also be observed (called ‘‘superquenching’’). Direct superquen- ching of CP ﬂuorescence can be described by the well- known Stern-Volmer relationships, and it has allowed the development of very sensitive sensors for some molecules or ions (although the selectivity observed was not usually very satisfactory). Selectivity can be in- creased by means of so-called quencher-tether-ligand complexes, resulting from the conjugation of a quencher group to a ligand of biological relevance, selectivity being achieved by means of the speciﬁc interaction between the resulting complex and the analyte (e.g., a protein). A special application of ﬂuorescence in CPs is to develop systems based on the deactivation of their intrinsic ﬂuo- rescent emission (so-called ‘‘turn off’’ optosensing sys- tems) and those based on an increase of the intensity of that emission previously quenched (so-called ‘‘turn off- turn on’’ systems). When comparing both approaches, probably the greatest advantage of the ﬂuorescence ‘‘turn-on’’ sensors over ‘‘turn-off’’ systems is the higher sensitivity typically achieved by ‘‘turn-on’’ sensors be- cause of the low ﬂuorescence background. Moreover, ‘‘turn-on’’ systems reduce the likelihood of false-positive signals as ﬂuorescence-enhancement processes are typi- cally more selective than ﬂuorescence quenching. The semiconductive nature of CPs makes such mate- rials a highly efﬁcient electron-transport medium. The collective optical and conducting properties of CPs lead to ultra-highly-sensitive optical-sensing systems. Thus, CPs are extremely sensitive to minor external structural per- turbations or electron-density changes within the poly- mer, as they self-amplify their ﬂuorescence-quenching response to perturbation of the electronic network upon binding of the analyte. Appropriate CPs can exhibit strong luminescence, and delocalization and/or polarization of their electronic structure may change such luminescence dramatically, so such polymers are good candidates as transducers for very sensitive ﬂuorescence sensing. Fig. 3 shows how CPs amplify the molecular recogni- tion signal via migration of electrons along the polymer chain. Whereas complete ﬂuorescence quenching would be observed with the CP upon interaction with an analyte, with non-conjugated sites exposed to the same analyte concentration, only a small quenching effect would be observed. Each analyte is conﬁned to its particular mole- cule and can sample only one binding site, so the emission is observed from those molecules that did not bind the analyte. In the CP approach, one single interaction can quench a large number of ﬂuorophores and the signal obtained in the presence of the analyte is ampliﬁed. The highly ampliﬁed quenching effect in CPs can be explained as a consequence of the electronic mobility and the transport of excitons (electron-hole pairs gener- ated through photoexcitation) along the polymer back- bone (‘‘molecular wire effect’’). Analyte binding produces a trapping site whereby the excitation is effectively deac- tivated by electron-transfer quenching. This energy migration should be considered a collective property of the Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 Trends http://www.elsevier.com/locate/trac 1515

system instead of a local property of discrete units of the CP. The length of the delocalized chains therefore affects the ampliﬁed quenching [3], whose efﬁciency is increased with increasing molecular weight of the polymers, although, after a certain size, it tends to a constant value. In the case of CPs incorporating charged pendant groups, the quenching efﬁciencies of water-soluble CPEs are even more intensely ampliﬁed in relation to the single units in solution, compared with neutral CPs. This can be explained because of the much stronger complexes formed between the polyelectrolyte and the quencher due to both electrostatic and hydrophobic interactions. Nevertheless, due to their charged nature, CPEs often self-assemble to generate aggregates, especially in aqueous media, thus leading to changes in their spectral characteristics and to decrease the ﬂuorescence quantum yield. Fluorescence in the aggregates is attributed to inter-chain excimers [4] instead of the intra-chain excitons. Quencher ions can also induce aggregation of CPEs, thus leading to enhancement of the quenching effects. When aggregation of the CPs due to interchain inter- actions occurs, ﬂuorescence is quenched due to p-stacking of the CP backbones. Some analytes can induce these processes, and several biological and chemical sensors developed in recent years rely on such analyte-induced aggregation of CPs. However, many analytical applications of CPs are based on ﬂuorescence resonance energy transfer (FRET) mechanisms. Excitons generated in the system after irradiation can migrate along the backbone of the CP and their energy can be transferred to an appropriate acceptor molecule bonded to the CP chain. Thus, the ﬂuorescence emission of the CP is quenched, whereas that of the acceptor is ampliﬁed. Typically, FRET-based sensing schemes using CPs exhibit signiﬁcant changes in emission proﬁles, allowing for ratiometric ﬂuorescence measurements. These assays reduce the possibilities of false positives due to non-binding interactions. Finally, we point out that conformational changes in the CPE backbone vary its absorption and emission characteristics. Such conformational changes can be induced by non-covalent interactions with an analyte. This was shown to be an effective, advantageous sensing mechanism, especially for DNA fragments. 