Alpha-particle
immunotherapy by targeted alpha-emitters or alpha-emitting
isotope generators is a novel form of extraordinarily potent
cancer therapy. A major impediment to the clinical use of targeted
actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter
radionuclides. The daughters, especially
bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of
tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac,
francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral
metal chelation with
2,3-dimercapto-1-propanesulfonic acid (
DMPS) or meso-2,3-dimercaptosuccinic
acid (
DMSA) caused a significant reduction (P < 0.0001) in the renal 213Bi uptake; however,
DMPS was more effective than
DMSA (P < 0.001). The results with
DMPS were also confirmed in a monkey model. The renal 213Bi and 221Fr activities were significantly reduced by
furosemide and
chlorothiazide treatment (P < 0.0001). The effect on renal 213Bi activity was further enhanced by the combination of
DMPS with either
chlorothiazide or
furosemide (P < 0.0001). Competitive antagonism by
bismuth subnitrate moderately reduced the renal uptake of 213Bi. The presence of a higher target-
tumor burden significantly prevented the renal 213Bi accumulation (P = 0.003), which was further reduced by
DMPS treatment (P < 0.0001).
Metal chelation, diuresis with
furosemide or
chlorothiazide, and competitive
metal blockade may be used as adjuvant
therapies to modify the renal accumulation of 225Ac daughters.