The alkaline hydrolysis of curcumin was studied in three types of micelles composed of the cationic surfactants cetyl trimethylammonium bromide (CTAB) and dodecyl trimethylammonium bromide (DTAB) and the anionic surfactant sodium dodecyl sulfate (SDS). At pH 13, curcumin undergoes rapid degradation by alkaline hydrolysis in the SDS micellar solution. In contrast, alkaline hydrolysis of curcumin is greatly suppressed in the presence of either CTAB or DTAB micelles, with a yield of suppression close to 90%. The results from fluorescence spectroscopic studies reveal that while curcumin remains encapsulated in CTAB and DTAB micelles at pH 13, curcumin is dissociated from the SDS micelles to the aqueous phase at this pH. The absence of encapsulation and stabilization in the SDS micellar solution results in rapid hydrolysis of curcumin.

The use of curcumin as an effective wound healing agent is of significant interest currently. It is well established that curcumin undergoes rapid degradation in physiological buffer by hydrolysis. The means by which curcumin is stabilized at the wound site to enable healing is poorly understood because blood plasma is composed of approximately 92% water. Plasma proteins, which constitute the remaining 6-8%, has been shown to stabilize curcumin. It is, however, still unclear which proteins are responsible for this phenomenon. In this study, the effects of major plasma proteins, which include human serum albumin (HSA), fibrinogen, immunoglobulin G (IgG), and transferrin, on stabilizing curcumin are investigated. In particular, we investigate their effects on the hydrolysis of curcumin at pH 7.4. In the presence of both transferrin and IgG, curcumin continues to undergo rapid hydrolysis but this reaction is suppressed by the presence of either HSA or fibrinogen with an impressive yield of approximately 95%. Furthermore, the binding constants of curcumin to HSA and fibrinogen are on the order of 10(4) and 10(5) M(-1), respectively. The binding constants of transferrin and IgG, however, are at least 1 order of magnitude less than those of HSA and fibrinogen. The results support that strong binding occurs at the hydrophobic moieties of HSA and fibrinogen, excluding water access. Therefore, strong interactions with HSA and fibrinogen inhibit hydrolysis of curcumin and in turn lead to effective suppression of degradation.

Diamide linked γ-cyclodextrin (γ-CD) dimers are used to capture curcumin and suppress its decomposition in water. In this study, succinamide and urea linked γ-CD dimers joined through the C6(A) carbon on each γ-CD are used. The γ-CD dimers, 66γCD(2)su and 66γCD(2)ur, show a remarkable ability to suppress the decomposition of curcumin and extend its half-life from less than 30 min to greater than 16 h. The 1:1 association of curcumin with 66γCD(2)su and 66γCD(2)ur has high stability constants of 8.7 × 10(6) M(-1) and 2.0 × 10(6) M(-1), respectively. In addition, 2D (1)H NOESY NMR results show specific hydrogen interactions in the association of curcumin with 66γCD(2)su and 66γCD(2)ur, consistent with the cooperative binding of curcumin by both γ-CD annuli of 66γCD(2)su and 66γCD(2)ur. The interactions between curcumin in the linked γ-CD dimers and surfactant micelles were studied using fluorescence spectroscopy. While linked γ-CD dimer-bound curcumin has a negligible fluorescence quantum yield, a significant increase in fluorescence intensity (Φ(fl) > 2%) in the presence of micelles suggests that curcumin is delivered to the micelle. The overall results indicate that the diamide linked γ-CD dimers are highly promising systems for curcumin delivery in vivo due to effective curcumin stabilization.

Colloidal solutions of surfactants that form micelles or vesicles are useful for solubilizing and stabilizing hydrophobic molecules that are otherwise sparingly soluble in aqueous solutions. In this paper we investigate the use of micelles and vesicles prepared from ionic surfactants for solubilizing and stabilizing curcumin, a medicinal natural product that undergoes alkaline hydrolysis in water. We identify spectroscopic signatures to evaluate curcumin partitioning and deprotonation in surfactant mixtures containing micelles or vesicles. These spectroscopic signatures allow us to monitor the interaction of curcumin with charged surfactants over a wide range of pH values. Titration data are presented to show the pH dependence of curcumin interactions with negatively and positively charged micelles and vesicles. In solutions of cationic micelles or positively charged vesicles, strong interaction between the Cur(-1) phenoxide ion and the positively charged surfactants results in a change in the acidity of the phenolic hydrogen and a lowering of the apparent lowest pK(a) value for curcumin. In the microenvironments formed by anionic micelles or negatively charged bilayers, our data indicates that curcumin partitions as the Cur(0) species, which is stabilized by interactions with the respective surfactant aggregates, and this leads to an increase in the apparent pK(a) values. Our results may explain some of the discrepancies within the literature with respect to reported pK(a) values and the acidity of the enolic versus phenolic protons. Hydrolysis rates, quantum yields, and molar absorption coefficients are reported for curcumin in a variety of solutions.