3. Synthesis procedures After the ﬁrst conducting polymer synthesis reported in the late 1970s, many different polymerization proce- dures have been developed. In the following paragraphs, we include short descriptions of the most common pro- cedures. 3.1. Electrochemical polymerization Electrochemical methods represent a classical way to fabricate CPs. Polythiophenes (PTs), polypyrroles or polyanilines were ﬁrst synthesized by means of an elec- trochemical-oxidation reaction, generating a polymeric ﬁlm with enhanced conductivity deposited on the anode. This polymerization process starts with the oxidation of the monomeric units to generate a radical cation, which can be coupled with a second monomeric unit before subsequent deprotonation occurs, leading to a dimer unit. The dimer will then be oxidized faster than the monomer, going through the same repetitive process, and, as a result, longer polymeric chains are generated [5]. 3.2. Chemical polymerization Chemical polymerization (especially catalytic versions) is nowadays the most common way to synthesize CPs. In general, well-known reaction procedures are employed, the most relevant being those summarized in Scheme 1. This approach typically involves an oxidation or dehalogenation polymerization reaction, in which a monomer or mixture of monomers reacts with the stoi- chiometric equivalent of a coupling agent to give the desired polymer and a signiﬁcant amount of side prod- ucts. Unlike electrochemical processes, this kind of Figure 3. The ‘‘molecular wire effect’’, which is responsible for signal ampliﬁcation in conjugated polyelectrolytes so as to exploit superquen- ching effects (Reproduced from [59] with permission). Trends Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 1516 http://www.elsevier.com/locate/trac

polymerization has already found industrial applications in the production of polyanilines and polythiophenes. 3.2.1. Non-catalytic chemical-polymerization meth- ods. Non-catalytic chemical-polymerization methods are mainly based on employing halogenated or ketonic precursors. With halogenated precursors, two methods should be mentioned: (1) the Wessling method, involving the transformation of different precursors in high molecular weight poly-p-(phenylene vinylenes) (PPVs) or derivative [6] through a water-soluble sulphonium salt, which is obtained as polyelectrolyte intermediate; and, (2) the widely used Gilch method, involving polycon- densation by dehydrohalogenation [7]. In the case of ketonic precursors, there are also two excellent methods of synthesis: (1) the well-known Wittig (and Wittig-Horner) reac- tion, involving condensation of a phosphorous ylide with an aldehyde or ketone carbonyl group to give an oleﬁn, with the phosphine oxide as sub-product (this method is also useful for PPV synthesis and allows for regioselectivity [8]); and, (2) the Knoevenagel condensation, which involves a base-catalyzed reaction between an electrophile (dialdehyde) and a nucleophilic group, and is useful for the synthesis of cyano-PPVs [9]. 3.2.2. Catalytic chemical-polymerization methods. The main catalytic chemical-polymerization processes can be divided into two categories: palladium-based catalysts and those using other metals. Methods employing palladium as catalyst include dif- ferent organometallic couplings (e.g., the Suzuki- Miyaura, Heck and Sonogashira couplings). Particularly, in the commonly used Suzuki-Miyaura reaction, palladium catalyzes the coupling between an aromatic boronic derivative and a vinyl or aryl-dihalide in basic media [10]. This method allows for the intro- duction of many different functional groups with differ- ent structures. Thus, the Suzuki-Miyaura reaction has become one of the main routes of synthesis of polyelec- trolytes. Poly(phenylene ethynylenes) (PPEs), PPVs, PTs and also poly(ﬂuorenes) (PFs) can be easily obtained through this method. The coupling of Cassar-Heck-Sonogashira is a widely- used alkyne arylation involving an aromatic halide (bromide or iodide) and a terminal alkyne. The reaction is carried (e.g., triethylamine, pyperidine and pyrroli- dine) to generate basic media. Copper (I) salts are used as co-catalyst. This coupling reaction has become the most frequent approach for the synthesis of PPEs, especially high molecular weight [11]. Some general advantageous characteristics of Pd- catalyzed couplings are the requirement of mild, one-pot Scheme 1. Summary of the main chemical synthesis methodologies to obtain conjugated polymers, including the reactions involved. Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 Trends http://www.elsevier.com/locate/trac 1517

