molecules Review Cyclodextrin-Based Contrast Agents for Medical Imaging Yurii Shepelytskyi 1,2 , Camryn J. Newman 3, Vira Grynko 1,2 , Lauren E. Seveney 4, Brenton DeBoef 4, Francis T. Hane 2,5 and Mitchell S. Albert 2,5,6,* 1 Chemistry and Materials Science Program, Lakehead University, Thunder Bay, ON P7B 5E1, Canada; [email protected] (Y.S.); [email protected] (V.G.) 2 Thunder Bay Regional Health Research Institute, Thunder Bay, ON P7B 6V4, Canada; [email protected] 3 Biology Department, Lakehead University, Thunder Bay, ON P7B 5E1, Canada; [email protected] 4 Chemistry Department, University of Rhode Island, Kingston, RI 02881, USA; [email protected] (L.E.S.); [email protected] (B.D.) 5 Chemistry Department, Lakehead University, Thunder Bay, ON P7B 5E1, Canada 6 Northern Ontario School of Medicine, Thunder Bay, ON P7B 5E1, Canada * Correspondence: [email protected]; Tel.: +1-807-355-9191 Academic Editors: Marina Isidori, Margherita Lavorgna and Rosa Iacovino Received: 30 October 2020; Accepted: 26 November 2020; Published: 27 November 2020 Abstract: Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides consisting of multiple glucose subunits. CDs are widely used in host–guest chemistry and biochemistry due to their structural advantages, biocompatibility, and ability to form inclusion complexes. Recently, CDs have become of high interest in the field of medical imaging as a potential scaffold for the development of a large variety of the contrast agents suitable for magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, positron emission tomography, single photon emission computed tomography, and computed tomography. The aim of this review is to summarize and highlight the achievements in the field of cyclodextrin-based contrast agents for medical imaging. Keywords: medical imaging; contrast agents; α-cyclodextrin; β-cyclodextrin; γ-cyclodextrin; MRI; PET; CT; SPECT; PAI 1. Introduction Cyclodextrins (CDs) are chemically stable naturally occurring cyclic oligosaccharides consisting of multiple glucose subunits connected by α-1,4 glycosidic bonds [1,2]. There are three main types of CDs that contain six (α-CD), seven (β-CD), and eight (γ-CD) glucose subunits in a ring (Figure1). These cyclodextrin macromolecules are cone-shaped with a hydrophobic interior cavity and polar exterior surface [3]. Due to their non-toxic nature [1,4–6] and water solubility [7–9], CDs became widely used in various biomedical fields such as drug solubilization [7,10–12], drug delivery [8,13–17], and nucleic acid transfer [18–20]. Molecules 2020, 25, 5576; doi:10.3390/molecules25235576 www.mdpi.com/journal/molecules Molecules 2020, 25, 5576 2 of 27 Molecules 2020, 25, x FOR PEER REVIEW 2 of 27 Figure 1. ChemicalChemical structure structure of of ( (aa)) αα-cyclodextrin,-cyclodextrin, ( (b)) β-cyclodextrin,-cyclodextrin, and and ( (cc)) γγ-cyclodextrin.-cyclodextrin. ComparedCompared to to other other macrocyclic macrocyclic hosts, hosts, cyclodextrins cyclodextrins are areby far by the far most the most extensively extensively used in used host– in guesthost–guest chemistry chemistry applications applications and medical and medical imaging imaging [21–25]. [They21–25 tend]. They to be tend the tomacrocycle be the macrocycle of choice dueof choice to their due structural to their structural advantages advantages and robust and robustability abilityto form to forminclusion inclusion complexes complexes [21,26]. [21 ,An26]. inclusionAn inclusion complex complex is formed is formed when when a guest a guest molecule, molecule, commonly commonly a asmall small drug, drug, is is partially partially or or fully fully encapsulatedencapsulated inside inside the the host’s interior cavity [1,3]. [1,3]. In In the the case case of of cyclodextrins, cyclodextrins, their their preferred preferred guest guest moleculesmolecules tend tend to to be be hydrophobic, hydrophobic, making making them them suitable suitable for for binding binding in in the the hydrophobic hydrophobic interior. interior. Therefore, cyclodextrins possess possess the the ability ability to to form form inclusion inclusion complexes complexes with with a a wide variety of hydrophobichydrophobic guest molecules [26–28]. [26–28]. Formation Formation of of inclusion inclusion complexes, complexes, or or molecular molecular encapsulation, encapsulation, cancan affect affect the the physiochemical physiochemical properties properties of of the the drug drug or or molecule molecule itself, itself, such such as assolubility solubility and and rate rate of dissolutionof dissolution [3]. [ 3CDs]. CDs are are often often exploited exploited because because of of this this property property in in addition addition to to enhancing enhancing water water