Diamide Linked γ‑Cyclodextrin Dimers as Molecular-Scale Delivery Systems for the Medicinal Pigment Curcumin to Prostate Cancer Cells

Diamide linked γ-cyclodextrin (γ-CD) dimers are proposed as molecular-scale delivery agents for the anticancer agent curcumin. <i>N,N</i>′-Bis­(6^A-deoxy-γ-cyclodextrin-6^A-yl)­succinamide (66γCD₂su) and <i>N,N</i>′-bis­(6^A-deoxy-γ-cyclodextrin-6^A-yl)­urea (66γCD₂ur) markedly suppress the degradation of curcumin by forming a strong 1:1 cooperative binding complexes. The results presented in this study describe the potential efficacy of 66γCD₂su and 66γCD₂ur for intracellular curcumin delivery to cancer cells. Cellular viability assays demonstrated a dose-dependent antiproliferative effect of curcumin in human prostate cancer (PC-3) cells that was preserved by the curcumin-66γCD₂su complex. In contrast, delivery of curcumin by 66γCD₂ur significantly delayed the antiproliferative effect. We observed similar patterns of gene regulation in PC-3 cells for curcumin complexed with either 66γCD₂su or 66γCD₂ur in comparison to curcumin alone, although curcumin delivered by either 66γCD₂su or 66γCD₂ur induces a slightly higher up-regulation of heme oxygenase-1. Highlighting their nontoxic nature, neither 66γCD₂su nor 66γCD₂ur carriers alone had any measurable effect on cell proliferation or candidate gene expression in PC-3 cells. Finally, confocal fluorescence imaging and uptake studies were used to demonstrate the intracellular delivery of curcumin by 66γCD₂su and 66γCD₂ur. Overall, these results demonstrate effective intracellular delivery and action of curcumin when complexed with 66γCD₂su and 66γCD₂ur, providing further evidence of their potential applications to deliver curcumin effectively in cancer and other treatment settings