reaction conditions, their compatibility with many functional groups, the usual absence of generated toxic products, and stability in the presence of water. Catalytic chemical-polymerization methods also utilize as catalysts metals other than Pd (e.g., Al, Cu and Ni). The Wurtz–Fittig reaction was the ﬁrst coupling of aromatic monomer units bearing a halogen atom to produce poly(p-phenylenes). The Ullman reaction, based on copper salts and taking place at high temperatures, has been used to polymerize iodinated monomers. In the Yamamoto reaction, the Ni(0) catalyst is gen- erated in situ by treating nickel bromide with zinc. The coupling reaction occurs in polar solvents in the pres- ence of triphenylphosphine-type ligands. In this case, ester or carbonyl groups can be used in the monomers before polymerization, producing CPs, in which a large number of poly(aryl) groups are present, together with the appropriate substituents, which can then produce conjugated polyelectrolytes containing carboxylate or other groups by standard synthetic routes. 3.3. Functionalized conjugated polymers To achieve selective interactions of the CPs with ana- lytes, a myriad of different polymer functionalizations have been studied. Polyalkyl-ether chains, crown-ether and aza-crown-ether moieties were among the ﬁrst functional groups to be bound to CPs, and they were demonstrated to be especially useful for the detection of several alkaline ions (e.g., Li + , Na + or K + ) [12]. Pyridil-based ligands provide another interesting func- tionalization, allowing the detection of a large amount of metals. Enantioselective CPs, with helical secondary structures have also been synthesized via chemical poly- merization and electropolymerization in the presence of chiral and non-chiral electrolytes [13]. Several other interesting functionalizations have been employed in CPs to allow efﬁcient chemical sensing {e.g., 1,10-phenan- throline-based ligand with pendant alkyl-chain-tethered pyrrole groups chelating Cu 2+ (the ﬁlm being rinsed with a KCN solution in CH 3 CN-H 2 O and thus losing electro- activity) [14], and calix[4]arene-functionalized systems highly sensitive and selective to Zn 2+ [15]}. However, the development of so-called conjugated polyelectrolytes allowed compatibility with polar sol- vents, especially with aqueous media, and that is very important to achieve biosensing applications. Several synthesis procedures, especially the Suzuki-Miyaura coupling, allow for the introduction of a huge variety of functionalizations in the polymeric structure, depending on the desired interactions, being the basis for the development of CPEs. As can be seen in Fig. 2, common functional electrolytic groups usually attached to CPs include quaternary amines, sulphonic, phosphate or carboxylic groups, and we describe several of their analytical applications in the following sections. 4. Applications to chemical and biochemical sensing Fluorescent CPs or CPEs have been applied in the development of many different sensing schemes. 4.1. Detection of ionic species Because of their ability to coordinate effectively with many organic compounds, metals (especially transition ones) were among the ﬁrst target analytes for CP-based chemical sensing. Polyalkyl-ether chains, crown-ether and aza-crown-ether moieties were proposed for the detection of some alkaline metals (e.g., Na + ), with high selectivity, but most transduction mechanisms were electrochemical in nature. Nevertheless, since the 1990s, many methods exploiting the inherently excellent optical properties of CPs (especially ﬂuorescence emission) have also been developed for the detection of metal ions and inorganic anions. An interesting example of a ﬂuorescent sensing system employing CPs was developed by Wang and Wasielewski in the late 1990s [16]. Two 2,2Õ-bipyridyl- phenylene-vinylene-based polymers partially conjugated in their metal-free state that fully conjugated when ex- posed to metal ions, so remarkable ionochromic effects were observed with many transition and main group metal ions (excluding those of the alkali and alkaline- earth groups). Both absorption and ﬂuorescence emis- sion bands of such polymers could be red-shifted up to as much as 120 nm, depending on the metal ions present and the polymers used. Fluorescent CPs have been widely used for the devel- opment of quenching metal-ion sensors [e.g., several ﬂuorescent CP-based sensing systems have been devel- oped for selective, sensitive determination of toxic heavy metals (e.g., lead and mercury)]. Liu and Zhu utilized a poly(thienylene phenylene) to obtain an ion-speciﬁc re- sponse to Hg 2+ in a CH 2 Cl 2 medium [17], while lower responses to other metal cations were observed. More recently, a ﬂuorescent CP-based mercury-sensitive system was obtained by the polymerization of 1,4- dibutoxy-2,5-diethynylbenzene with 1,4-diazidobenzene, via click reaction [18]. The polymer emitted blue ﬂuor- escence in THF, the response for mercury ions being much higher than for other metal cations. Such selec- tivity was attributed to the presence of triazole moieties in the polymer main chain acting as metal-binding ligands. Fluorescent CPs with a carboxylate-substituted poly(phenylene-ethynylene) were developed for Pb 2+ detection in water media, but attained limited selectivity (important undesirable responses were found towards interaction with other ionic species) [19]. Fluorescent CPs have also been exploited for the development of sensing materials for monitoring other less toxic metals. In particular, a hybrid inorganic/or- Trends Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 1518 http://www.elsevier.com/locate/trac

