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. 2025 Jan 30;26(3):1213.
doi: 10.3390/ijms26031213.

Leveraging Cholesterol-Functionalized Cyclodextrin Nanosponges for Enhanced Drug Delivery in Cancer Cells

Ilona Krabicová  1   2 , Yousef Khazaei Monfared  2   3 , Fabrizio Caldera  2   4 , Mohammad Mahmoudian  5   6 , Christopher Hobbs  7 , Rosangela Santalucia  2   4 , Silvia Lucia Appleton  8 , Adrián Matencio  2 , Parvin Zakeri-Milani  9 , Francesco Trotta  2
Affiliations

Leveraging Cholesterol-Functionalized Cyclodextrin Nanosponges for Enhanced Drug Delivery in Cancer Cells

Ilona Krabicová et al. Int J Mol Sci. .

Abstract

Cholesterol, the essential building block of cellular membranes, has proven to be a useful tool for increasing the biocompatibility and bioavailability of drug delivery systems in cancer treatment. Resveratrol, a natural polyphenolic compound with promising anticancer properties, faces significant limitations due to its low solubility and bioavailability, hindering its clinical utility. Therefore, in the present study, we aimed to design cholesterol-functionalized cyclodextrin nanosponges (Chol-NSs) with a tunable cholesterol content to optimize resveratrol encapsulation and delivery. Both formulations, free carbonyl diimidazole (CDI) NSs and functionalized Chol-NSs, demonstrated high drug loading and encapsulation efficiency. In vitro experiments revealed that cholesterol incorporation significantly improved the cellular uptake of nanocarriers and potentiated the cytotoxic effects of resveratrol on breast cancer cells. Importantly, both free CDI NSs and functionalized Chol-NSs, even at varying cholesterol percentages, demonstrated a safe profile against both fibroblast and breast cancer cell lines. These results indicate that cholesterol-functionalized nanosponges represent a promising platform for the effective and safe delivery of natural compounds in cancer therapy.

Keywords: cholesterol; crosslinked polymer; drug delivery; functionalization; nanosponge.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structure of trans-resveratrol (RSV).
Scheme 1
Scheme 1
The preparation route of CD nanosponges functionalized with cholesterol.
Figure 2
Figure 2
(a) FTIR spectra of Chol-β-CD compared with the spectrum of cholesteryl hemisuccinate; (b) FTIR spectra of Chol-NS and CDI NS.
Figure 3
Figure 3
(a) Direct pulse 13C{1H} SS-NMR spectra of CDI NSs (orange) and Chol-β-CD (light blue). (b) Direct pulse 13C{1H} SS-NMR spectra of Chol-NS 10% (dark blue) and Chol-NS 30% (green). * is likely partially reacted CDI with CD, whereby one unreacted imidazole group remains. ** are the residual solvent peaks.
Figure 4
Figure 4
Cell viability of (a) fibroblasts and (b) breast cancer cells after treatment with blank CD and functionalized with cholesterol. One-way ANOVA: ns, not significant; * p < 0.05.
Figure 5
Figure 5
Cell viability of (a) fibroblasts and (b) breast cancer cells after treatment with suspensions of CDI-NSs and Chol-NSs functionalized with cholesterol. One-way ANOVA: ns, not significant; * p < 0.05.
Figure 6
Figure 6
Cell viability of MCF-7 cancer cell line treated with (a) the free resveratrol (RSV), loaded on β-CD, and β-CD functionalized with cholesterol; (b) RSV loaded on CDI NSs and cholesterol-functionalized Chol-NSs at 10 and 30%. One-way ANOVA: ns, not significant; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001.
Figure 7
Figure 7
The fluorescence microscopy cellular uptake of β-CD, CDI-NSs, and those functionalized with cholesterol after 24 h of incubation. The scale bar corresponds to 100 μm.
Figure 8
Figure 8
(a) Gating results of flow cytometry; (b) cellular uptake percentages of β-CD, CDI-NSs, and those functionalized with cholesterol; (c) mean of fluorescent intensity.
See this image and copyright information in PMC

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