C60-β-cyclodextrin conjugates for enhanced nucleus delivery of doxorubicin

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 Water-soluble C60-β-cyclodextrin conjugates were prepared to encapsulate and deliver doxorubicin to the cell nucleus. The behaviour of the fullerene aggregates inside cells is dictated by the functionalization of the C60 cage. While both the C60 conjugates are taken up by lysosomes upon cellular entry, only the one with a hydroxylated cage rapidly escaped the lysosome. The drug delivery system (DDS) with a hydroxylated C60 cage showed significantly enhanced doxorubicin delivery to the cell nucleus, whereas the DDS with a hydrophobic C60 cage was trapped in the lysosome for a longer time and showed significantly reduced doxorubicin delivery to the nucleus. This study opens new paths towards advanced fullerene-based DDSs for small molecule drugs.

Schematic depiction of Dox@CD (PEG–β-CD conjugate), Dox@FCD (PEG–fullerene–β-CD conjugate), and Dox@hFCD (hydroxylated PEG–fullerene–β-CD conjugate) delivering doxorubicin in to cells. The dark grey sphere and light ellipse denote the cell and the nucleus, respectively.

 The monoderivative of C60 was prepared via Bingel–Hirsch reaction, from malonic ester that bears a PEG (750 g mol−1) and an alkynyl group and then connected to a β-cyclodextrin-6-azide via the Cu(i)-catalyzed azide–alkyne cycloaddition click chemistry to yield the water-soluble C60-β-cyclodextrin conjugate, FCD. hFCD was prepared by further reacting this compound with NaOH and H2O2, catalyzed by 18-crown-6 following the classical procedure of fullerenol synthesis, which typically randomly adds 20–30 hydroxyl groups on the cage.

Rohin Biswas, Shilong Yang, Ryan A. Crichton, Patrick Adly-Gendi, Tyler K. Chen, William P. Kopcha, Zheng Shi and Jianyuan Zhang: C60-β-cyclodextrin conjugates for enhanced nucleus delivery of doxorubicin. Nanoscale, 2022,14, 4456-4462. https://doi.org/10.1039/D2NR00777K

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