ganic polymer was used for Fe 2+ detection [20]. In this approach, the polymer was exposed to Cu 2+ ions that interacted with the amino groups of the CPs with the consequent quenching of the initial ﬂuorescence of the CP. Addition of an aqueous solution containing FeCl 2 resulted in recovery of the initial ﬂuorescence signal. Thus, a ‘‘turn on’’ sensing system was developed, in contrast to the more common ‘‘turn off’’ sensing systems, allowing measurement of low analyte concen- trations relative to a very low ﬂuorescent background. CPs have also been synthesized as ﬂuorescent sensing materials for Ni 2+ determination in organic media, based on a ‘‘turn off’’ sensing scheme. In this line, Liu et al. recently synthesized, via Suzuki coupling, a dipyrido- [3,2-a:2,3-c]phenazine-based metal ion-sensing CP highly sensitive and selective to nickel cation [21], which could be detected in tetrahydrofuran solution even at picomolar (pM) concentration levels. Fluorescent polymers were also exploited for sensing inorganic anions. As an example, water-soluble cationic polythiophene derivatives were employed for the detec- tion (based on colorimetric and ﬂuorimetric spectral changes) of iodide with high selectivity in the presence of a wide range of other anions [22]. The simple methodol- ogy developed was based on the different electrostatic interactions (self-assembly of two opposite charges) and the conformational changes of the cationic poly(3-alkoxy- 4-methylthiophene) after interaction with the analyte. Also, a series of conjugated poly(p-phenylene carba- zole) copolymers were prepared using palladium-cata- lyzed Suzuki coupling reactions. The UV-Vis and ﬂuorescence spectra of the polymers were signiﬁcantly modiﬁed by the addition of tetrabutylammonium iodide and other metal iodides. This was exploited for the development of a colorimetric/ﬂuorimetric sensor for iodide anion [23]. High selectivity was obtained, as the presence in the sample of other concomitant anions (e.g., ﬂuoride, chloride and bromide) did not affect the ﬂuor- escence response to iodide. More recently, two polyazomethine derivatives con- taining ﬂuorene and/or quinoxaline units in their main chains were synthesized via simple Suzuki-coupling polymerization followed by reduction and azomethine- formation reaction. These ﬂuorescent polymers were used for colorimetric anion detection for iodide and acetate ions by naked-eye detection [24]. Polyﬂuorene derivatives with imidazole were used in the development of a ‘‘turn off’’ sensing scheme for the selective and sensitive detection of Cu 2+ (see Fig. 4) [25]. The same ﬂuorescent CPs were also employed for sensing the extremely toxic cyanide anion following an alter- native ‘‘turn on’’ approach, (taking advantage of the recovery of the polymer ﬂuorescence that had been previously quenched with a high concentration of cop- per). Unfortunately, such ‘‘turn off-turn on’’ sensor system is not stable in aqueous media, and application Figure 4. The ‘‘turn off-turn on’’ sensing system, based on a poly(ﬂuorene) derivative showing decrease of its intrinsic ﬂuorescence in the presence of Cu 2+ ions that can be recovered by addition of CN À (Reproduced from [25] with permission). Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 Trends http://www.elsevier.com/locate/trac 1519

was demonstrated only for metal determinations in a tetrahydrofuran medium. Very recently, further research on this topic led to a novel water-compatible ﬂuorescent CP, synthesized as microspheres imidazole-functionalized in the side chain and containing terminal double bonds covalently linked to an organic matrix. The authors applied those CPs to detect both Cu 2+ and cyanide in aqueous media by a ‘‘turn off-turn on’’ scheme [26]. Many other examples of applications of CPs for ﬂuor- escent ion sensing can be found in the literature. Unfortunately, many of them suffer from very limited selectivity and/or poor solubility in aqueous solutions. Research is trying to ﬁnd sensing strategies (e.g., modiﬁcation of the CPs with appropriate functional groups) aiming to get around such limitations to achieve more selective sensing systems. 