Inorganica Chimica Acta 409 (2014) 26–33

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Inorganica Chimica Acta

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Review

Recent advances in the metallo-glycodendrimers and its potentialapplications

Shadab Ali Khan received his M.Sc. degree in Biochemistry from Amravati University (M.S.), India in 2003. He obtained his Ph.D. degNational Chemical Laboratory, Pune, India in 2012 in Biotechnology. After Ph.D. he joined the group of Dr. Raghavendra Kikkeri as a PostResearch Associate at Department of Chemistry, Indian Institute of Science Education & Research (IISER), Pune, India. His researchinclude 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 Mprogramme in Indian Institute of Science Education and Research,Pune. During her MS in Chemistry she had joined Dr. Raghavendragroup .Her research focuses on designing carbohydrate based smart molecules to study glycan-protein interaction in more efficient ma

0020-1693/$ - see front matter � 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.ica.2013.06.017

⇑ Corresponding author. Tel.: +91 20 2590 8207.E-mail address: rkikkeri@iiserpune.ac.in (R. Kikkeri).

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:CarbohydratesMetalloglycodendrimersOptical propertiesTransition metal complexesRadioactiveLanthanide complexes

a b s t r a c t

Ever since the discovery of the phenomenon of multivalent representation of sugar to enhance the bind-ing affinity of specific carbohydrate-protein interactions, the quest for the construction of carbohydrateclusters, 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 willimprove the prospect of direct readout of specific carbohydrate-protein interactions. To address thisquestion, the design of metallo-glycodendrimers with precise sugar topology is critically important. Inthis review, we provides an overview of the important roles that metallo-glycodendrimers can play aslectin binding molecules, highlighting the unique properties metals can confer to these studies.

� 2013 Elsevier B.V. All rights reserved.

ree fromDoctoralinterests

S – PhDKikkeri’snner.

Raghavendra Vasudeva Murthy received his M.Sc. degree from university of Mysore in 2001, He obtained his Ph.D degree from University ofCatanzaro, Italy. After Ph.D. he joined the group of Dr. Raghavendra Kikkeri as a postdoctoral research associate. His research interests includeoncology, glycobiology and glyconanotechnology.

Raghavendra Kikkeri received his master degree from university of Mysore, where he studied organic chemistry as major, In 2001 he moved toWeizmann Institute of science, Israel, where he earned his Ph.D in organic chemistry under the guidance of Prof. Abraham Shanzer. Afterpostdoctoral fellowship with Prof. Peter Seeberger and Prof. Ajit Varki at ETH Zurich, MPI Berlin and UCSD San Diego. He became Assistantprofessor at the Indian Institute of Science Education and Research (IISER) in Dec 2010. Recently, he started Max- Planck partner group in IISER,Pune.

S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33 27

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272. What makes metallo-glycodendrimers special?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272. What makes metallo-glycodendrimers special?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283. Synthesis of metallo-glycodendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284. Metalloglycodendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

4.1. Glycodendrimers with transition metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284.2. Complexes with lanthanide metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304.3. Metal complexes with radioactive properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

1. Introduction

Lectins are specific carbohydrate-binding or carbohydratecross-linking proteins. The interactions between lectins and sugarsare involved in a large number of biological processes, such as celladhesion and migration, phagocytosis, cell differentiation andapoptosis [1–4]. Over the past 120 years, numerous lectins havebeen isolated from plants, microorganisms, fungi, animals andviruses [5–7]. Lectins have been used as tools for the detection, iso-lation and characterization of various glycoproteins and for theclinical diagnosis of carcinoma and leukemia [8,9]. Despite theprevalence of lectin in biological systems, the binding betweenan individual lectin and monovalent carbohydrate are quite weakand not particularly specific [10,11]. Nature provides strong andspecific responses by carbohydrate multivalency. In multivalentinteractions, multiple copies of the ligand and receptors sequen-tially or simultaneously bind and significantly increase bindingaffinity for a meaningful and biologically relevant recognition pro-cesses [12,13]. A host of glycoclusters have been prepared and ex-plored in different applications. It has been shown that multivalentmannose glycoclusters inhibited HIV infection [14,15]. Multivalentglycoclusters have also been shown to function against bacterialtoxins [16,17] and against bacterial adhesion to human cells [18–

20]. Multivalent glycoconjugates are also being used for stimula-tion of immune system [21–23]. Similarly, several glycoclustershave been used as a potential target for drug development, genedelivery and diagnostic tools [24–27]. Hence there is a need fornew multivalent probe to study carbohydrate-protein interactionsin order to unravel the finer details of these interactions. Researchgroups of Seeberger, Roy, Penadés and Marra have reported carbo-hydrate clusters on dendrimers, polymers, liposomes, micelles aswell as cyclodextrin and calixarenes templates [28–36].

