Ultrafast spectroscopy and drug delivery of the medicinal pigment curcumin in molecular assemblies.

Abstract

Curcumin is a natural pigment extracted from turmeric. It is well known as a spice and herbal medicine in east Asia. The medicinal effects of curcumin have been demonstrated for cancer, inflammation, Alzheimer’s disease, and cystic fibrosis. Recent studies have explored a number of delivery systems to suppress rapid aqueous degradation of curcumin and improve its bioavailability. Previously, we have demonstrated that diamide linked γ-cyclodextrin dimers, namely 66γCD₂su and 66γCD₂ur, suppress the degradation of curcumin by forming strong 1:1 cooperative binding complexes under physiological conditions. This result indicates the potential for 66-γCD₂su and 66γCD₂ur as curcumin delivery systems. As a part of the thesis work, both 66γCD₂su and 66γCD₂ur are used as molecularscale delivery agents for curcumin in potential treatment of cancer. Cellular viability assays and gene regulation in human prostate cancer (PC-3) cells show an antiproliferative effect of curcumin complexed with 66γCD₂su and 66γCD₂ur, which is comparable with that of curcumin alone. Both 66γCD₂su and 66γCD₂ur carriers show a lack of toxicity to the cells. Fluorescence studies show the intracellular delivery of curcumin by 66γCD₂su and 66γCD₂ur. Our results strongly suggest the potential of these carriers for future studies involving animal models. To further understand the properties of curcumin, particularly its photo-therapeutic effect, ultrafast dynamics of curcumin complexed with 66γCD₂su and 66γCD₂ur are investigated using femtosecond transient absorption spectroscopy. Both curcumin complexes show only an excited state absorption (ESA) band without any stimulated emission signals. The ESA decay kinetics reveals the non-radiative relaxation of curcumin through solvent reorganization, excited state intramolecular hydrogen atom transfer, and other slow dynamics of inclusion molecules and flexibility of the γ-CD moieties of 66γCD₂su and 66γCD₂ur. In addition, transient absorption anisotropy studies reveal slow rotational motions of the curcumin complexes due to their large hydrodynamic volumes. Hydrophobically modified polyacrylates are also potential delivery systems for curcumin because they suppress its degradation under physiological conditions. The 3% octadecyl randomly substituted polyacrylate, PAAC18, shows a remarkable ability to suppress the degradation of curcumin, which is attributed to strong hydrophobic interactions between curcumin and the octadecyl substituents of PAAC18 within the micelle-like aggregates and the hydrogel. In contrast, the 3% dodecyl randomly substituted polyacrylate, PAAC12, shows a negligible effect on slowing the degradation of curcumin, which is consistent with the dodecyl substituents being insufficiently long to capture curcumin in an adequately hydrophobic environment. The ultrafast dynamics of water molecules and curcumin in the PAAC18 hydrogel are also studied using ultrafast spectroscopic techniques. The solvation dynamics (reorganization) of water molecules in the PAAC18 hydrogel exhibit a triexponential characteristic, as shown using femtosecond fluorescence upconversion spectroscopy. We attribute the slow solvation dynamics to the confinement of water molecules in the three-dimensional cross-linking network of the octadecyl substituents of PAAC18. Moreover, non-radiative relaxation processes of curcumin were investigated using femtosecond transient absorption spectroscopy.