Cyclodextrin-Based Functional Glyconanomaterials

Abstract

Cyclodextrins (CDs) have long occupied a prominent position in most pharmaceutical laboratories as "off-the-shelve" tools to manipulate the pharmacokinetics of a broad range of active principles, due to their unique combination of biocompatibility and inclusion abilities. The development of precision chemical methods for their selective functionalization, in combination with "click" multiconjugation procedures, have further leveraged the nanoscaffold nature of these oligosaccharides, creating a direct link between the glyco and the nano worlds. CDs have greatly contributed to understand and exploit the interactions between multivalent glycodisplays and carbohydrate-binding proteins (lectins) and to improve the drug-loading and functional properties of nanomaterials through host-guest strategies. The whole range of capabilities can be enabled through self-assembly, template-assisted assembly or covalent connection of CD/glycan building blocks. This review discusses the advancements made in this field during the last decade and the amazing variety of functional glyconanomaterials empowered by the versatility of the CD component.

Keywords: cyclodextrins; drug delivery; gene delivery; glyconanomaterials; glyconanoparticles; glycopolymers; glycotargeting; multivalency; self-assembly; supramolecular nanomaterials.

Figure 1

Structures of α, β and γCD (left), 3D view of βCD (upper-right) and schematic representation of CD basket-shape architecture (lower right), with indication of the height, and average internal and external diameters for the three commercially available representatives. CD, cyclodextrin.

Figure 2

Docetaxel (DTX) carrier consisting of a hexamannosylated dimeric βCD derivative designed on the basis of the drug clusterization concept [35]. Adapted with permission from Reference [3]. Copyright 2013 Royal Society of Chemistry.

Figure 3

Heptamannosyl-βCD/Ru(II)-scaffolded hexa-adamantyl host–guest complex reported by Seeberger and coworkers [38] (a) and bis-adamantyl analogs with anti-apoptotic activity reported by Kikkeri and coworkers [40] (b). Adapted with permission from Reference [40]. Copyright 2016 Royal Society of Chemistry.

Figure 4

Structures of the CD-Man₇ glycoCD host and BTA tritopic guest used by Zhang, Yin and coworkers (a) and schematic representation of their self-assembly into nanoaggregates for targeted photodynamic therapy against breast cancer (b) [42]. CD, cyclodextrin; Man, mannose; BODIPY, boron-dipyrromethene; BTA, BODIPY-tris-Ad derivative; LSD, dynamic light scattering; MR, mannose receptor.

Figure 5

Schematic illustration of the superamphiphile strategy developed by Zhang and coworkers for the self-assembly of acid-sensitive ASGPR-targeted prodrug glyconanoparticles [46]. ASGPR, asialoglycoprotein receptor; LA, lactobionic acid; PEG, poly(ethylenglycol); βCD, β-cyclodextrin; BM, benzimidazole; DOX, doxorubicin.

Figure 6

Structures of the GaCD derivative C₃-CD-Man₇, doxorubicin (DOX) and amphotericin B (AmB) (upper panel) and schematic representations of their co-assembly to afford pH-sensitive nanoparticles (Amb@DOX@C₃-CD-Man₇) (middle panel) and internalization in macrophages to treat visceral leishmaniasis (lower panel), as reported by Seeberger, Yin and coworkers [55,57]. GaCD, glycoamphiphilic cyclodextrin; Man, mannose; NP, nanoparticle.

Figure 7

Average structure of the triblock copolymer (P1) and structures of the βCD derivatives used by Bercer and coworkers [61] to self-assemble glycomicelles trough equimolecular mixing in water (a) and turbidity plots obtained upon mixing with concanavalin A (ConA) at 40 °C (b). Adapted with permission from Reference [61]. Copyright 2016 Royal Society of Chemistry. PDMA, poly(N,N-dimethylacrylamide); PNIPAM, poly(N-isopropyl acrylamide); PAdac, poly(adamantane-acrylate).

Figure 8

Triblock glycocopolymers bearing βCD units designed by Bercer and coworkers [63] to modulate the C-type lectin binding properties through intramolecular host–guest control of the folding state. Adapted with permission from Reference [63], https://pubs.acs.org/doi/abs/10.1021/acs.biomac.8b00600. Copyright 2018 American Chemical Society. ConA, concanavalin A.

Figure 9

One-pot multicomponent synthesis of polyrotaxane-based heteroglycopolymers developed by Gao, Chen and coworkers [68]. CuAAC, copper(II) azide-alkyne cycloaddition; PPG, polypropylene glycol.

Figure 10

Polyrotaxane-based glycopolymers developed by Jia, Ren and coworkers [76] and a schematic representation of their self-assembly into doxorubicin-loaded micelles for the targeted delivery of the drug to tumor cells. A representative transmission electron microscopy (TEM) micrograph of the later is also shown. Adapted with permission from Reference [76]. Copyright 2019 WILEY-VCH. PEG, polyethylene glycol; PPR, pseudo(polyrotaxane); GlcN-PR, 2-amino-2-deoxy-β-D-glucopyranose-appended αCD-based polyrotaxane; DOX, doxorubicin.

Figure 11

Structures and schematic representation of the functional supramolecular glycosystems developed by Vargas-Berenguel and coworkers for targeted nitric oxide-based therapies [80]. NO, nitric oxide.

