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Recent advances in the metallo-glycodendrimers and its potential applications
Inorganica Chimica Acta 409 (2014) 26–33
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Review
Recent advances in the metallo-glycodendrimers and its potential applications Shadab Ali Khan, Anindita Adak, Raghavendra Vasudeva Murthy, Raghavendra Kikkeri ⇑ Department of Chemistry, Indian Institute of Science Education and Research, Pune 411021, India
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Article history: Available online 26 June 2013 Metallodendrimers Special Issue Keywords: Carbohydrates Metalloglycodendrimers Optical properties Transition metal complexes Radioactive Lanthanide complexes
a b s t r a c t Ever since the discovery of the phenomenon of multivalent representation of sugar to enhance the binding affinity of specific carbohydrate-protein interactions, the quest for the construction of carbohydrate clusters, with precise geometries that are highly specific to lectin, has been the goal of synthetic chemists. In addition to multivalency, the presence of redox, fluorescence, radioactive nature of glyco-cluster will improve the prospect of direct readout of specific carbohydrate-protein interactions. To address this question, the design of metallo-glycodendrimers with precise sugar topology is critically important. In this review, we provides an overview of the important roles that metallo-glycodendrimers can play as lectin binding molecules, highlighting the unique properties metals can confer to these studies. Ó 2013 Elsevier B.V. All rights reserved.
Shadab Ali Khan received his M.Sc. degree in Biochemistry from Amravati University (M.S.), India in 2003. He obtained his Ph.D. degree from National Chemical Laboratory, Pune, India in 2012 in Biotechnology. After Ph.D. he joined the group of Dr. Raghavendra Kikkeri as a Post Doctoral Research Associate at Department of Chemistry, Indian Institute of Science Education & Research (IISER), Pune, India. His research interests include Nanobiotechnology, biomedical applications of nanomaterials and glyconanotechnology.
Anindita Adak received her BSc. Degree in Biology in 2011 from University of Rajasthan, India. Currently enrolled in Integrated MS – PhD programme in Indian Institute of Science Education and Research,Pune. During her MS in Chemistry she had joined Dr. Raghavendra Kikkeri’s group .Her research focuses on designing carbohydrate based smart molecules to study glycan-protein interaction in more efficient manner.
⇑ Corresponding author. Tel.: +91 20 2590 8207. E-mail address: [email protected] (R. Kikkeri). 0020-1693/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ica.2013.06.017
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Raghavendra Vasudeva Murthy received his M.Sc. degree from university of Mysore in 2001, He obtained his Ph.D degree from University of Catanzaro, Italy. After Ph.D. he joined the group of Dr. Raghavendra Kikkeri as a postdoctoral research associate. His research interests include oncology, glycobiology and glyconanotechnology.
Raghavendra Kikkeri received his master degree from university of Mysore, where he studied organic chemistry as major, In 2001 he moved to Weizmann Institute of science, Israel, where he earned his Ph.D in organic chemistry under the guidance of Prof. Abraham Shanzer. After postdoctoral fellowship with Prof. Peter Seeberger and Prof. Ajit Varki at ETH Zurich, MPI Berlin and UCSD San Diego. He became Assistant professor at the Indian Institute of Science Education and Research (IISER) in Dec 2010. Recently, he started Max- Planck partner group in IISER, Pune.
Contents 1. 2. 2. 3. 4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What makes metallo-glycodendrimers special?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What makes metallo-glycodendrimers special?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of metallo-glycodendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metalloglycodendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Glycodendrimers with transition metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Complexes with lanthanide metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Metal complexes with radioactive properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Lectins are specific carbohydrate-binding or carbohydrate cross-linking proteins. The interactions between lectins and sugars are involved in a large number of biological processes, such as cell adhesion and migration, phagocytosis, cell differentiation and apoptosis [1–4]. Over the past 120 years, numerous lectins have been isolated from plants, microorganisms, fungi, animals and viruses [5–7]. Lectins have been used as tools for the detection, isolation and characterization of various glycoproteins and for the clinical diagnosis of carcinoma and leukemia [8,9]. Despite the prevalence of lectin in biological systems, the binding between an individual lectin and monovalent carbohydrate are quite weak and not particularly specific [10,11]. Nature provides strong and specific responses by carbohydrate multivalency. In multivalent interactions, multiple copies of the ligand and receptors sequentially or simultaneously bind and significantly increase binding affinity for a meaningful and biologically relevant recognition processes [12,13]. A host of glycoclusters have been prepared and explored in different applications. It has been shown that multivalent mannose glycoclusters inhibited HIV infection [14,15]. Multivalent glycoclusters have also been shown to function against bacterial toxins [16,17] and against bacterial adhesion to human cells [18–
27 27 28 28 28 28 30 31 32 32 32
20]. Multivalent glycoconjugates are also being used for stimulation of immune system [21–23]. Similarly, several glycoclusters have been used as a potential target for drug development, gene delivery and diagnostic tools [24–27]. Hence there is a need for new multivalent probe to study carbohydrate-protein interactions in order to unravel the finer details of these interactions. Research groups of Seeberger, Roy, Penadés and Marra have reported carbohydrate clusters on dendrimers, polymers, liposomes, micelles as well as cyclodextrin and calixarenes templates [28–36]. Interactions between carbohydrates and proteins can be studied by using a range of biophysical techniques. The strength of interactions between a given glycoclusters and the lectins have been calculated by Isothermal Titration Calorimetry (ITC), Surface Plasmon Resonance (SPR), Fluorescence Resonance Energy Transfer (FRET) and dialysis. Most glycoclusters reported to date are able to display inherent optical, electrochemical or gravimetric properties for bioimaging or biosensing processes [37–42]. Apart from the purely organic or nanoparticles based glycoclusters reported as lectin binders [43,44], it has recently been shown that metallo-glycodendrimers can also be a potential glycoclusters for lectins [45– 47], with the number of reported example increasing rapidly over the past couple of years. In this review we aim to provide an overview of the important roles of the metallo-glycodendrimers. The
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(a) (b)
o
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(d)
Fig. 1. Selected metalloglycodendrimers: (a) Ru(II)-glycodendrimer by Seeberger and co-workers [60] (b) Tc(I)-glycocomplex by Orvig and co-workers [71,72] (c) Gd(III)glycocomplex by Toth and co-workers [64] (d) Pd(II)-glycocluster by Fujita and co-workers [47].