Interactions between carbohydrates and proteins can be stud-ied by using a range of biophysical techniques. The strength ofinteractions between a given glycoclusters and the lectins havebeen calculated by Isothermal Titration Calorimetry (ITC), SurfacePlasmon Resonance (SPR), Fluorescence Resonance Energy Transfer(FRET) and dialysis. Most glycoclusters reported to date are able todisplay inherent optical, electrochemical or gravimetric propertiesfor bioimaging or biosensing processes [37–42]. Apart from thepurely organic or nanoparticles based glycoclusters reported aslectin binders [43,44], it has recently been shown that metallo-gly-codendrimers can also be a potential glycoclusters for lectins [45–47], with the number of reported example increasing rapidly overthe past couple of years. In this review we aim to provide an over-view of the important roles of the metallo-glycodendrimers. The

(a)

(b)

(c)(d)

o

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].

28 S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33

review also highlights the current efforts made to synthesizemetallo-glycodendrimers for evaluating their lectin recognitionproperties 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 forthe development of specific lectin-carbohydrate biosensors. A me-tal center can be envisaged as a structural locus that organizes che-lators in specific geometries or clustures to propagate specificsugar mediated lectin binding. The relative ease of synthesis of me-tal complexes can allow the generation of small libraries of relatedcompounds. Moreover, variations can be introduced by modifyingthe ligands or metal center to tune the multivalency and structuralarrangements of the clusters. These variations render metal com-plexes advantageous over their organic counterparts, where analo-gous geometrical changes are often more difficult to introduce.Finally, metal complexes allow one of the best methods to studythe influence of internal or external chirality and orientation ofthe sugar clusters with respect to external stimuli.

3. Synthesis of metallo-glycodendrimers

There are two methods generally accepted for the synthesis ofmultivalent metallo-glycodendrimers: the convergent approach

and the divergent approach. A convergent synthesis is essentiallythe polyvalent construction from the ‘outside-in’ toward a suitablecore. Here, synthesis of ligand carrying carbohydrates followed bymetal complex formation. A divergent approach corresponds toopposite building from the ‘inside-out’ starting with a multi-func-tional core. A suitable metallodendrimers was constructed fol-lowed by encapsulation of carbohydrate at the final modificationstep. Both approaches result in glycoclusters having 3-dimensionaltopology similar to cell surface glycans topology and play animportant role in elucidating carbohydrate-protein interactions.However, the divergent method is considered to be more suitablefor generation of metalloglycodendrimers, as it is more straightfor-ward to control the clusterization and multivalency.

4. Metalloglycodendrimers

4.1. Glycodendrimers with transition metals

Iron complexes were one of the earliest examples of metallogly-codendrimers to be evaluated for the importance of chirality dur-ing specific carbohydrate protein interactions. The authorsshowed the synthesis of the sugar substituted by bipyridine li-gands, which subsequently form D and K sugar Fe(III) complexesto study specific carbohydrate-lectin interactions [48]. Metallo-glycodendrimers focused on Cu(II), Fe(II), Ir(II), Rh(II) and Ru(II)were also reported [49–54]. Among these metals, ferrocene and

Fig. 2. Schematic representation of metalloglycodendrimer and synthetic methods (a) convergent method; (b) divergent method.

S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33 29

Ru(II) complexes were most attractive metallo-glycodendrimersfor their robustness and photophysical properties [55]. Ru(II) com-plexes exhibit a lowexcited triple metal-to-ligand charge transferstate (3MLCT) and the room temperature 3MLCT lifetimes wereup to 1 ls, high-emission quantum yields and strong oxidizingand reducing capabilities [56,57]. Ru(II) dendrimers were exten-sively used as photo-catalysts, as reactions in intermolecular andintramolecular energy and electron-transfer process [58]. The syn-thesis of Ru(II)-glycodendrimers were started from 2,20-bipyridine(bpy) functionalization at 4 and 40 positions, so that a variety ofdendritic wedges could be appended to build glycodendrimerscontained on [Ru(bpy)3]2+ core. Both convergent and divergentmethod was applied to synthesize Ru(II)-glycodendrimers bearingvarying numbers of carbohydrates. In the convergent method, li-gands carrying sugar dendrons weresynthesized separately andthen united with Ru(II) ion to get octahedral symmetric metallo-glycodendrimers [59]. A straight forward Huisgen [3+2] cyclo-

addition, host–guest strategy were applied in divergent methodto synthesize a library of metalloglycodendrimers [60].