4.2. Detection of biomolecules Water-soluble CPs are required to develop CP-based bio- logical applications. Nevertheless, most reported CPs ex- hibit rather poor stability in water media, probably due to their low charge densities that compete with the aromatic p-p stacking of the hydrophobic backbones. The intro- duction of hydrophilic side-chains or ionic functional groups to the CP backbone has been described as an efﬁcient strategy to improve the water stability of the CP. The electrical charge and the functional groups, attached to the polymer side-chains and the hydrophobic back- bones, allow the CPEs to associate with different proteins through versatile interactions, giving rise to speciﬁc optical responses to the presence of target proteins. Fluorescent CPs have also been employed in different biosensing applications and some selected biosensing schemes are illustrated in the following sections. 4.2.1. Direct ﬂuorescence superquenching-based systems. Polyﬂuorenes and their derivatives have been demon- strated to be highly useful for detecting biomolecules based on the measurement of changes in their ﬂuores- cence. Very recently, the sensitive, selective monitoring of R-amino acids, using polyﬂuorene-based CPs and a ‘‘turn on’’ scheme, was published [27]. In such an approach, the strong ﬂuorescence of the polyﬂuorene was quenched by trace copper ions, and then it was recovered upon the addition of R-amino acids to the media. Larger biomolecules (e.g., hemoglobin) have also been detected by ﬂuorescent CPs [28]. In this case, a micro- ﬂuidic sensor chip for hemoglobin containing a novel partially-conjugated water-soluble polymer (derived from a PPV) was developed. Analyte detection was based on measuring the quenching effect on the polymerÕs ﬂuorescence emission after analyte interaction (increas- ing concentrations of hemoglobin in the lg/mL range could be detected). Interestingly, simple, sensitive, fast, highly-speciﬁc assays have been developed for assessing the activity of proteolytic enzymes (enterokinase, caspase-3/7, and b- secretase) based on ﬂuorescent CP superquenching [29]. A reactive peptide sequence, within a tether linking a quencher to biotin, binds to sensors containing a biotin- binding protein and ﬂuorescent polymer by means of avidin–biotin-binding-protein interactions. The peptide binding results in efﬁcient quenching of CP ﬂuorescence, which is then recovered by means of an enzyme-medi- ated cleavage of the peptide. 4.2.2. FRET-based biosensing systems. FRET phenomena could offer a general approach to design of biosensors using cationic CPEs with energy donor-acceptor architecture, as shown with the water-soluble cationic polyﬂuorene derivative recently reported for polysaccharide heparin detection [30]. The CP containing 2,1,3-benzo- thiadiazole (BT) was synthesized via typical Suzuki cross-coupling polymerization. When negatively-charged heparin was added into the polymer solution, the analyte induced polymer aggregation, giving rise to an ampliﬁed energy transfer from the ﬂuorene units to the BT units. It was found that orange-emission intensity of BT increased with increasing heparin concentrations, whereas the blue ﬂuorene emission diminished. By contrast, the addition of hyaluronic acid, an analogue of heparin, did not cause signiﬁcant changes in BT emission, thus suggesting selectivity against heparin. Polyﬂuorene derivatives have been successfully used for many biosensing applications based on a FRET mecha- nism. A water-soluble cationic polyﬂuorene with boro- nate-protected ﬂuorescein (peroxyﬂuor-1) covalently linking to the polymer backbone was synthesized as a ﬂuorescence probe to detect hydrogen peroxide and glu- cose in serum optically [31]. The peroxyﬂuor-1 exists as a lactone form that is colorless and non-ﬂuorescent. With- out addition of H 2 O 2 , only blue-donor emission is ob- served upon excitation of the ﬂuorene units. However, in the presence of H 2 O 2 , the peroxyﬂuor-1 can speciﬁcally react with H 2 O 2 to deprotect the boronate-protecting groups and to generate green ﬂuorescent ﬂuorescein. The absorption of ﬂuorescein overlaps the emission of poly- ﬂuorene, which brings about efﬁcient FRET from the ﬂu- orene units to the ﬂuorescein. The probe can detect H 2 O 2 in the range 4.4–530 lM. Since glucose oxidases can speciﬁcally catalyze the oxidation of b-D-(+)-glucose to generate H 2 O 2 , glucose detection was also realized with the probe developed as the signal transducer. Thus, an optical assay for hydrogen peroxide and glucose in serum was created, combining a ﬂuorescent ratiometric tech- nique based on FRET with the light-harvesting properties of CPs. Another example of using ﬂuorescent polyﬂuorene derivatives via FRET mechanisms is metalloprotein cyto- chrome C detection [32]. Here, the positively-charged Trends Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 1520 http://www.elsevier.com/locate/trac