solubilitysolubility of of water-insoluble water-insoluble molecules [3]. [3]. The The exte exteriorrior of of cyclodextrin cyclodextrin is is predominantly predominantly hydrophilic hydrophilic duedue to the extensive hydrogenhydrogen bondingbonding network,network, making making it it a a biocompatible biocompatible agent agent for for a widea wide range range of ofapplications applications [1– 3[1–3,6–17].,6–17]. These These structural structural factors factors are largely are whylargely CDs why are favored CDs are when favored synthesizing when synthesizinginclusion complexes. inclusion Electronicscomplexes. and Electronics thermodynamics and thermodynamics both play a roleboth in play determining a role in determining if a CD will ifform a CD an will inclusion form an complex inclusion with complex a guest moleculewith a gues [1].t molecule The driving [1]. force The fordriving inclusion force complexationfor inclusion complexationinvolves various involves noncovalent various interactions noncovalent such interact as desolvation,ions such or as removal, desolvation, of water or moleculesremoval, of from water the moleculesinterior cavity from and the formation interior cavity of Van and der Waals,formatio hydrophobic,n of Van der and Waals, hydrogen hydrophobic, bonding interactions and hydrogen [29]. bondingThe major interactions driving forces [29]. for The cyclodextrin major driving complexation forces for arecyclodextrin van der Waals complexation interaction are and van hydrophobic der Waals interactioninteraction, and whereas hydrophobic hydrogen interaction, bonding and whereas electrostatic hydrogen interaction bonding mostly and electrostatic affect the conformation interaction mostlyof a particular affect the inclusion conformation complex of a [29 particular]. CD’s ability inclusion to form complex inclusion [29]. complexesCD’s ability with to form small inclusion organic complexesmolecules haswith pioneered small organic the field molecules of supramolecular has pioneered chemistry. the field More of supramolec recently, CDsular havechemistry. successfully More recently,been used CDs to buildhave successfully various molecular been used architectures to build various such asmolecular catenanes, architectures rotaxanes, such pseudorotaxanes, as catenanes, rotaxanes,polyrotaxanes, pseudorotaxanes, and other molecular polyrotaxanes, machines and [30 other,31]. molecular machines [30,31]. DuringDuring thethe pastpast few few decades, decades, cyclodextrins cyclodextrins have have become become of interest of interest as contrast as contrast agents and agents potential and potentialbiosensors biosensors for different for medicaldifferent imaging medical modalities imaging modalities [32]. In the [32]. context In the of context imaging, of CDs imaging, have beenCDs haveused been primarily used asprimarily a scaffold as to a supportscaffold andto support/or solubilize and/or smaller solubilize molecules smaller that molecules produce that or quenchproduce a orsignal quench for enhanceda signal for imaging. enhanced However, imaging. inHowever, a few cases, in a thefew uniquecases, the supramolecular unique supramolecular nature of thenature CD ofis essentialthe CD is inessential producing in producing the signal the for signal imaging. for imaging. Examples Examples of CD-containing of CD-containing constructs constructs that can that be canimaged be imaged by a wide by a variety wide variety of modern of modern imaging imaging technologies technologies are discussed are discussed herein. herein. MagneticMagnetic resonance resonance imaging imaging (MRI) (MRI) was was the the first first imaging modality to utilize cyclodextrins as contrastcontrast agents agents [33]. [33]. CD-based CD-based MRI MRI contrast contrast agents agents produced produced contrast contrast through through the reduction the reduction in spin- in lattice relaxation (T1) time of the water protons. There are two different established methods of spin-lattice relaxation (T1) time of the water protons. There are two different established methods synthesisof synthesis of CD-based of CD-based MRI MRI contrast contrast agents: agents: (1) host (1)–guest host–guest interactions interactions between between CD cavity CD and cavity metal– and organicmetal–organic complexes complexes [33,34] [33 and,34 ](2) and by (2) direct by direct conjugation conjugation of ofCDs CDs to tothe the metal–organic metal–organic complexes complexes through the external hydroxyl groups of CD molecule [35,36]. The reduction in T1 relaxation for CD- through the external hydroxyl groups of CD molecule [35,36]. The reduction in T1 relaxation for basedCD-based contrast contrast agents, agents, and therefore and therefore their contrast their contrast,,