The luminescent Ru(II) and Ir(II) complexes of mannose or gal-actose glycodendrimers have been utilized to address biochemicaland biomedical questions [29,61]. In this context, carbohydrate-protein interactions were studied by using fluorescent turbidity as-say and microarray techniques. Seeberger and co-workers haveshown that the density of sugar around the metal complex directlyinfluence the binding affinity and photo-physical properties of thecomplexes. This alteration in photo-physical properties is due tobettershielding of Ru(II) core by the topology of the hydrophiliccore of the sugar [29]. Based on optical properties of Ru(II) com-plexes, lectin biosensors were developed on microarray plates.ConcanavalinA (ConA) lectin was immobilized on a microarraysprior to incubation with mannose or galactose Ru(II) complexes.Upon fluorescence scanning of rinsed slides, strong fluorescent sig-nals were observed on slides that were incubated with mannose

(a)

(c)

(b)

(d)

(b)

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.

30 S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33

complexes and ConA could be detected at as low as 0.125 mg/mL(620 nM). To probe the versatility of the Ru(II)-glycodendrimersas a potential lectin biosensor, photo-induced electron transfer(PET) between Ru(II)-glycodendrimers and methyl viologen dica-tion (MV2+) was applied to detect ConA at 25–28 nM [46] (Fig.4c).The redox properties of Ru(II) complexes were also exploited to de-velop electrochemical biosensors. ConA was immobilized on a self-assembled monolayer gold surface prior to incubation with Ru(II)complexes [30]. The chip was transferred to a cyclic voltameter cellto record square wave voltametric (SWV) signal of Ru(II) complex.Based on the electrochemical signals, lectin-metalloglycodendri-mer interaction was established and ConA was sensed at a lowestlimit of 2.5 nM, which was comparable to other sugar sensor mod-els. A reusable sugar sensor, based on the displacement of the re-dox glyco-probes by preferential lectin binding carbohydrateswas also developed. Using this method biologically important sug-ars such as glucose, phosphatidylinositol mannose (PIM) glycanswere detected at a detection limit of 7.0 and 0.6 lM concentra-tions. Thereproducibility of the above chip was established byexposing the gold chips to boronic acid substituted merrified resinto regenerate the lectin surface for the next measurement (Fig. 4a).

More recently, Seeberger et al. have extended the synthesis ofmetalloglycodendrimers by using host–guest concept. FluorescentRu(II) complexes were functionalized with 14, 28 or 42 mannopyr-anosyl units using adamantine-cyclodextrin based host–guest

chemistry. These systems proved to be very well suited to probethe structural arrangement of glycodendrimer for efficient bindingto immobilized ConA lectin by surface plasmon resonance (SPR).Additionally, the optical properties of Ru(II)-glycodendrimers al-lowed direct imaging of their association with E. coli (stainORN178), having mannose binding FimH lectin in the pili, by con-focal microscopic imaging [60] (Fig. 4d).

Our work in this area has centered on the development ofmetalloglycodendrimers that can be used to increase the local con-centration of essential elements to amplify the growth and otherfunctions in living species. A catechol coupled Fe(III) glycodendri-mers have been prepared using self-assembly process for targetinga specific stain of E. coli (ORN 178) and we have shown that theinteraction of Fe(III)-glycodendrimers and FimH receptor mediatediron delivery, inducing iron mediated growth promotion, bygrowth promotion assay and LB plate assay [49] (Fig. 4b). These re-sults have confirmed that transition metallo-glycodendrimers canbe use in biosensors and imaging studies.

4.2. Complexes with lanthanide metals

Among lanthanides, Gd(III) complexes are the most studiedand popular choice for functionlization with carbohydrates toobtain Gd(III) based glycodendrimers. Lanthanide ions speciallyGd(III)-glycoconjugates have been extensively used in Magnetic

Fig. 4. Applications of metalloglycodendrimers.

S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33 31

Resonance Imaging(MRI), which is a diagnostic modality based onthe enhancement of contrast given by paramagnetic contrastagents (CAs). Gd(III) complexes demonstrated to be the most suit-able paramagnetic CAs for MRI, due to the high paramagnetism ofthe 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 galact-ose) of different valencies (mono, di and tetra) and their lanthanideions complexes such as Gd(III), Eu(III) and Sm(III) ions. The authorsalso studied the interaction of Gd(III)-glycoconjugates in vitro withthe model lectin Ricinus communis agglutinin (RCA) throughrelaxometric measurements. Their results could open the way forthe study of Gd(III)-glycoconjugates as potential candidates for lec-tin-mediated molecular imaging agents [64]. Similar kind of workhas been carried out by Fulton et al. where they have synthesizedglycoconjugates of Gd(III) complexes with enhanced relaxivity assharp contrast agents for MRI [65]. Vera et al. have also developedGd-DTPA conjugate of polylysine (PL) derivatized with galactosylgroups (Gd-DTPA-gal-PL) as potential contrast agents for liverMRI by targeting the hepatocyte ASGPR (asyaloglycoprotein recep-tor) and tested in cells and mice [66]. Gd(III)-based glycodendri-mers have also been shown to be useful for in vitro and in vivo(Xenopus laevis embryos) visualisation and localisation of geneexpression by MRI (Fig. 5a) [67,68].

