Multicolumn selectivity inversion generator for production of high purity actinium for use in therapeutic nuclear medicine

#The use of radioactive materials in diagnostic medicine has been readily accepted because these procedures are safe, minimally invasive, cost effective, and they provide unique structural and/or functional information that is otherwise unavailable to the clinician. The utility of nuclear medicine is reflected by the more than 13 million diagnostic procedures that are performed each year in the U.S. alone, which translates to approximately one of every four admitted hospital patients receiving a nuclear medical procedure. [Adelstein et al. Eds. Isotopes for Medicine and the Life Sciences; National Academy Press: Washington, D.C., 1995; Wagner et al., “Expert Panel: Forecast Future Demand for Medical Isotopes,” Department of Energy, Office of Nuclear Energy, Science, and Technology, 1999; Bond et al., Industrial and Engineering Chemistry Research 2000, 39, 3130-3134.]

#The use of radiation in disease treatment has long been practiced, with the mainstay external beam radiation therapy now giving way to more targeted delivery mechanisms including sealed-source implants containing palladium-103 or iodine-125 that are employed in the brachytherapeutic treatment of prostate cancer and samarium-153 or rhenium-188 that are conjugated to diphosphonate-based biolocalization agents that concentrate at metastasis in the palliation of bone cancer pain. More recently, the U.S. Food and Drug Administration (FDA) has approved use of the first radioimmunotherapy (RIT) drug that relies on radionuclide conjugation to peptides, proteins, or antibodies to selectively concentrate at the disease site whereby radioactive decay imparts cytotoxic effects. Radioimmunotherapy represents the most selective means of delivering a cytotoxic dose of radiation to diseased cells while sparing healthy tissue, [Geerlings et al., Akzo Nobel, N. V.: US, 1993; Whitlock et al., Industrial and Engineering Chemistry Research 2000, 39, 3135-3139; Imam, Int. J. Radiation Oncology Biol. Phys. 2001, 51, 271-278; Hassfjell et al., Chemical Reviews 2001, 101, 2019-2036; McDevitt et al., Science 2001, 294, 1537-1540] and the plethora of information about disease genesis and function arising from the human genome project and proteomics technologies is expected to propel RIT into a leading treatment for micrometastatic carcinoma (e.g., lymphomas and leukemias) and small- to medium-sized tumors.

#Because of their use in medical procedures, various governing bodies (e.g., the U.S. FDA) mandate rigorous purity requirements for radiopharmaceuticals. Regulations governing the use of radionuclides for therapeutic applications are even more stringent, and such strict regulation is warranted given the greater potential harm posed by long-lived high linear energy transfer (LET) radionuclidic impurities. Manufacturers that can ensure the production of therapeutically useful radionuclides with the following three characteristics will be at a significant advantage entering the FDA review process and, subsequently, in the deployment of their products in the medical technology markets:

#In the drawings forming a portion of this disclosure,

#FIG. 1 is a schematic depiction of the separation of actinium(III) and radium(II), if present, from thorium(IV) using a multicolumn selectivity inversion generator described herein and in which PSC refers to Primary Separation Column, and GC refers to Guard Column and Yttrium Resin is present in a third column that separates actinium(III) from radium(II).

#FIG. 2 is a chromatographic graph of counts per minute per milliliter (cpm/mL) of eluate versus bed volumes (BV) of eluate passed through a column at 25(±2)° C. during the loading (0.0-4.5 BV), rinsing (4.5-9.25 BV), and stripping phases (9.25-18 BV) in the separation of 0.10 M Th(SO4)2 [spiked with 230Th(Iv); (open squares)] from tracer 133Ba(II) [open circles] and 139Ce(III) [open triangles] using a 0.50 mL bed of AG-50Wx8 sulfonic acid cation-exchange resin. Load: 2.0 mL 0.10 M Th(SO4)2 in 0.40 M (NH4)2SO4 at pH=2.0(±0.1), rinse (and preconditioning solution): 0.40 M (NH4)2SO4 at pH=2.0(1), Strip: 6.0 M HNO3. The horizontal dashed line indicates background counts.

#The present invention is particularly adapted for use in the preparation of purified actinium-225 (225Ac) ions for the preparation of bismuth-213 (213Bi) ions that are used in medical treatments. It is to be understood, however, that the contemplated separation process can be used with other isotopes than those specifically mentioned so long as those isotopes decay to form the recited daughter ions.

#Radionuclide generators for the production of 213Bi for use in radiotherapeutic applications rely on the efficient production of the 225Ac parent radionuclide. A contemplated separation process or method for obtaining actinium ions in purified form comprises the steps of:

#(a) contacting an aqueous, preferably acidic, parent-daughter radionuclide ion solution having a pH value of about 8 or less. The solution at least contains sulfate ions as well as thorium parental radionuclide ions and actinium and optionally present radium desired daughter radionuclide ions with a first solid phase separation medium having a high affinity for the desired daughter radionuclide ions and a low affinity for the parent radionuclide ions. That contact is maintained for a time period sufficient for said actinium and optionally present radium ions to be bound to form a desired daughter ion-laden first separation medium and a thorium ion-containing, desired daughter-depleted parent-daughter solution. That first separation medium preferably comprises a strong acid, sulfonate-containing polymeric extractant such as a cation-exchange resin as is discussed hereinafter. The aqueous, preferably acidic, sulfate solution of radioactive parent and daughters is preferably at about radioactive steady state as ions in solution prior to contacting the first separation medium.