review also highlights the current efforts made to synthesize metallo-glycodendrimers for evaluating their lectin recognition properties and bioimaging studies (See Figs. 1, 2 and 3). 2. What makes metallo-glycodendrimers special? Metal complexes have a very broad range of optical, magnetic, or redox properties that could be, in principle, be exploited for the development of specific lectin-carbohydrate biosensors. A metal center can be envisaged as a structural locus that organizes chelators in specific geometries or clustures to propagate specific sugar mediated lectin binding. The relative ease of synthesis of metal complexes can allow the generation of small libraries of related compounds. Moreover, variations can be introduced by modifying the ligands or metal center to tune the multivalency and structural arrangements of the clusters. These variations render metal complexes advantageous over their organic counterparts, where analogous geometrical changes are often more difficult to introduce. Finally, metal complexes allow one of the best methods to study the influence of internal or external chirality and orientation of the sugar clusters with respect to external stimuli. 3. Synthesis of metallo-glycodendrimers There are two methods generally accepted for the synthesis of multivalent metallo-glycodendrimers: the convergent approach
and the divergent approach. A convergent synthesis is essentially the polyvalent construction from the ‘outside-in’ toward a suitable core. Here, synthesis of ligand carrying carbohydrates followed by metal complex formation. A divergent approach corresponds to opposite building from the ‘inside-out’ starting with a multi-functional core. A suitable metallodendrimers was constructed followed by encapsulation of carbohydrate at the final modification step. Both approaches result in glycoclusters having 3-dimensional topology similar to cell surface glycans topology and play an important role in elucidating carbohydrate-protein interactions. However, the divergent method is considered to be more suitable for generation of metalloglycodendrimers, as it is more straightforward to control the clusterization and multivalency. 4. Metalloglycodendrimers 4.1. Glycodendrimers with transition metals Iron complexes were one of the earliest examples of metalloglycodendrimers to be evaluated for the importance of chirality during specific carbohydrate protein interactions. The authors showed the synthesis of the sugar substituted by bipyridine ligands, which subsequently form D and K sugar Fe(III) complexes to study specific carbohydrate-lectin interactions [48]. Metalloglycodendrimers focused on Cu(II), Fe(II), Ir(II), Rh(II) and Ru(II) were also reported [49–54]. Among these metals, ferrocene and
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Fig. 2. Schematic representation of metalloglycodendrimer and synthetic methods (a) convergent method; (b) divergent method.
Ru(II) complexes were most attractive metallo-glycodendrimers for their robustness and photophysical properties [55]. Ru(II) complexes exhibit a lowexcited triple metal-to-ligand charge transfer state (3MLCT) and the room temperature 3MLCT lifetimes were up to 1 ls, high-emission quantum yields and strong oxidizing and reducing capabilities [56,57]. Ru(II) dendrimers were extensively used as photo-catalysts, as reactions in intermolecular and intramolecular energy and electron-transfer process [58]. The synthesis of Ru(II)-glycodendrimers were started from 2,20 -bipyridine (bpy) functionalization at 4 and 40 positions, so that a variety of dendritic wedges could be appended to build glycodendrimers contained on [Ru(bpy)3]2+ core. Both convergent and divergent method was applied to synthesize Ru(II)-glycodendrimers bearing varying numbers of carbohydrates. In the convergent method, ligands carrying sugar dendrons weresynthesized separately and then united with Ru(II) ion to get octahedral symmetric metalloglycodendrimers [59]. A straight forward Huisgen [3+2] cyclo-
addition, host–guest strategy were applied in divergent method to synthesize a library of metalloglycodendrimers [60]. The luminescent Ru(II) and Ir(II) complexes of mannose or galactose glycodendrimers have been utilized to address biochemical and biomedical questions [29,61]. In this context, carbohydrateprotein interactions were studied by using fluorescent turbidity assay and microarray techniques. Seeberger and co-workers have shown that the density of sugar around the metal complex directly influence the binding affinity and photo-physical properties of the complexes. This alteration in photo-physical properties is due to bettershielding of Ru(II) core by the topology of the hydrophilic core of the sugar [29]. Based on optical properties of Ru(II) complexes, lectin biosensors were developed on microarray plates. ConcanavalinA (ConA) lectin was immobilized on a microarrays prior to incubation with mannose or galactose Ru(II) complexes. Upon fluorescence scanning of rinsed slides, strong fluorescent signals were observed on slides that were incubated with mannose
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(a) (b)
(c)
(b)
(d)
Fig. 3. Assembly of metallo-glycodendrimers using convergent method and host–guest method: (a) SOCl2/mantripod-amine linker/TEA/RT/12 h; (b) Ru(bipy)2Cl2/EtOH/ 80 °C/4 h; (c) SOCl2/mantripod-amine linker/TEA/RT/12 h; (d) Cd-man/H2O.