metalloprotein quenched the intrinsic ﬂuorescence of CPs via energy transfer and electron transfer. When summarizing novel schemes for the detection of relevant biomacromolecules, DNA detection should be particularly stressed. Considerable effort has been made in recent years using several CPs for successful electro- chemical DNA sensing, and exploiting CP ﬂuorescence by taking advantage of FRET formats together with conformational changes in DNA or CPEs. In this vein, detection of single-stranded and even double-stranded DNA (ss-DNA and ds-DNA, respectively) is possible employing cationic poly(thiophene) derivatives [33]. Complexation interactions generating more planar backbone structures resulted in red-shifts in absorption and emission spectra and also led to changes in emission efﬁciencies that enabled the development of new ﬂuores- cent FRET assays for DNA (see Fig. 5). Similarly, DNA detection was reported by resorting to complexation of the analytes with poly(ﬂuorene-co-phenylene) derivatives, resulting in changes in intermolecular distances and thus varying FRET efﬁciencies [34]. Some successful biosensor schemes for DNA detection proposed are based on the different conformations adopted by a cationic polythio- phene when electrostatically bound to ss-DNA or ds-DNA. Such conformation changes result in different efﬁciencies on energy transfer between the resulting ﬂuorescent polythiophene/ds-DNA complex and neighboring ﬂuoro- phores attached to ss-DNA probes [35]. Self-assembled molecular structures, comprising ﬂuorophore-tagged oligonucleotide probes and an optical polymeric transducer immobilized on solid substrates, allowed FRET trace-level detection of DNA-target mole- cules [36]. Efﬁcient energy transfer between the polymeric transducer and ﬂuorophores within the molecular aggregates leads to a massive intrinsic ampliﬁcation of the ﬂuorescence signal, thus allowing for the label-free detection of attomolar concentration levels of DNA. This could lead to the development of biochip platforms for fast, simple PCR-free, multi-target DNA detection. Conjugated polyelectrolytes, combined with surface- energy patterning, were investigated to fabricate DNA chips by taking advantage of the ﬂuorescence signal ampliﬁcation of the CPs. Following this scheme, choles- terol-modiﬁed DNA strands, complexed with a CPE, were adsorbed to a surface-energy pattern, formed by printing with soft elastomer stamps. Hybridization of the surface- bound DNA strands with a short complementary strand from solution was monitored using both ﬂuorescence microscopy and imaging surface plasmon resonance. In that scheme, CPEs act as antennas, enhancing resonance- energy transfer to the dye-labeled DNA when comple- mentary hybridization of the double strand occurred [37]. Figure 5. The proposed signal-ampliﬁcation-detection mechanism based on the conformation change of cationic poly(thiophene) and energy transfers for DNA detection. Stoichiometric (neutral) duplexes were made from a chromic cationic polythiophene (which serves as a potential donor) and oligonucleotide capture probes labeled with a ﬂuorophore (acceptor). While the initial nanoaggregates of duplexes exist, no signif- icant ﬂuorescence resonance-energy transfer (FRET) mechanism is observed. By means of hybridization with the DNA target, the cationic poly- thiophene becomes more ﬂuorescent, leading to efﬁcient energy transfer to the neighbouring acceptor (Reproduced from [33] with permission). Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 Trends http://www.elsevier.com/locate/trac 1521

Magnetic microparticles have also been employed to improve the selectivity of CP-based DNA sensors signiﬁ- cantly [38]. Unlike previously reported DNA sensors with CP ampliﬁcation, following the scheme represented in Fig. 6, it was possible to discriminate unknown DNA in the presence of a protein mixture or even of human serum. Such a magnetically-assisted DNA sensor could also conveniently identify even a single-nucleotide mis- match in the target sequence. In order to develop a label-free DNA sensor, PicoGreen (a commercially available sensitive ﬂuorescent nucleic- acid stain used for quantiﬁcation of ds-DNA in solution) was combined with cationic CPs [39]. The high selec- tivity reported for this sensor scheme enabled detection of single-nucleotide mismatches even at room tempera- ture. Sensitivity could be signiﬁcantly improved further by means of a FRET mechanism using poly[(9,9-di(3,3 0 - N,N 0 -trimethylammonium) propylﬂuorenyl-2,7-diyl)- alt-co-(1,4-phenylene)] diiodide salt as a light-harvesting complex. Interestingly, the conformational changes occurring when cationic CPs interact with ss-DNA, with G-rich sequences, also allowed the development of a FRET-based sensing system for detecting potassium in water (as potassium ions speciﬁcally bind to the G-quadruplex DNA formed) [40]. Complexes of DNA and water-soluble cationic CPs can also be employed as probes for sensitive, homoge- neous, and ratiometric detection of restriction and non- restriction DNA-related enzymes (e.g., endonucleases and methyltransferases) [41]. FRET and light-harvesting properties of CPs are combined in this approach. In contrast to previous reports, this assay requires only a single ﬂuorescent label on the oligonucleotide probe, thus signiﬁcantly reducing the