Cyclodextrins as Multifunctional Platforms in Drug Delivery and Beyond: Structural Features, Functional Applications, and Future Trends

Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides capable of forming inclusion complexes with various guest molecules, enhancing solubility, stability, and bioavailability. This review outlines the structural features of native CDs and their chemically modified derivatives, emphasizing the influence of functionalization on host-guest interactions. Synthetic approaches for CD derivatization are summarized, with attention to recent developments in stimuli-responsive systems and targeted drug delivery. Analytical techniques commonly employed for characterizing CD complexes, such as spectroscopy, thermal analysis, and molecular modeling, are briefly reviewed. Applications in pharmaceutical formulations are discussed, including inclusion complexes, CD-based conjugates, and nanocarriers designed for solubility enhancement, controlled release, and site-specific delivery. Special consideration is given to emerging multifunctional platforms with biomedical relevance. The regulatory status of CDs is addressed, with reference to FDA- and EMA-approved formulations. Safety profiles and toxicological considerations associated with chemically modified CDs, particularly for parenteral use, are highlighted. This review presents an integrative perspective on the design, characterization, and application of CD-based systems, with a focus on translational potential and current challenges in pharmaceutical development.

Keywords: inclusion complexes; nanocarriers; stimuli-responsive systems.

Figure 1

Formation of a cyclodextrin inclusion complex in an aqueous solution and self-assembly of cyclodextrin complexes. Reproduced from Ref. [21], under the terms of the Creative Commons Attribution License (CC BY).

Figure 2

Representations of: (a) the general chemical structure; (b) the tridimensional structure of cyclodextrins; (c) chemical structure and dimensions for α-, β-, and γ-cyclodextrin (n = 6, 7, and 8, respectively).

Figure 3

The dimeric complex TBCDFLU: (a) Stick representation of the two independent host molecules (A and B), with the guest molecule FLU shown in space-filling mode; (b) Cutaway view from the same angle, displaying both host and guest molecules in space-filling representation. Reproduced from Ref. [84], under the terms of the Creative Commons Attribution License (CC BY).

Figure 4

The complex MBCDFLU: (a) The asymmetric unit, with water oxygen atoms omitted for clarity; (b) The (β-CD)₂–FLU complex unit, showing the disordered components of the FLU guest molecule. Reproduced from Ref. [84], under the terms of the Creative Commons Attribution License (CC BY).

Figure 5

Crystal packing arrangements: (a) TBCDFLU viewed along the (100) projection; (b) MBCDFLU viewed along the (001) projection. Hydrogen atoms are omitted for clarity. Water oxygen atoms are shown as red spheres. The C-centered arrangement of the complex units is clearly visible in (b). Reproduced from Ref. [84], under the terms of the Creative Commons Attribution License (CC BY).

Figure 6

Molecular electrostatic surface potential maps of (a) β-CD, (b) CM-β-CD, (c) MDE-β-CD (mono(2,6-di-O-methyl)-β-cyclodextrin), and (d) DFB-β-CD (difluorobenzyl-β-cyclodextrin). Pink regions indicate areas of high electron density (electron-rich), while green regions represent electron-deficient zones. The accompanying scale bar denotes the range of electrostatic potential values at each surface position. Reproduced with permission from Ref. [94]. Copyright 2025, Elsevier.

Figure 7

Diagrammatic representation of preparation and tumor therapy of PS-CMCD (protamine-modified carboxymethyl-β-cyclodextrin)/HCPT (hydroxycamptothecin)/HA (hyaluronic acid) NPs (nanoparticles). Reproduced with permission from Ref. [124]. Copyright 2025, Elsevier.

Figure 8

Strategies for cyclodextrin modification: (A) ‘clever’ for methods using inclusion of reagents to obtain selectivity; (B) ‘long’ for methods using protection groups; (C) ‘sledgehammer’ for methods requiring extensive separation of isomers. Color scheme: gray—native, unmodified cyclodextrin; intermediate teal—cyclodextrin undergoing functionalization, protection, or partial derivatization; cyan—final modified or fully functionalized cyclodextrin.

Figure 9

Illustrative depiction of the stepwise construction of drug-loaded nanogels with targeting capability. Reproduced with permission from Ref. [181]. Copyright 2025, Elsevier.

Figure 10

(a) Chemical structure of protonated desferrioxamine B and its iron(III) complex, ferrioxamine B. (b) Structure of β-cyclodextrin, highlighting one α-D-glucopyranose subunit and its toroidal conformation. The wider and narrower openings of the torus expose secondary and primary hydroxyl groups to the solvent, respectively. Proton positions relevant to the NMR study are also indicated. Reproduced with permission from Ref. [203]. Copyright 2025, Elsevier.

Figure 11

500 MHz ¹H NMR spectra of pure (a) β-cyclodextrin (β-CD) and (b) desferrioxamine B (DFOB) recorded in D₂O. Reproduced with permission from Ref. [203]. Copyright 2025, Elsevier.

Figure 12

Phase solubility diagram illustrating the effect of cyclodextrin concentration on guest solubility, showing distinct profiles for complexation types AL, AP, AN, and B.

Figure 13

The process of the non-covalent system to release the anticancer drug. K_d is the dissolution rate constant; K_c is the stability constant of the complex of the drug with the CD; K_i is the stability constant of the complex of the competing agent with CD; K_a is the absorption rate constant. Reproduced with permission from Ref. [266]. Copyright 2025, Elsevier.

Figure 14

Synthesis of β-CD-Aza[5]helicene. Reagents and conditions: (i) synthesis of aza[5]helicene core—(a) triphenylphosphine, toluene, r.t, 24 h, yield 78%; (b) NaOMe, 3-quinolinecarboxaldehyde, CH3OH, refluxed 3 h, yield 88%; (ii) functionalization and macrocyclization of the helicene—(c) NaOH, p-TsCI, 3 h r.t; (d) HCl, 4 °C, overnight, yield 85%; (iii) host–guest complexation; (e) DMF, 90°, 24 h, yield 80%. Reproduced from Ref. [271], under the terms of the Creative Commons Attribution License (CC BY).