Figure 12

Molecular structures and schematic illustrations of the mannosylated βCD derivative βCD-Man, the adamantane-equipped poly(ethylene glycol) derivative Ada-PEG, concanavalin A (ConA) and αCD, and of their combination to obtain supramolecular nanoparticles and hydrogels, as reported by Chen and coworkers [82]. CD, cyclodextrin; Man. Mannose; Ada-PEG, adamantane-equipped poly(ethylene glycol), ConA, concanavalin A.

Figure 13

Structures of the polycationic amphiphilic βCD derivative paCD-N₁₄ (14 cationizable primary amines), the glycoamphiphilic βCD derivative GaCD-Man₇ (neutral; 7 mannosyl residues) and the polycationic glycoamphiphilic βCD derivative (7 cationizable primary amines and 7 mannosyl residues) reported by García Fernández and coworkers [156]. A representative image at high magnification of the CDplexes obtained from the latter and the luciferase-encoding plasmid DNA (pDNA) pTG11236 (5739 bp) is also shown. Adapted with permission from Reference [156]. Copyright 2011 Elsevier.

Figure 14

Structures of the paCD-triazol (a), paCD-thiourea (b) and ManEt-NCS (c) precursors used by Di Giorgio, Benito and coworkers [164] to prepare pGaCDs with variable proportions of mannosyl motifs, and a schematic representation of their co-assembly with pDNA to form glycoCDplexes that selectively promoted receptor (MMR)-mediated transfection of the targeted cells (macrophages) (d). Adapted with permission from Reference [164]. Copyright 2015 Royal Society of Chemistry. paCD, polycationic amphiphilic cyclodextrin; Man, mannose; pGaCDs, polycationinc glycoamphiphlic cyclodextrins; MMR, macrophage mannose receptor.

Figure 15

Structures of the polycationic amphiphilic CDs (paCDs) and glycoamphiphilic CDs (GaCDs) used by O’Driscoll and coworkers [165] for the formulation of pDNA-templated nanocomplexes (glycoCDplexes) targeting the asialoglycoprotein receptor (ASGPR). DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine.

Figure 16

Schematic representation of the statistically galactosylated paCD (GalCD) vectors used by Rejman and coworkers to formulate glycoCDplexes with mRNA for the ASGPR-mediated transfection of hepatocytes [167].

Figure 17

Structure of the 6-amino-6-deoxy β-D-glucopyranosylthioureido/βCD conjugate prepared by Jiménez Blanco, Di Giorgio and coworkers, and an illustration of their co-assembly with pDNA to form nanocomplexes that promoted ASGPR-mediated transfection of hepatocytes [170,171]. A representative TEM micrograph of the nanocomplexes is also shown. Adapted with permission from Reference [170]. Copyright Centre National de la Recherche Scientifique (CNRS) and Royal Society of Chemistry.

Figure 18

Structures of the lactosylated (a) and thiomannosylated (b) αCD-coated glycodendrimers prepared by Arima and coworkers and a schematic representation of their co-assembly with siRNA to form dendriplexes targeted to hepatocytes or antigen-presenting cells (APCs) respectively, for the treatment of transthyretin-related (TTR) amyloidosis [176] or fulminant hepatitis [177].

Figure 19

Illustration of the strategy developed by Ravoo and coworkers for the preparation of self-assembled CD-based vesicles (CDVs), their coating with mannosyl dendrons through host–guest interactions and the potential of the resulting Man-CDVs in anti-adhesive therapy against uropathogenic FimH-expressing E. coli [184].

Figure 20

Illustration of the nanospheres (NSs) prepared by nanoprecipitation of βCD-calix[4]arene hybrids by Sansone, Casnati, García Fernández, Ceña and coworkers [185,186,187], their loading with anticancer drugs (e.g., docetaxel, DTX) and their host–guest decoration with glycoligands for targeted delivery. A representative tapping-mode atom force microscopy (AFM) image of the NSs (5 × 5 μM; insert 0.7 × 0.7 μM) is also shown. Adapted with permission from Reference [187]. Copyright Royal Society of Chemistry.

Figure 21

Illustration of the method for separation of proteins reported by Samanta and Ravoo [188] using the cross-linking and magnetic precipitation of magnetic nanoparticles modified with cyclodextrin-acid derivatives (MNP-CDA) and adamantane-armed glycoligands (G1 and G2). Reprinted with permission from Reference [188]. Copyright 2014 WILEY-VCH. FITC-PNA, fluorescein isothiocyanate-labelled peanut agglutinin; TRITC-ConA, tetramethylrhodamine-labelled concanavalin A.

Figure 22

Illustration of the lactose- and βCD-decorated gold nanoparticles developed by Vargas-Berenguel and coworkers [195] for the selective delivery of methotrexate (MTX) to human tumors expressing galectin-3 (Gal-3). Adapted with permission from Reference [195]. Copyright 2014 American Chemical Society.

Figure 23

Structures and schematic representation of the strategy developed by Riela, Lazzala and coworkers to assemble hybrid glycoCD/halloysite nanotubes to achieve functional glyconanomaterials for the co-administration of curcumin (Cur) and silibinin (Sil) in thyroid cancer cells [196,197].