(212)Pb@C(60) and its water-soluble derivatives: synthesis, stability, and suitability for radioimmunotherapy

Fullerenes could potentially play a valuable role in radioimmunotherapy by more stably encapsulating radionuclides, especially where conventional chelation chemistry is inadequate due to the physical and/or chemical properties of the radionuclide. One of the therapeutically useful radionuclides that requires improved containment in vivo is 212Pb (tau1/2 = 10.6 h), the beta-emitting parent to alpha-emitting 212Bi (tau1/2 = 60.6 min). Myelotoxicity resulting from the accumulation of 212Pb in the bone marrow has limited the use of this radionuclide despite its favorable decay characteristics. In this work, 212Pb@C60 and its malonic ester derivatives were prepared for the first time by allowing the 212Pb to recoil into C60 following alpha-decay from its parent, 0.15-s 216Po, generated in situ from the decay of 224Ra (tau1/2 = 15 days). Repeated washing of the organic phase containing the 212Pb@C60 malonic esters with challenge solutions containing cold Pb2+ ions demonstrated that some of the 212Pb could not be exchanged and was apparently inside of the fullerenes. Malonic esters of endohedral alpha-emitting 213Bi (tau1/2 = 45 min) fullerenes were prepared by an analogous procedure. Following acidification of the esters, a preliminary biodistribution study in mice was performed with the untargeted water-soluble radiofullerenes. It was found that 212Pb did not accumulate in bone after being administered as an endohedral fullerene, in contrast to results with polyhydroxylated radiofullerenes and conventional polyaminocarboxylate chelators for 212Pb. The results indicate that 212Pb is held more tightly in the fullerene than in other methods and suggest that fullerenes may have an important role in the targeted delivery of 212Pb.