complexes and ConA could be detected at as low as 0.125 mg/mL (620 nM). To probe the versatility of the Ru(II)-glycodendrimers as a potential lectin biosensor, photo-induced electron transfer (PET) between Ru(II)-glycodendrimers and methyl viologen dication (MV2+) was applied to detect ConA at 25–28 nM [46] (Fig.4c). The redox properties of Ru(II) complexes were also exploited to develop electrochemical biosensors. ConA was immobilized on a selfassembled monolayer gold surface prior to incubation with Ru(II) complexes [30]. The chip was transferred to a cyclic voltameter cell to record square wave voltametric (SWV) signal of Ru(II) complex. Based on the electrochemical signals, lectin-metalloglycodendrimer interaction was established and ConA was sensed at a lowest limit of 2.5 nM, which was comparable to other sugar sensor models. A reusable sugar sensor, based on the displacement of the redox glyco-probes by preferential lectin binding carbohydrates was also developed. Using this method biologically important sugars such as glucose, phosphatidylinositol mannose (PIM) glycans were detected at a detection limit of 7.0 and 0.6 lM concentrations. Thereproducibility of the above chip was established by exposing the gold chips to boronic acid substituted merrified resin to regenerate the lectin surface for the next measurement (Fig. 4a). More recently, Seeberger et al. have extended the synthesis of metalloglycodendrimers by using host–guest concept. Fluorescent Ru(II) complexes were functionalized with 14, 28 or 42 mannopyranosyl units using adamantine-cyclodextrin based host–guest
chemistry. These systems proved to be very well suited to probe the structural arrangement of glycodendrimer for efficient binding to immobilized ConA lectin by surface plasmon resonance (SPR). Additionally, the optical properties of Ru(II)-glycodendrimers allowed direct imaging of their association with E. coli (stain ORN178), having mannose binding FimH lectin in the pili, by confocal microscopic imaging [60] (Fig. 4d). Our work in this area has centered on the development of metalloglycodendrimers that can be used to increase the local concentration of essential elements to amplify the growth and other functions in living species. A catechol coupled Fe(III) glycodendrimers have been prepared using self-assembly process for targeting a specific stain of E. coli (ORN 178) and we have shown that the interaction of Fe(III)-glycodendrimers and FimH receptor mediated iron delivery, inducing iron mediated growth promotion, by growth promotion assay and LB plate assay [49] (Fig. 4b). These results have confirmed that transition metallo-glycodendrimers can be use in biosensors and imaging studies. 4.2. Complexes with lanthanide metals Among lanthanides, Gd(III) complexes are the most studied and popular choice for functionlization with carbohydrates to obtain Gd(III) based glycodendrimers. Lanthanide ions specially Gd(III)-glycoconjugates have been extensively used in Magnetic
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Fig. 4. Applications of metalloglycodendrimers.