cost. The authors suggested this system could be extended for detecting other small and biological molecules with DNA-cleaving activity. Detection of DNA, RNA, proteins and small organic molecules has been also reported using bioassays that take advantage of the collective response of water-soluble CPs and the self-assembly characteristics of aqueous polyelectrolytes [42]. For such FRET bioapplications, cationic polyﬂuorene derivatives and chromophores (e.g., ﬂuorescein or Texas Red) labeled with single-stranded DNA molecules constitute the donor/acceptor pairs. We conclude this sub-section by stressing that, in most of the reported developments so far, the transfer of energy along the whole backbone of the CPs to the ﬁnal reporter results in an ampliﬁed ﬂuorescence signal. This reinforces the concept of using CPs as optical platforms to develop highly sensitive biological sensors. 4.3. Detection of other chemical species Most of the reported sensing applications of ﬂuorescent CPs are focused on the detection of inorganic ions and biochemical species. However, ﬂuorimetric applications of CPs have been also reported for sensing {e.g., organic vapors [43] and amines [44]}. In particular, it is worth discussing here the use of CPs for ﬂuorescence detection of explosives. In the late 1990s, Swager et al. developed different PPE derivatives allowing the detection of dinitrotoluene and trinitrotol- uene (TNT) vapors in explosives. The detection was based on using the reversible quenching of the ﬂuores- cence of these polymers even at very low concentrations of both compounds [45]. More recently, the behavior of three blue-emitting silaﬂuorene-ﬂuorene conjugated copolymers was studied in the presence of several explosives (including TNT, dinitrotoluene and picric acid) in a typical ‘‘turn off’’ approach [46], and all three polymers could detect explosive particulates at trace- concentration levels. Other TNT-sensing devices have been developed in recent years, employing multi-photon ﬂuorescence [47] or most recently by synthesizing CP- grafted silica NPs [48]. TNT and various other nitroa- romatic compounds in gas phase have been also detected by a type of ﬂuorescent ﬁlm in which pyrene was assembled, in a monolayer manner, on glass-slide sur- faces via various ﬂexible spacers of different lengths and substructures [49]. Moreover, ﬁber-optic probes have been developed using ﬂuorene-based polymers for the detection of some nitroaromatic-based explosives [50]. Another approach to sensing explosive vapors employs an efﬁcient sensing nanoﬁber ﬁlm fabricated from the alkoxycarbonyl-substituted, carbazole-cornered, aryl- ene-ethynylene tetracycle [51]. Polymers and copoly- mers containing tetraphenylsilole-vinylene or silaﬂuorene-vinylene repeat units have also been re- ported for the detection of this kind of compound, and, in the case of silaﬂuorene-containing polymers, a surface- detection method for the analysis of solid particulates of these compounds was also reported [52]. 4.4. Combination of nanoparticles with ﬂuorescent conjugated polymers An exciting topic at the moment is the use of function- alized nanoparticles (NPs) for optical sensing purposes. Nanomaterials with particle sizes below 100 nm have been demonstrated to exhibit fascinating optical and electronic properties. Therefore, in recent years, the use of such NPs has replaced conventional organic ﬂuoro- phores in many diverse bioanalytical applications. In this line most recently, CPEs based on polyﬂuorene derivatives were combined with an array of AgNPs on a glass slide to exploit the metal-enhanced ﬂuorescence for DNA detection [53]. Water-soluble CdTe quantum dots (QDs) were also combined to ﬂuorescent conjugated polyﬂuorene derivatives to generate a FRET-based sens- ing system for monitoring DNA-hybridization detection [54]. The CPE is used to amplify the emission of QDs by Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 Trends http://www.elsevier.com/locate/trac 1523

the ﬁrst-level FRET and also to change the sign of the surface charge of QDs to a positive value. In this way, the negatively-charged dye-labeled DNA can interact with the complex, leading to a second-level FRET to the infrared-emitting dye labeled on the probe DNA. Fig. 7 shows this interesting sensing platform, allowing for the reliable discrimination between complementary and non-complementary DNA. Such preliminary studies open new perspectives for the combined use of NPs in the development of enhanced CP-based biosensors. 