Exploring Cyclodextrin-Based Nanosponges as Drug Delivery Systems: Understanding the Physicochemical Factors Influencing Drug Loading and Release Kinetics

Abstract

Cyclodextrin-based nanosponges (CDNSs) are complex macromolecular structures composed of individual cyclodextrins (CDs) and nanochannels created between cross-linked CD units and cross-linkers. Due to their unique structural and physicochemical properties, CDNSs can possess even more beneficial pharmaceutical features than single CDs. In this comprehensive review, various aspects related to CDNSs are summarized. Particular attention was paid to overviewing structural properties, methods of synthesis, and physicochemical analysis of CDNSs using various analytical methods, such as DLS, PXRD, TGA, DSC, FT-IR, NMR, and phase solubility studies. Also, due to the significant role of CDNSs in pharmaceutical research and industry, aspects such as drug loading, drug release studies, and kinetics profile evaluation of drug-CDNS complexes were carefully reviewed. The aim of this paper is to find the relationships between the physicochemical features and to identify crucial characteristics that are influential for using CDNSs as convenient drug delivery systems.

Keywords: cyclodextrin; drug delivery system; nanosponge; physicochemical; synthesis.

Figure 1

Family of nanosponge particles, with diverse representation of carbohydrate-based nanosponges. Marked boxes indicate the nanosponge groups included in this paper.

Figure 2

(a) Cyclodextrin structure based on β-CD with glucose units in chair conformation. The numbering order of carbon atoms of the glucose subunit is marked in orange. (b) Schematic representation of the CD shape, with labeled primary and secondary hydroxyl groups on the outer surfaces of the narrower and wider edges, respectively.

Figure 3

The structure of cyclodextrin-based nanosponges: Blue beads represent cross-linker molecules, which bind mostly to C₆ hydroxyl groups on the narrower edge of the CD units (schematic structure, for visualization purposes only; degree of cross-linking not preserved).

Figure 4

Chemical structures of the most frequently used cross-linkers. The donor moieties of each cross-linker group are labeled with red.

Figure 5

Schematic presentation of different phase solubility diagram types.

Figure 6

Graphical presentation of DLS measurements for the evaluation of (A) particle size and (B) zeta potential of baricitinib-loaded β-CD:DPC (1:4.5). Adapted from [83], licensed under CC BY 3.0.

Figure 7

Comparison of PXRD patterns of (5-fluorouracil)-loaded β-CD:DPC (1:4), pure 5-fluorouracil, and pure β-CD:DPC (1:4). Adapted from [93], licensed under CC Attribution-NonCommercial-ShareAlike 4.0.

Figure 8

DSC thermograms of (a) pure domperidone and (b) domperidone-loaded β-CD:DPC. Disappearance of the endothermic signal of the drug indicates full incorporation of the drug into CDNS. A small signal at around 50 °C is most likely the result of water evaporation from CDNS. Adapted from [110], licensed under CC BY 4.0.

Figure 9

FT-IR spectra of (A) non-loaded β-CD:DPC, (B) pure domperidone, and (C) domperidone-loaded β-CD:DPC. The diminishing of drug signals, especially in the fingerprint region, can be observed after incorporation into nanosponges. Adapted from [110], licensed under CC BY 4.0.

Figure 10

The network of relationships occurring between synthesis conditions and starting parameters (marked in orange) and CDNSs’ physicochemical properties, with particular emphasis on the most influential factors of drug release properties (marked in green). The boxes marked yellow represent important, nodal points of the whole relationship network.