Resonance Imaging(MRI), which is a diagnostic modality based on the enhancement of contrast given by paramagnetic contrast agents (CAs). Gd(III) complexes demonstrated to be the most suitable paramagnetic CAs for MRI, due to the high paramagnetism of the Gd(III) ion (4f7) and to its slow electron spin relaxation [62,63]. Andre et al. have successfully synthesized a new class of DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) monoamide-linked glycoconjugates (glucose, lactose and galactose) of different valencies (mono, di and tetra) and their lanthanide ions complexes such as Gd(III), Eu(III) and Sm(III) ions. The authors also studied the interaction of Gd(III)-glycoconjugates in vitro with the model lectin Ricinus communis agglutinin (RCA) through relaxometric measurements. Their results could open the way for the study of Gd(III)-glycoconjugates as potential candidates for lectin-mediated molecular imaging agents [64]. Similar kind of work has been carried out by Fulton et al. where they have synthesized glycoconjugates of Gd(III) complexes with enhanced relaxivity as sharp contrast agents for MRI [65]. Vera et al. have also developed Gd-DTPA conjugate of polylysine (PL) derivatized with galactosyl groups (Gd-DTPA-gal-PL) as potential contrast agents for liver MRI by targeting the hepatocyte ASGPR (asyaloglycoprotein receptor) and tested in cells and mice [66]. Gd(III)-based glycodendrimers have also been shown to be useful for in vitro and in vivo (Xenopus laevis embryos) visualisation and localisation of gene expression by MRI (Fig. 5a) [67,68]. The fluorescent and relaxometric properties of Eu(III) and Gd(III) complexes respectively with bound sugars (galactose, glucose) were used to gain mechanistic insights into their water binding behaviour [69]. Very recently Rodríguez et al. have reported the synthesis of a luminescent Tb3+-DOTA complex bearing an
a-D-mannose residue and the related study of binding affinity with concanavalin A (Con A) labelled with rhodamine-B-isothiocyanate (RITC-Con A). Luminescence spectroscopy and dynamic studies show changes in emission spectra that can be ascribed to a luminescence resonance energy transfer (LRET) from Tb(III) complex (donor) to RITC-Con A (acceptor).The binding constant value between the two species was found to be one order of magnitude larger than those previously reported for similar types of recognition (Fig 5b) [70]. These results confirmed that it is possible to generate lanthanide-glycodendrimers, which can be used in MRI imaging studies. 4.3. Metal complexes with radioactive properties Due to the rapid development of imaging techniques like singlephoton emission computed tomography (SPECT) or positron emission tomography (PET) and coupled procedures like PET/computed tomography (CT), radioactive-labelled biomolecules are being increasingly used for the visualisation of certain cell types and tissues. Glycoclusters conjugated with radioactive metal complexes are gradually becoming important tools for in vivo cell and tissue imaging. Among this 99mTc(I) based glycoconjugates are the most widely used and extensively studied [71,72]. Most of the synthesised complexes are glucose-based aiming to take advantage of the over expression of glucose transporters (GLUT1). Schibli et al. tested the cellular uptake of the 99mTc(I) complexes bound to the C-2, C-3 or C-6 position of glucose by oxygen, by colon carcinoma cells HT29 [73]. 99mTc-DTPA-GSA, a conjugate of galactosylated serum albumin (GSA) with 99mTc-DTPA (DTPA = 3,6,9 tris(carboxymethyl)-3,6,9-triazaundecan-1,11-dioic acid) (Fig. 6a), has been shown to be useful in SPECT (single photon emission computed
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(a)
(b)
Fig. 5. (a) Gd(III) based glycodendrimer [65]; (b) Tb(III) based glycodendrimer [70].
(a)
(b)
Fig. 6. (a) Radiolabelled
99
Tc glycodendrimer [72]; (b) 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) [80].
tomography) hepatic imaging to assess ASGPR in mice [74] and used clinically in humans [75,76]. The targeting of the ASGPR has been demonstrated both in a cell line and mice with a 111In-radiolabelled galactopyranosyl conjugate of DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) [77]. So far, 99m Tc-/188Re-DTPA (diethylenetriamine pentaacetic acid) complexes are the most promising candidates to act as functional imaging agents which are derived from 2-N-2-deoxy-D-glucosamine. These derivatives were phosphorylated by hexokinase exhibiting cellular uptake probably by a multifunctional glucose transport system and reveal higher tumor-to-tissue ratios than observed for other tracers in in vivo experiments in small animal tumour models [78,79]. Another radiolabelled metal complexe of 2-18F-2-deoxy-Dglucose (FDG) is used as a sugar-based tracer to monitor glucose transporter (GLUT1) activity by PET/CT, and to image tumour cell metabolism (Fig 6b) [80]. Despite all these results, only few in vivo experiments are reported with radioactive metallo-glycodendrimers. Therefore, the final goal should lie in the development of stable and facile method to synthesize radioactive glycodendrimers. 5. Conclusions The past few years have seen a steady growth of multivalent glycodendrimer that are reported to improve the prospect of
decoding several biological information’s hidden by carbohydrates. In contrast to number of organic and nanoparticles based glycodendrimers, metalloglycodendrimers have only recently started to systematically investigated. Taking full advantage of fluorescence, electrochemical, radioactive properties of metal complexes, receptor-targeted molecular biosensors, bio-imaging and growth promoter were achieved. Despite significant studies, the employment of these dendrimers in therapeutics and in vivo targeting represents largely untapped areas. It is expected that new developments will certainly broaden horizon of metalloglycodendrimers, both at the fundamental and biomedical applications of these complexes. Acknowledgements We thank IISER, Pune, Indo-German (DST-MPG) program and DAE (Grant No.2011/37C/20/BRNS) and CSIR, India for financial support. References [1] D.B. Werz, P.H. Seeberger, Nat. Rev. 4 (2000) 751. [2] T. Angata, A. Varki, Chem. Rev. 102 (2000) 439. [3] A. Varki, R. Cummins, J. Esko, H. Freeze, G. Hart, J. Marth (Eds.), Essentials of Glycobiology. Consortium of Glycobiology, La Jolla, California, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999.