5. Conclusions and future prospects The growing popularity of ﬂuorescent CPs as novel materials for sensitive and selective luminescent bio- sensing is well documented by the number of publica- tions in recent years. Their synthesis procedures are nowadays well established. They are cheap and versatile and allow an enormous variety of functionalizations, particularly aiming at selective interactions with the target analytes. Their excellent ampliﬁed optical prop- erties are responsible for the most salient feature, the extremely high sensitivity achievable. Fluorescent CPs have experienced extraordinary experimental develop- ment in the past three decades, and their capabilities and analytical potential for improved chemical sensing seem well founded today. CPs hold a promising future in the development of biosensing materials, particularly when the main drawback, the lack of appropriate selectivity, is properly tackled. An interesting future research ﬁeld, related to ﬂuo- rescent CPEs, is their incorporation into molecularly imprinted polymers (MIPs) for the development of im- proved selective sensing schemes. Few examples of this approach have been developed yet, but a cross-linked molecularly imprinted ﬂuorescent CP material (that offers an intrinsic capability for signal transduction and potential to enhance selectivity and sensitivity of CP- sensor devices) was developed for the detection of TNT and related nitroaromatic compounds [55]. The combi- nation of CPEsÕ great luminescent properties with the analyte selectivity offered by MIPs is still an unexplored strategy in the search for new highly-selective ﬂuores- cent sensing materials for both non-luminescent molecules and luminescent analytes, fulﬁlling the requirements to develop FRET-based approaches of high sensitivity. Finally, aptamers (artiﬁcial nucleic-acid-derived ligands that can be generated against amino acids, drugs, proteins and other molecules, ﬁrst reported in 1990) are attracting great interest in the areas of ther- apeutics and diagnostics and could be ideal candidates for use as recognition elements in biosensors (the so- called aptasensors), exhibiting many advantages over state-of-the-art afﬁnity sensors. Fluorescent CPs are starting to be used in combination with such novel and promising analyte-recognition elements. The measure- ment of the recovery of the ﬂuorescence of a newly synthesized anionic CP initially quenched by hemin, {poly(9,9-bis(6 0 -phosphatehexyl) ﬂuorenealt-1,4-pheny- lene) sodium salt}, was the basis of a sensitive, selective sensor of hemin when the aptamer/hemin complex was formed [56]. A conjugated polyelectrolyte was used to amplify the ﬂuorescent signal of aptamer-functionalized silica NPs employed in the development of a speciﬁc sensing system for thrombin detection in blood serum [57]. The recent marriage between MIP technology and aptamer production for recognition and ﬂuorescent CPs for detection is another exciting line of research that could further extend signiﬁcantly the sensing applica- tions of ﬂuorescent CPs. In brief, recent years have witnessed growing interest in the use of ﬂuorescent CPs for biochemical sensing with applications mainly focused on metal ions and bio- macromolecules (e.g., DNA). However, further research is needed in order to enhance analytical sensitivity even further and, especially, to improve present strategies to tackle the main problem of the analytical selectivity of CP-based sensing systems. Acknowledgments Financial support from the Spanish Ministry of Educa- tion and Science (research project CTQ2006-02309) and FEDER program co-financing funds is gratefully acknowledged. A.A.D. acknowledges the Ph.D. scholar- ship from the Asturias Government (BP07-061). Figure 7. The cascaded ﬂuorescence resonance-energy transfer (FRET) for DNA hybridization detection developed by G. Jian and co-workers (Reproduced from [54] with permission). Trends Trends in Analytical Chemistry, Vol. 30, No. 9, 2011 1524 http://www.elsevier.com/locate/trac

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References (59)

H. Shirakawa, E.J. Louis, A.G. MacDiarmid, C.K. Chiang, A.J. Heeger, J. Chem. Soc., Chem. Commun. 16 (1977) 578.
S.W. Thomas III, G.D. Joly, T.M. Swager, Chem. Rev. 107 (2007) 1339.
X.Y. Zhao, H. Jiang, K.S. Schanze, Macromolecules 41 (2008) 3422.
L.J. Rothberg, M. Yang, F. Papadimitrakopoulos, M.E. Galvin, E.W. Kwok, T.M. Miller, Synth. Metals 80 (1996) 41.
M.R.A. Alves, H.D.R. Calado, C.L. Donnici, T. Matencio, Synth. Metals 160 (2010) 22.
K.B. Becker, Synthesis 5 (1983) 341.
H.G. Gilch, W.L. Wheelwright, J. Polym. Sci., Part A: Polym. Chem. 4 (1966) 1337.
H.E. Katz, S.F. Bent, W.L. Wilson, M.L. Schilling, S.B. Ungashe, J. Am. Chem. Soc. 116 (1994) 6631.
R.W. Lenz, C.E. Handlovits, J. Org. Chem. 25 (1960) 813.
N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457.
U.H.F. Bunz, Chem. Rev. 100 (2000) 1605.
B. Fabre, J. Simonet, Coord. Chem. Rev. 178 (1998) 1211.
B.M.W. Langeveld-Voss, M.P.T. Christians, R.A.J. Janssen, E.W. Meijer, Macromolecules 31 (1998) 6702.
G. Bidan, B. Divisia-Blohorn, J.-M. Kern, J.-P. Sauvage, J. Chem. Soc., Chem. Commun. 11 (1988) 723.
C. Kaewtong, G. Jiang, Y. Park, T. Fulghum, A. Baba, B. Pulpoka, R. Advincula, Chem. Mater. 20 (2008) 4915.
B. Wang, M.R. Wasielewski, J. Am. Chem. Soc. 119 (1997) 12.
X. Liu, J. Zhu, J. Phys. Chem. B 113 (2009) 8214.
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Fluorescence; Fluorescence resonance energy transfer (FRET); Metal-ion sensing; Molecular wire effect

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