Formulation considerations of gadolinium lipid nanoemulsion for intravenous delivery to tumors in neutron-capture therapy.

The effects of the formulation and particle composition of gadolinium (Gd)-containing lipid nanoemulsion (Gd-nanoLE) on the biodistribution of Gd after its intravenous (IV) injection in D(1)-179 melanoma-bearing hamsters were evaluated for its application in cancer neutron-capture therapy. Gd-nanoLEs whose particles had an oily core (soybean oil, ethyl oleate, lipiodol, or triolein) and a surface layer of hydrogenated phosphatidylcholine, gadolinium-diethyl-enetriaminepentaacetic acid-distearylamide, and a cosurfactant (Myrj 53, Brij 700, or HCO-60) were prepared by a thin-layer hydration-sonication method. Biodistribution data revealed that Brij 700 and HCO-60 prolonged the retention of Gd in the blood and enhanced its accumulation in tumors. Among the core components employed, soybean oil yielded the highest Gd concentration in the blood and tumor and the lowest in the liver and spleen. Gd-nanoLEs with a Gd content of 1.5-4.5 mg/ml could be formulated by using HCO-60 and soybean oil at a constant oil-to-water ratio, and by enriching Gd in the surface layer with the particle size maintained below 100 nm. When each Gd-nanoLE was IV injected once or twice at a 24-h interval, the Gd concentration in the tumor correlated well with the total dose of Gd, and it reached a maximum of 189 microg/g wet tumor. This maximum Gd level was greater than the limit required for significantly suppressing tumor growth in neutron-capture therapy.

In vitro cellular accumulation of gadolinium incorporated into chitosan nanoparticles designed for neutron-capture therapy of cancer.

The accumulation of gadolinium loaded as gadopentetic acid (Gd-DTPA) in chitosan nanoparticles (Gd-nanoCPs), which were designed for gadolinium neutron-capture therapy (Gd-NCT) for cancer, was evaluated in vitro in cultured cells. Using L929 fibroblast cells, the Gd accumulation for 12 h at 37 degrees C was investigated at Gd concentrations lower than 40 ppm. The accumulation leveled above 20 ppm and reached 18.0+/-2.7 (mean+/-S.D.) microg Gd/10(6) cells at 40 ppm. Furthermore, the corresponding accumulations in B16F10 melanoma cells and SCC-VII squamous cell carcinoma, which were used in the previous Gd-NCT trials in vivo, were 27.1+/-2.9 and 59.8+/-9.8 microg Gd/10(6) cells, respectively, hence explaining the superior growth-suppression in the in vivo trials using SCC-VII cells. The accumulation of Gd-nanoCPs in these cells was 100-200 times higher in comparison to dimeglumine gadopentetate aqueous solution (Magnevist), a magnetic resonance imaging contrast agent. The endocytic uptake of Gd-nanoCPs, strongly holding Gd-DTPA, was suggested from transmission electron microscopy and comparative studies at 4 degrees C and with the solution system. These findings indicated that Gd-nanoCPs had a high affinity to the cells, probably contributing to the long retention of Gd in tumor tissue and leading to the significant suppression of tumor growth in the in vivo studies that were previously reported.