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Contents lists available at SciVerse ScienceDirect
Inorganica Chimica Acta journal homepage: www.elsevier.com/locate/ica
Review
Recent advances in the metallo-glycodendrimers and its potential applications Shadab Ali Khan, Anindita Adak, Raghavendra Vasudeva Murthy, Raghavendra Kikkeri ⇑ Department of Chemistry, Indian Institute of Science Education and Research, Pune 411021, India
a r t i c l e
i n f o
Article history: Available online 26 June 2013 Metallodendrimers Special Issue Keywords: Carbohydrates Metalloglycodendrimers Optical properties Transition metal complexes Radioactive Lanthanide complexes
a b s t r a c t Ever since the discovery of the phenomenon of multivalent representation of sugar to enhance the binding affinity of specific carbohydrate-protein interactions, the quest for the construction of carbohydrate clusters, with precise geometries that are highly specific to lectin, has been the goal of synthetic chemists. In addition to multivalency, the presence of redox, fluorescence, radioactive nature of glyco-cluster will improve the prospect of direct readout of specific carbohydrate-protein interactions. To address this question, the design of metallo-glycodendrimers with precise sugar topology is critically important. In this review, we provides an overview of the important roles that metallo-glycodendrimers can play as lectin binding molecules, highlighting the unique properties metals can confer to these studies. Ó 2013 Elsevier B.V. All rights reserved.
Shadab Ali Khan received his M.Sc. degree in Biochemistry from Amravati University (M.S.), India in 2003. He obtained his Ph.D. degree from National Chemical Laboratory, Pune, India in 2012 in Biotechnology. After Ph.D. he joined the group of Dr. Raghavendra Kikkeri as a Post Doctoral Research Associate at Department of Chemistry, Indian Institute of Science Education & Research (IISER), Pune, India. His research interests include Nanobiotechnology, biomedical applications of nanomaterials and glyconanotechnology.
Anindita Adak received her BSc. Degree in Biology in 2011 from University of Rajasthan, India. Currently enrolled in Integrated MS – PhD programme in Indian Institute of Science Education and Research,Pune. During her MS in Chemistry she had joined Dr. Raghavendra Kikkeri’s group .Her research focuses on designing carbohydrate based smart molecules to study glycan-protein interaction in more efficient manner.
⇑ Corresponding author. Tel.: +91 20 2590 8207. E-mail address: [email protected] (R. Kikkeri). 0020-1693/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ica.2013.06.017
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Raghavendra Vasudeva Murthy received his M.Sc. degree from university of Mysore in 2001, He obtained his Ph.D degree from University of Catanzaro, Italy. After Ph.D. he joined the group of Dr. Raghavendra Kikkeri as a postdoctoral research associate. His research interests include oncology, glycobiology and glyconanotechnology.
Raghavendra Kikkeri received his master degree from university of Mysore, where he studied organic chemistry as major, In 2001 he moved to Weizmann Institute of science, Israel, where he earned his Ph.D in organic chemistry under the guidance of Prof. Abraham Shanzer. After postdoctoral fellowship with Prof. Peter Seeberger and Prof. Ajit Varki at ETH Zurich, MPI Berlin and UCSD San Diego. He became Assistant professor at the Indian Institute of Science Education and Research (IISER) in Dec 2010. Recently, he started Max- Planck partner group in IISER, Pune.
Contents 1. 2. 2. 3. 4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What makes metallo-glycodendrimers special?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What makes metallo-glycodendrimers special?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of metallo-glycodendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metalloglycodendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Glycodendrimers with transition metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Complexes with lanthanide metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Metal complexes with radioactive properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Lectins are specific carbohydrate-binding or carbohydrate cross-linking proteins. The interactions between lectins and sugars are involved in a large number of biological processes, such as cell adhesion and migration, phagocytosis, cell differentiation and apoptosis [1–4]. Over the past 120 years, numerous lectins have been isolated from plants, microorganisms, fungi, animals and viruses [5–7]. Lectins have been used as tools for the detection, isolation and characterization of various glycoproteins and for the clinical diagnosis of carcinoma and leukemia [8,9]. Despite the prevalence of lectin in biological systems, the binding between an individual lectin and monovalent carbohydrate are quite weak and not particularly specific [10,11]. Nature provides strong and specific responses by carbohydrate multivalency. In multivalent interactions, multiple copies of the ligand and receptors sequentially or simultaneously bind and significantly increase binding affinity for a meaningful and biologically relevant recognition processes [12,13]. A host of glycoclusters have been prepared and explored in different applications. It has been shown that multivalent mannose glycoclusters inhibited HIV infection [14,15]. Multivalent glycoclusters have also been shown to function against bacterial toxins [16,17] and against bacterial adhesion to human cells [18–
27 27 28 28 28 28 30 31 32 32 32
20]. Multivalent glycoconjugates are also being used for stimulation of immune system [21–23]. Similarly, several glycoclusters have been used as a potential target for drug development, gene delivery and diagnostic tools [24–27]. Hence there is a need for new multivalent probe to study carbohydrate-protein interactions in order to unravel the finer details of these interactions. Research groups of Seeberger, Roy, Penadés and Marra have reported carbohydrate clusters on dendrimers, polymers, liposomes, micelles as well as cyclodextrin and calixarenes templates [28–36]. Interactions between carbohydrates and proteins can be studied by using a range of biophysical techniques. The strength of interactions between a given glycoclusters and the lectins have been calculated by Isothermal Titration Calorimetry (ITC), Surface Plasmon Resonance (SPR), Fluorescence Resonance Energy Transfer (FRET) and dialysis. Most glycoclusters reported to date are able to display inherent optical, electrochemical or gravimetric properties for bioimaging or biosensing processes [37–42]. Apart from the purely organic or nanoparticles based glycoclusters reported as lectin binders [43,44], it has recently been shown that metallo-glycodendrimers can also be a potential glycoclusters for lectins [45– 47], with the number of reported example increasing rapidly over the past couple of years. In this review we aim to provide an overview of the important roles of the metallo-glycodendrimers. The
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(a) (b)
o
(c)
(d)
Fig. 1. Selected metalloglycodendrimers: (a) Ru(II)-glycodendrimer by Seeberger and co-workers [60] (b) Tc(I)-glycocomplex by Orvig and co-workers [71,72] (c) Gd(III)glycocomplex by Toth and co-workers [64] (d) Pd(II)-glycocluster by Fujita and co-workers [47].
