Preparation and biodistribution studies of folate receptor targeting 177Lu-labelled folate dimer: 177Lu -DOTA-FA2

Objectives Frequent overexpression of folate receptor-αwas found in most ovarian cancers of all subtypes[1-3]. Limited expression and highly restricted to only a few sites such as kidneys, lungs, and the choroid plexus.[4,5] We prepared 177Lu-DOTA-FA2 with the aim to optimize its biodistribution and increase tumor uptake in FR overexpressed ovarian cancer.

Methods 177Lu-DOTA-FA2 was synthesized straightforward and its stability experiments were conducted in plasma. Cell uptake studies were performed on FR-positive SKOV3 Ovarian cancer cells. Biodistribution studies were performed in nude mice bearing SKOV3 ovarian tumors 1, 12, 48h after administration of 177Lu-DOTA-FA2 or 177Lu-DOTA-FA2 monomer. MicroSPECT-CT imaging were carried out in nude mice bearing SKOV3 ovarian tumors or FR-negative A549 lung cancer 2h after tail vein injection of 68Ga-DOTA-FA2. All animals accepted folate-free diet for 2 weeks.

Results 177Lu-DOTA-FA2 was synthesized at a specific activity of 25MBq/nmol, a radiochemical yield of more than 95%. It was stable with radioactive purity of (96.3±1.5) over 48h in plasma. SKOV3 cells uptake and internalization of 68Ga-DOTA-FA2 was FR specific. This is confirmed by the biodistribution data. In biodistribution studies tumor uptake of 177Lu-DOTA-FA2 in SKOV3 group was (13.78±1.54)%ID/g at 1h and (9.22±1.46)%ID/g at 12h. They were higher than that of 177Lu-DOTA-FA (7.36±1.28)%ID/g at 2h and (4.27±1.35)%ID/g at 12h. Retention of 177Lu-DOTA-FA2 in kidneys at 4h after injection (24.6±7.24%)ID/g was lower than that of 177Lu-DOTA-FA (33.5±7.48) %ID/g. MicroSPECT-CT imaging demonstrated significantly higher tumor accumulation of 177Lu-DOTA-FA2 in SKOV3 ovarian tumors (10.18±1.52)%ID/g than that in A549 lung cancer (2.25±0.92)%ID/g.

Conclusions 177Lu -DOTA-FA2, with higher tumor uptake and less undesired accumulation in kidneys than FA monomer, was potential for targeted therapy of FR-positive ovarian tumors. RESEARCH SUPPORT: National Natural Science Foundation of China (No. 81301247), Natural Science Foundation of Jiangsu Province (No. BK20130082 ).