Curcumin-encapsulated polyester nanoparticles (Cur-polyester NPs) of approximately 100 nm diameter with a negatively charged surface were prepared using a one-step nanoprecipitation method. The Cur-polyester NPs were prepared using polylactic acid, poly(D,L-lactic-co-glycolic acid) and poly(ϵ-caprolactone) without any emulsifier or surfactant. The encapsulation of curcumin in these polyester NPs greatly suppresses curcumin degradation in the aqueous environment due to its segregation from water. In addition, the fluorescence of curcumin in polyester NPs has a quantum yield of 4 to 5%, which is higher than that of curcumin in micellar systems and comparable to those in organic solvents, further supporting the idea that the polyester NPs are capable of excluding water from curcumin. Furthermore, the results from femtosecond fluorescence upconversion spectroscopy reveal that there is a decrease in the signal amplitude corresponding to solvent reorganization of excited state curcumin in the polyester NPs compared with curcumin in micellar systems. The Cur-polyester NPs also show a lack of deuterium isotope effect in the fluorescence lifetime. These results indicate that the interaction between curcumin and water in the polyester NPs is significantly weaker than that in micelles. Therefore, the aqueous stability of curcumin is greatly improved due to highly effective segregation from water. The overall outcome suggests that the polyester NPs prepared using the method reported herein are an attractive system for encapsulating and stabilizing curcumin in the aqueous environment.

Ligand-metal interaction between curcumin and Cu(II) in methanol and sodium dodecyl sulfate (SDS) micelles was investigated using fluorescence spectroscopy and transient absorption spectroscopy. The Cu(II) ion exhibits a high efficiency in quenching the fluorescence of curcumin. By quantifying fluorescence quenching as a function of Cu(II) concentration, the complexation constants, K(1) and K(2), for the formation of the 1 : 1 and 1 : 2 Cu(II)-curcumin complexes, [Cu(II)-Cur](+) and [Cu(II)-Cur(2)], have been determined. In methanol, K(1) and K(2) are (1.33 ± 0.47) × 10(8) M(-1) and (6.79 ± 1.77) × 10(5) M(-1), respectively, whereas those in SDS micelles are (9.90 ± 1.68) × 10(5) M(-1) and (1.70 ± 0.48) × 10(6) M(-1), respectively. The transient absorption spectra of curcumin and the Cu(II)-curcumin complexes from 520 nm to 700 nm show a combination of stimulated emission and excited state absorption (ESA). However, the transient absorption signal at 500 nm corresponds to ESA exclusively. For curcumin, the ESA kinetics exhibit two rising components with time constants of 0.9 ps and 8.2 ps in methanol, and 0.5 ps and 2.5 ps in SDS micelles, which are consistent with solvation dynamics of excited state curcumin in these media. In addition, the ESA kinetics show a decay component with a time constant of 125 ps in methanol and 64 ps in SDS micelles, reflecting the excited state intramolecular hydrogen atom transfer of curcumin in these media. The ESA kinetics of the Cu(II)-curcumin complexes exhibit a sharp rise and a fast decay with a time constant of approximately 1 ps in both media due to the strong interaction between Cu(II) and curcumin.

The ability to control particle size and size distribution of nanoparticles for drug delivery is essential because it impacts on the biodistribution and cellular uptake of nanoparticles. We present a novel microfluidic assisted nanoprecipitation strategy that enables synthesis of surfactant-free curcumin encapsulated poly(lactide- co-glycolide) nanoparticles (Cur-PLGA NP) with adjustable particle diameters (30-70 nm) and narrow particle size distribution (polydispersity index less than 0.2). Our Cur-PLGA NP exhibit excellent colloidal stability and inhibit degradation of curcumin. We further demonstrate the potential of our Cur-PLGA NP as a nanotoxic delivery system for curcumin. Cellular viability assay validates a dose-dependent cytotoxicity of Cur-PLGA NP in leukemia Jurkat cells. In contrast, Cur-PLGA NP does not alter the viability of fibroblast NIH3T3 cells, which suggests that the cytotoxicity of Cur-PLGA NP is specific to cell types. Furthermore, there is no detectable effect by PLGA NP to both leukemia Jurkat cells and fibroblast NIH3T3 cells, highlighting the nontoxic nature of our delivery system. Confocal cell uptake studies indicate that PLGA NP do not alter the cell uptake of curcumin. Our microfluidic assisted approach offers a controlled and effective nanobiomaterials synthesis of drug delivery system for curcumin, which can be extended to different capsule materials for a variety of biomedical applications.

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