review also highlights the current efforts made to synthesize metallo-glycodendrimers for evaluating their lectin recognition properties and bioimaging studies (See Figs. 1, 2 and 3). 2. What makes metallo-glycodendrimers special? Metal complexes have a very broad range of optical, magnetic, or redox properties that could be, in principle, be exploited for the development of specific lectin-carbohydrate biosensors. A metal center can be envisaged as a structural locus that organizes chelators in specific geometries or clustures to propagate specific sugar mediated lectin binding. The relative ease of synthesis of metal complexes can allow the generation of small libraries of related compounds. Moreover, variations can be introduced by modifying the ligands or metal center to tune the multivalency and structural arrangements of the clusters. These variations render metal complexes advantageous over their organic counterparts, where analogous geometrical changes are often more difficult to introduce. Finally, metal complexes allow one of the best methods to study the influence of internal or external chirality and orientation of the sugar clusters with respect to external stimuli. 3. Synthesis of metallo-glycodendrimers There are two methods generally accepted for the synthesis of multivalent metallo-glycodendrimers: the convergent approach
and the divergent approach. A convergent synthesis is essentially the polyvalent construction from the ‘outside-in’ toward a suitable core. Here, synthesis of ligand carrying carbohydrates followed by metal complex formation. A divergent approach corresponds to opposite building from the ‘inside-out’ starting with a multi-functional core. A suitable metallodendrimers was constructed followed by encapsulation of carbohydrate at the final modification step. Both approaches result in glycoclusters having 3-dimensional topology similar to cell surface glycans topology and play an important role in elucidating carbohydrate-protein interactions. However, the divergent method is considered to be more suitable for generation of metalloglycodendrimers, as it is more straightforward to control the clusterization and multivalency. 4. Metalloglycodendrimers 4.1. Glycodendrimers with transition metals Iron complexes were one of the earliest examples of metalloglycodendrimers to be evaluated for the importance of chirality during specific carbohydrate protein interactions. The authors showed the synthesis of the sugar substituted by bipyridine ligands, which subsequently form D and K sugar Fe(III) complexes to study specific carbohydrate-lectin interactions [48]. Metalloglycodendrimers focused on Cu(II), Fe(II), Ir(II), Rh(II) and Ru(II) were also reported [49–54]. Among these metals, ferrocene and
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Fig. 2. Schematic representation of metalloglycodendrimer and synthetic methods (a) convergent method; (b) divergent method.
Ru(II) complexes were most attractive metallo-glycodendrimers for their robustness and photophysical properties [55]. Ru(II) complexes exhibit a lowexcited triple metal-to-ligand charge transfer state (3MLCT) and the room temperature 3MLCT lifetimes were up to 1 ls, high-emission quantum yields and strong oxidizing and reducing capabilities [56,57]. Ru(II) dendrimers were extensively used as photo-catalysts, as reactions in intermolecular and intramolecular energy and electron-transfer process [58]. The synthesis of Ru(II)-glycodendrimers were started from 2,20 -bipyridine (bpy) functionalization at 4 and 40 positions, so that a variety of dendritic wedges could be appended to build glycodendrimers contained on [Ru(bpy)3]2+ core. Both convergent and divergent method was applied to synthesize Ru(II)-glycodendrimers bearing varying numbers of carbohydrates. In the convergent method, ligands carrying sugar dendrons weresynthesized separately and then united with Ru(II) ion to get octahedral symmetric metalloglycodendrimers [59]. A straight forward Huisgen [3+2] cyclo-
addition, host–guest strategy were applied in divergent method to synthesize a library of metalloglycodendrimers [60]. The luminescent Ru(II) and Ir(II) complexes of mannose or galactose glycodendrimers have been utilized to address biochemical and biomedical questions [29,61]. In this context, carbohydrateprotein interactions were studied by using fluorescent turbidity assay and microarray techniques. Seeberger and co-workers have shown that the density of sugar around the metal complex directly influence the binding affinity and photo-physical properties of the complexes. This alteration in photo-physical properties is due to bettershielding of Ru(II) core by the topology of the hydrophilic core of the sugar [29]. Based on optical properties of Ru(II) complexes, lectin biosensors were developed on microarray plates. ConcanavalinA (ConA) lectin was immobilized on a microarrays prior to incubation with mannose or galactose Ru(II) complexes. Upon fluorescence scanning of rinsed slides, strong fluorescent signals were observed on slides that were incubated with mannose
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S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33
(a) (b)
(c)
(b)
(d)
Fig. 3. Assembly of metallo-glycodendrimers using convergent method and host–guest method: (a) SOCl2/mantripod-amine linker/TEA/RT/12 h; (b) Ru(bipy)2Cl2/EtOH/ 80 °C/4 h; (c) SOCl2/mantripod-amine linker/TEA/RT/12 h; (d) Cd-man/H2O.
