Liquid purification or separation – Processes – Liquid/liquid solvent or colloidal extraction or diffusing...
Reexamination Certificate
2002-10-30
2004-04-06
Therkorn, Ernest G. (Department: 1723)
Liquid purification or separation
Processes
Liquid/liquid solvent or colloidal extraction or diffusing...
C210S656000, C210S198200, C423S003000, C423S006000, C423S249000
Reexamination Certificate
active
06716353
ABSTRACT:
The present invention relates to methods of preparing medically useful radioisotopes, particularly high specific activity no-carrier-added radioisotopes, and more particularly to methods of preparing high specific activity, no-carrier-added Lutetium-177 (
177
Lu).
The use of beta particle-emitting radioisotopes for applications in nuclear medicine, oncology and interventional cardiology is rapidly increasing, because of the availability of new pharmaceutical targeting approaches, which effectively concentrate or localize the radioactive vector at the target site with low uptake in non-target tissues. In this manner the energy released from radioactive decay can be localized for killing cells at the target site, such as a tumor. In this regard the use of such radiopharmaceuticals has been shown to be effective in treating a variety of tumors.
Some peptides radiolabeled with
177
Lu (T ½=6.7 days), a low-energy beta emitter (E
max
0.497 MeV), are considered particularly useful as a result of rapid cellular uptake whereby radioactive decay occurs within the cell. Low-energy beta emissions are highly effective in the immediate vicinity of the cell, and the effect on adjacent, normal and sensitive tissues is minimal. Therefore, it is desirable to obtain
177
Lu in high purity, high specific activity form.
177
Lu can be produced in a nuclear reactor by the conventional “direct” production method involving neutron capture of enriched
176
Lu, as shown in FIG.
1
. Since the nonradioactive target atoms and radioactive product atoms cannot be separated by chemical means, the radioactive
177
Lu is diluted with significant amounts of the
176
Lu carrier. Moreover, metastable
177m
Lu is also produced by the “direct” method. Metastable
177m
Lu, having a half-life of 160 days, is generally considered harmful for nuclear medicine applications because of the potential for extended patient exposure to radiation.
The amount of
176
Lu target (carrier) determines the specific activity (Curies/gram), with higher specific activity products being produced in higher neutron flux reactors such as the Oak Ridge National Laboratory (ORNL) High Flux Isotope Reactor (HFIR). Although high specific activity (>80 Curies/mg) can be produced by this method in a high flux reactor such as the ORNL HFIR, it is desirable to obtain higher specific activity
177
Lu in order to attain a higher specific dosage and also to extend the shelf life of
177
Lu inventory. It is also desirable to have a method available to provide high specific activity
177
Lu that is essentially free of long-lived
177m
Lu impurity.
There has been interest for several years in the “indirect” method of reactor production of
177
Lu, which is obtained from decay of the short-lived (T ½=2 hours)
177
Yb radioisotope, which is produced in a reactor by irradiation of enriched
176
Yb targets (also shown in FIG.
1
). The indirect method is advantageous over the direct method in that there is little or no metastable
177m
Lu produced by the indirect method. However, there remain large amounts of Yb target material that should be removed.
A major hindrance in the feasibility of producing no-carrier-added
177
Lu is lack of an effective method of the separating no-carrier-added
177
Lu from high levels of Yb. Separation of adjacent lanthanides is notoriously difficult using conventional ion exchange chromatography and other known methods because of the close similarity in the chemical properties of lanthanides.
An effective and efficient method of separating
177
Lu from reactor-produced
177
Yb is needed to provide high specific activity, no carrier-added
177
Lu. The only successful preparative scale separation of Lu and Yb which has been reported in the literature is the recent paper by Lebedev, et al., which describes the use of a difficult and cumbersome cementation process, in which tracer levels of
177
Lu are separated from macroscopic levels of Yb by the repetitive, selective extractions of Yb using a sodium (mercury) amalgam from chloride/acetate electrolytes, followed by a final cation exchange purification step. Such a method is not generally considered feasible for preparing
177
Lu in sufficient amounts for practical applications in nuclear medicine because of potential contamination with toxic mercury.
Accordingly, objectives of the present invention include provision of: methods of separating microscopic amounts of Lu from macroscopic amounts of Yb; methods of preparing
177
Lu that is at least one of high specific activity, no-carrier-added, and essentially free of
177m
Lu; and methods of treating disease using no-carrier-added
177
Lu. Further and other objectives of the present invention will become apparent from the description contained herein.
In accordance with one aspect of the present invention, the foregoing and other objects are achieved by a method of separating lutetium from a solution containing Lu and Yb includes the steps of: providing a chromatographic separation apparatus containing LN resin; loading the apparatus with a solution containing Lu and Yb; and eluting the apparatus to chromatographically separate the Lu and the Yb.
In accordance with another aspect of the present invention, a composition of matter comprising essentially
177
Lu which is characterized by at least one of: essentially
177m
Lu-free (no or insignificant presence thereof), no-carrier-added, and a specific activity of at least 100 Ci/mg Lu.
REFERENCES:
patent: 5809394 (1998-09-01), Bray et al.
Resin Information, Eichrom Industries Apr. 1998, pp. 1-4 from the internet site URL at www.eichrom.com/analytical/radio
ewsletters/resin/a98-Inres.hmt.*
Shuang Liu et al, “90-Y and 177-Lu Labeling of a DOTA-Conjugated Vitronectin Receptor Antagonist Useful for Tumor Therapy,” Bioconjugate Chem. 2001, p. 559-568.
Nikolai A. Lebedev, et al, “Radiochemical Separation of No-Carrier-Added 177-Lu as Produced via the 176-Yb(n,&ggr;) 176-Yb→177-Lu Process,” App. Radiation & Isotopes (2000), p. 421-425.
Beets Arnold L.
Du Miting
Knapp, Jr. Furn F.
Mirzadeh Saed
Marasco Joseph A.
Therkorn Ernest G.
UT-Battelle LLC
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