Preparation of gadolinium-containing emulsions stabilized with phosphatidylcholine-surfactant mixtures for neutron-capture therapy

Abstract

Gadolinium-containing lipid emulsions for neutron-capture therapy were designed to fulfill the following requirements: particle size smaller than 100 nm; gadolinium content as high as possible; surface of the emulsions modified with hydrophilic moieties to provide prolonged circulation in the blood. Emulsions containing soybean oil, water, Gd- diethylenetriaminepentaacetic acid-distearylamide (Gd-DTPA-SA), as an amphiphilic drug, and hydrogenated egg yolk phosphatidylcholine (HEPC), as an emulsifier, in a weight ratio of 7.36:92:1:2 were prepared without co- surfactants by the thin-layer hydration method using a bath-type sonicator. The mean particle size of the emulsions was 280.7 nm. In order to make the droplet size of the emulsions smaller than 100 nm, as well as to modify the emulsion surfaces, a co-surfactant, Tween® 80, HCO®-60, Pluronic® F68, polyoxyethylene alkyl ether (Brij®) or polyoxyethylene alkyl ester (Myrj®), was introduced into the standard system. Tween 80, HCO-60, Brij 76, 78 and 700 were effective in reducing the particle size to below 100 nm when the co- surfactant weight ratio (CWR), defined as co-surfactant/(HEPC+Gd-DTPA-SA) (w/w), was larger than 0.67; the particle size with Tween 80 and HCO-60 was reduced to 52.7 and 74.7 nm, respectively, at a CWR of 1.0 (w/w). In order to increase the gadolinium content, the weight ratio of Gd-DTPA-SA to HEPC was increased from 1:2 of the standard-Gd formulation to 2:1 of the high-Gd formulation. The measured particle size of the HCO-60 high-Gd emulsions was 78.7nm when the CWR was 1.0 (w/w). In this case, the calculated gadolinium content reached 3.0 mg Gd/ml. These results indicate that HCO-60 is an effective co-surfactant not only in terms of particle size reduction but also with respect to gadolinium enrichment.