Biodistribution of gadolinium incorporated in lipid emulsions intraperitoneally administered for neutron-capture therapy with tumor-bearing hamsters.
Emulsions containing a distearylamide (Gd-DTPA-SA) or a distearylester (Gd-DTPA-SE) of Gd (gadolinium)-diethylenetriaminepentaacetic acid (Gd-DTPA) were intraperitoneally injected in Greene's melanoma-bearing hamsters at a dose of 2.0 ml (3.0 or 6.0 mg Gd) per hamster. In the standard-Gd and high-Gd formulations used, the weight ratios of soybean oil, water, Gd-DTPA derivative (Gd-DTPA-SA or Gd-DTPA-SE), hydrogenated L-alpha-phosphatidylcholine from egg yolk (HEPC) and co-surfactant (HCO-60, Myrj 53, Myrj 59 or Brij 700) were 7.36:92:1:2:3 and 7.36:92:2:1:3, respectively. When the effects of the co-surfactants on the biodistribution of Gd from Gd-DTPA-SA-containing emulsions in the standard-Gd formulation were compared, the HCO-60 emulsion exhibited the highest Gd accumulation in tumors, possibly resulting from its fast and complete absorption, its small particle size (78 nm) and the stable coat on the particle surfaces with polyoxyethylene. Brij 700 emulsion kept the highest blood Gd concentration for a prolonged period, possibly due to particle properties similar to those of HCO-60. However, it exhibited a slower Gd accumulation in tumors, only reaching an identical level, in comparison with the HCO-60 emulsion. This suggested the tumor to be saturated with lipid particles. When Gd-DTPA-SE was used instead of Gd-DTPA-SA, its HCO-60 emulsion exhibited only very poor Gd-accumulation due to its easy degradation. The HCO-60 emulsion particles containing Gd-DTPA-SA in the high-Gd formulation (6.0 mg Gd in 2 ml) exhibited in vivo behavior identical to those in the standard-Gd formulation; then the Gd level in tumors reached 107 micrograms Gd/g tumor (wet), and the tumor:blood (T/B) and tumor:skin (T/Sk) Gd concentration ratios were 13.2 and 5.6, respectively, at 48 h after intraperitoneal administration. These results suggest that when intraperitoneally administered, this HCO-60 emulsion, and possibly also the corresponding Brij 700 emulsion, may be an excellent delivery system for accumulating Gd in tumors in neutron-capture therapy (NCT).
Miyamoto
M
M
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
Hirano
K
K
Ichikawa
H
H
Fukumori
Y
Y
Akine
Y
Y
Tokuuye
K
K
D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004337:Drug Carriers; D004655:Emulsions / Q000008:administration & dosage; D005260:Female; D005682:Gadolinium / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019786:Gadolinium DTPA / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007263:Infusions, Parenteral; D008545:Melanoma / Q000378:metabolism / Q000532:radiotherapy*; D008647:Mesocricetus; D008657:Metabolic Clearance Rate; D017247:Neutron Capture Therapy; D013501:Surface-Active Agents / Q000494:pharmacology; D014018:Tissue Distribution
D004337:Drug Carriers; D004655:Emulsions; D013501:Surface-Active Agents; D005682:Gadolinium; D019786:Gadolinium DTPA