complexes and ConA could be detected at as low as 0.125 mg/mL (620 nM). To probe the versatility of the Ru(II)-glycodendrimers as a potential lectin biosensor, photo-induced electron transfer (PET) between Ru(II)-glycodendrimers and methyl viologen dication (MV2+) was applied to detect ConA at 25–28 nM [46] (Fig.4c). The redox properties of Ru(II) complexes were also exploited to develop electrochemical biosensors. ConA was immobilized on a selfassembled monolayer gold surface prior to incubation with Ru(II) complexes [30]. The chip was transferred to a cyclic voltameter cell to record square wave voltametric (SWV) signal of Ru(II) complex. Based on the electrochemical signals, lectin-metalloglycodendrimer interaction was established and ConA was sensed at a lowest limit of 2.5 nM, which was comparable to other sugar sensor models. A reusable sugar sensor, based on the displacement of the redox glyco-probes by preferential lectin binding carbohydrates was also developed. Using this method biologically important sugars such as glucose, phosphatidylinositol mannose (PIM) glycans were detected at a detection limit of 7.0 and 0.6 lM concentrations. Thereproducibility of the above chip was established by exposing the gold chips to boronic acid substituted merrified resin to regenerate the lectin surface for the next measurement (Fig. 4a). More recently, Seeberger et al. have extended the synthesis of metalloglycodendrimers by using host–guest concept. Fluorescent Ru(II) complexes were functionalized with 14, 28 or 42 mannopyranosyl units using adamantine-cyclodextrin based host–guest
chemistry. These systems proved to be very well suited to probe the structural arrangement of glycodendrimer for efficient binding to immobilized ConA lectin by surface plasmon resonance (SPR). Additionally, the optical properties of Ru(II)-glycodendrimers allowed direct imaging of their association with E. coli (stain ORN178), having mannose binding FimH lectin in the pili, by confocal microscopic imaging [60] (Fig. 4d). Our work in this area has centered on the development of metalloglycodendrimers that can be used to increase the local concentration of essential elements to amplify the growth and other functions in living species. A catechol coupled Fe(III) glycodendrimers have been prepared using self-assembly process for targeting a specific stain of E. coli (ORN 178) and we have shown that the interaction of Fe(III)-glycodendrimers and FimH receptor mediated iron delivery, inducing iron mediated growth promotion, by growth promotion assay and LB plate assay [49] (Fig. 4b). These results have confirmed that transition metallo-glycodendrimers can be use in biosensors and imaging studies. 4.2. Complexes with lanthanide metals Among lanthanides, Gd(III) complexes are the most studied and popular choice for functionlization with carbohydrates to obtain Gd(III) based glycodendrimers. Lanthanide ions specially Gd(III)-glycoconjugates have been extensively used in Magnetic
S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33
31
Fig. 4. Applications of metalloglycodendrimers.
