A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting

Abstract

Background: The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells.

Methods: Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research.

Results: The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor(®) EL, 32.5% Transcutol(®) HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells.

Conclusion: FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin.

Keywords: SMEDDS; colon targeting; curcumin; folate receptor.

Figure 1

Ternary phase diagrams studies for selecting of oil, surfactant, and cosurfactant.

Figure 2

The contour plots of response for the contour plot of mean particle size (A), the contour plot of solubility (B), and the mixed contour plot of mean particle size and solubility (C). Abbreviations: S, surfactant; CoS, cosurfactant.

Figure 3

Transmission electron microscope micrographs of curcumin-loaded self-microemulsifying drug delivery system with the scale bar for the image representing 50 nm.

Figure 4

Dissolution profiles of curcumin from curcumin-loaded folate-modified self-microemulsifying drug delivery system colon-targeted capsules in stimulated gastrointestinal fluids of different pH at a speed of 50 rpm. Note: Results are represented by mean ± standard deviation (n = 3).

Figure 5

Fluorescence microscopy images showcasing the time dependent (0.5, 1, 2, 5, and 24 hours) intracellular uptake of Coumarin 6 from Coumarin 6-loaded self-microemulsifying drug delivery system, Coumarin 6-loaded folate-modified self-microemulsifying drug delivery system, and Coumarin 6-loaded folate-modified self-microemulsifying drug delivery system+1mM folic acid by HT-29 (human colon carcinoma cell line) (A) and Hela (human uterine cervix cancer line) cells (B), the concentration of Coumarin 6 is 15 μg/mL. Abbreviations: FA, folic acid; FSMEDDS, folate-modified self-microemulsifying drug delivery system; h, hours; SMEDDS, self-microemulsifying drug delivery system.

Figure 6

Flow cytometry results of HT-29 (human colon carcinoma cell line) (A) and Hela (human uterine cervix cancer cell line) (B) cells incubated with Coumarin 6-loaded folate-modified self-microemulsifying drug delivery system + 1 mM folate (black), Coumarin 6-loaded folate-modified self-microemulsifying drug delivery system (green), Coumarin 6-loaded self-microemulsifying drug delivery system (blue) at an equivalent Coumarin 6 concentration of 15 μg/mL for 2 hours at 37°C.