Folate-tethered emulsion for the target delivery of retinoids to cancer cells.

Folic acid, conjugated to poly(ethylene glycol)-distearoylphosphatidylethanolamine (folate-PEG-DSPE), was used to target emulsions of all-trans retinoic acid (ATRA) to folate receptor-overexpressing tumor cells. Two kinds of ATRA-incorporated folate-tethered emulsions (ATRA-FTE 2000/3400) were prepared using soybean oil, egg phosphatidylcholine and folate-PEG-DSPE with different PEG length. As a control, ATRA-incorporated non-tethered emulsion (ATRA-NTE) was prepared by using PEG2000-DSPE without folate instead of using folate-PEG-DSPE. The mean particle diameters of ATRA-FTE 2000/3400 were about 100-130 nm. The cellular uptake in KB cells of fluorescence-labeled ATRA-FTE 3400 was determined with HPLC (for ATRA) and confocal microscopy (for lipid emulsion). The growth inhibitory activity of ATRA was evaluated by MTT assay. The folate ligands in emulsion increased the cellular uptake of ATRA about 3-fold and 1.6-fold in ATRA-FTE 3400 and ATRA-FTE 2000, respectively. Growth inhibitory activity of ATRA-FTE 3400 in KB cells was higher than that of ATRA-NTE at the same dose. Whereas the growth inhibitory effect in MCF-7 cells of ATRA was similar between ATRA-NTE and ATRA-FTE 3400. The addition of free folate significantly reduced the uptake of ATRA regardless of the length of PEG attached to folate. Folate-tethered lipid emulsion showed effective and selective delivery to the folate receptor-abundant carcinomas, suggesting a potential for targeted delivery of anticancer agents.