Resonance Imaging(MRI), which is a diagnostic modality based on the enhancement of contrast given by paramagnetic contrast agents (CAs). Gd(III) complexes demonstrated to be the most suitable paramagnetic CAs for MRI, due to the high paramagnetism of the Gd(III) ion (4f7) and to its slow electron spin relaxation [62,63]. Andre et al. have successfully synthesized a new class of DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) monoamide-linked glycoconjugates (glucose, lactose and galactose) of different valencies (mono, di and tetra) and their lanthanide ions complexes such as Gd(III), Eu(III) and Sm(III) ions. The authors also studied the interaction of Gd(III)-glycoconjugates in vitro with the model lectin Ricinus communis agglutinin (RCA) through relaxometric measurements. Their results could open the way for the study of Gd(III)-glycoconjugates as potential candidates for lectin-mediated molecular imaging agents [64]. Similar kind of work has been carried out by Fulton et al. where they have synthesized glycoconjugates of Gd(III) complexes with enhanced relaxivity as sharp contrast agents for MRI [65]. Vera et al. have also developed Gd-DTPA conjugate of polylysine (PL) derivatized with galactosyl groups (Gd-DTPA-gal-PL) as potential contrast agents for liver MRI by targeting the hepatocyte ASGPR (asyaloglycoprotein receptor) and tested in cells and mice [66]. Gd(III)-based glycodendrimers have also been shown to be useful for in vitro and in vivo (Xenopus laevis embryos) visualisation and localisation of gene expression by MRI (Fig. 5a) [67,68]. The fluorescent and relaxometric properties of Eu(III) and Gd(III) complexes respectively with bound sugars (galactose, glucose) were used to gain mechanistic insights into their water binding behaviour [69]. Very recently Rodríguez et al. have reported the synthesis of a luminescent Tb3+-DOTA complex bearing an
a-D-mannose residue and the related study of binding affinity with concanavalin A (Con A) labelled with rhodamine-B-isothiocyanate (RITC-Con A). Luminescence spectroscopy and dynamic studies show changes in emission spectra that can be ascribed to a luminescence resonance energy transfer (LRET) from Tb(III) complex (donor) to RITC-Con A (acceptor).The binding constant value between the two species was found to be one order of magnitude larger than those previously reported for similar types of recognition (Fig 5b) [70]. These results confirmed that it is possible to generate lanthanide-glycodendrimers, which can be used in MRI imaging studies. 4.3. Metal complexes with radioactive properties Due to the rapid development of imaging techniques like singlephoton emission computed tomography (SPECT) or positron emission tomography (PET) and coupled procedures like PET/computed tomography (CT), radioactive-labelled biomolecules are being increasingly used for the visualisation of certain cell types and tissues. Glycoclusters conjugated with radioactive metal complexes are gradually becoming important tools for in vivo cell and tissue imaging. Among this 99mTc(I) based glycoconjugates are the most widely used and extensively studied [71,72]. Most of the synthesised complexes are glucose-based aiming to take advantage of the over expression of glucose transporters (GLUT1). Schibli et al. tested the cellular uptake of the 99mTc(I) complexes bound to the C-2, C-3 or C-6 position of glucose by oxygen, by colon carcinoma cells HT29 [73]. 99mTc-DTPA-GSA, a conjugate of galactosylated serum albumin (GSA) with 99mTc-DTPA (DTPA = 3,6,9 tris(carboxymethyl)-3,6,9-triazaundecan-1,11-dioic acid) (Fig. 6a), has been shown to be useful in SPECT (single photon emission computed
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(a)
(b)
Fig. 5. (a) Gd(III) based glycodendrimer [65]; (b) Tb(III) based glycodendrimer [70].
(a)
(b)
Fig. 6. (a) Radiolabelled
99
Tc glycodendrimer [72]; (b) 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) [80].
tomography) hepatic imaging to assess ASGPR in mice [74] and used clinically in humans [75,76]. The targeting of the ASGPR has been demonstrated both in a cell line and mice with a 111In-radiolabelled galactopyranosyl conjugate of DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) [77]. So far, 99m Tc-/188Re-DTPA (diethylenetriamine pentaacetic acid) complexes are the most promising candidates to act as functional imaging agents which are derived from 2-N-2-deoxy-D-glucosamine. These derivatives were phosphorylated by hexokinase exhibiting cellular uptake probably by a multifunctional glucose transport system and reveal higher tumor-to-tissue ratios than observed for other tracers in in vivo experiments in small animal tumour models [78,79]. Another radiolabelled metal complexe of 2-18F-2-deoxy-Dglucose (FDG) is used as a sugar-based tracer to monitor glucose transporter (GLUT1) activity by PET/CT, and to image tumour cell metabolism (Fig 6b) [80]. Despite all these results, only few in vivo experiments are reported with radioactive metallo-glycodendrimers. Therefore, the final goal should lie in the development of stable and facile method to synthesize radioactive glycodendrimers. 5. Conclusions The past few years have seen a steady growth of multivalent glycodendrimer that are reported to improve the prospect of
decoding several biological information’s hidden by carbohydrates. In contrast to number of organic and nanoparticles based glycodendrimers, metalloglycodendrimers have only recently started to systematically investigated. Taking full advantage of fluorescence, electrochemical, radioactive properties of metal complexes, receptor-targeted molecular biosensors, bio-imaging and growth promoter were achieved. Despite significant studies, the employment of these dendrimers in therapeutics and in vivo targeting represents largely untapped areas. It is expected that new developments will certainly broaden horizon of metalloglycodendrimers, both at the fundamental and biomedical applications of these complexes. Acknowledgements We thank IISER, Pune, Indo-German (DST-MPG) program and DAE (Grant No.2011/37C/20/BRNS) and CSIR, India for financial support. References [1] D.B. Werz, P.H. Seeberger, Nat. Rev. 4 (2000) 751. [2] T. Angata, A. Varki, Chem. Rev. 102 (2000) 439. [3] A. Varki, R. Cummins, J. Esko, H. Freeze, G. Hart, J. Marth (Eds.), Essentials of Glycobiology. Consortium of Glycobiology, La Jolla, California, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1999.
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