The fluorescent and relaxometric properties of Eu(III) andGd(III) complexes respectively with bound sugars (galactose, glu-cose) were used to gain mechanistic insights into their water bind-ing behaviour [69]. Very recently Rodríguez et al. have reportedthe synthesis of a luminescent Tb3+-DOTA complex bearing an

a-D-mannose residue and the related study of binding affinity withconcanavalin A (Con A) labelled with rhodamine-B-isothiocyanate(RITC-Con A). Luminescence spectroscopy and dynamic studiesshow changes in emission spectra that can be ascribed to a lumi-nescence resonance energy transfer (LRET) from Tb(III) complex(donor) to RITC-Con A (acceptor).The binding constant value be-tween the two species was found to be one order of magnitude largerthan those previously reported for similar types of recognition (Fig5b) [70]. These results confirmed that it is possible to generate lan-thanide-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 single-photon emission computed tomography (SPECT) or positron emis-sion tomography (PET) and coupled procedures like PET/computedtomography (CT), radioactive-labelled biomolecules are beingincreasingly used for the visualisation of certain cell types and tis-sues. Glycoclusters conjugated with radioactive metal complexesare gradually becoming important tools for in vivo cell and tissueimaging. Among this 99mTc(I) based glycoconjugates are the mostwidely used and extensively studied [71,72]. Most of the synthes-ised complexes are glucose-based aiming to take advantage of theover expression of glucose transporters (GLUT1). Schibli et al.tested the cellular uptake of the 99mTc(I) complexes bound to theC-2, C-3 or C-6 position of glucose by oxygen, by colon carcinomacells HT29 [73]. 99mTc-DTPA-GSA, a conjugate of galactosylatedserum albumin (GSA) with 99mTc-DTPA (DTPA = 3,6,9 tris(carboxy-methyl)-3,6,9-triazaundecan-1,11-dioic acid) (Fig. 6a), has beenshown to be useful in SPECT (single photon emission computed

(a) (b)

Fig. 5. (a) Gd(III) based glycodendrimer [65]; (b) Tb(III) based glycodendrimer [70].

(a)

(b)

Fig. 6. (a) Radiolabelled 99Tc glycodendrimer [72]; (b) 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) [80].

32 S.A. Khan et al. / Inorganica Chimica Acta 409 (2014) 26–33

tomography) hepatic imaging to assess ASGPR in mice [74] andused clinically in humans [75,76]. The targeting of the ASGPR hasbeen demonstrated both in a cell line and mice with a 111In-radio-labelled galactopyranosyl conjugate of DOTA (1,4,7,10-tetra-kis(carboxymethyl)-1,4,7,10-tetraazacyclododecane) [77]. So far,99mTc-/188Re-DTPA (diethylenetriamine pentaacetic acid) com-plexes are the most promising candidates to act as functionalimaging agents which are derived from 2-N-2-deoxy-D-glucosamine.These derivatives were phosphorylated by hexokinase exhibiting cel-lular uptake probably by a multifunctional glucose transport systemand reveal higher tumor-to-tissue ratios than observed for othertracers in in vivo experiments in small animal tumour models[78,79]. Another radiolabelled metal complexe of 2-18F-2-deoxy-D-glucose (FDG) is used as a sugar-based tracer to monitor glucosetransporter (GLUT1) activity by PET/CT, and to image tumour cellmetabolism (Fig 6b) [80]. Despite all these results, only few in vivoexperiments are reported with radioactive metallo-glycodendrimers.Therefore, the final goal should lie in the development of stable andfacile method to synthesize radioactive glycodendrimers.

5. Conclusions

The past few years have seen a steady growth of multivalentglycodendrimer 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 glyco-dendrimers, metalloglycodendrimers have only recently startedto systematically investigated. Taking full advantage of fluores-cence, electrochemical, radioactive properties of metal complexes,receptor-targeted molecular biosensors, bio-imaging and growthpromoter were achieved. Despite significant studies, the employ-ment of these dendrimers in therapeutics and in vivo targeting rep-resents largely untapped areas. It is expected that newdevelopments will certainly broaden horizon of metalloglycoden-drimers, both at the fundamental and biomedical applications ofthese complexes.

Acknowledgements

We thank IISER, Pune, Indo-German (DST-MPG) program andDAE (Grant No.2011/37C/20/BRNS) and CSIR, India for financialsupport.

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