Purification of cyclotron-produced 203Pb for labeling Herceptin

https://doi.org/10.1016/j.nucmedbio.2004.11.004Get rights and content

Abstract

A simple and rapid procedure was developed for the purification of cyclotron-produced 203Pb via the 203Tl(d,2n) 203Pb reaction. A Pb(II) selective ion-exchange resin, with commercial name Pb Resin from Eichrom Technologies, Inc., was used to purify 203Pb from the cyclotron-irradiated Tl target with excellent recovery of the enriched Tl target material. The purified 203Pb was used to radiolabel the monoclonal antibody Herceptin. The in vitro and in vivo properties of the 203Pb radioimmunoconjugate were evaluated.

Introduction

Owing to their short range and high linear energy transfer, α-emitting radionuclides have been under investigation for radioimmunotherapy (RIT) therapies of leukemia, lymphoma and metastatic cancers [1], [2], [3]. Currently, α-emitters for RIT include 213Bi and 212Bi, with 211At and 225Ac being investigated to a lesser degree [4], [5], [6]. The parent/daughter radionuclide pairing of 212Pb/212Bi with the 10.6-h half-life of the 212Pb (β emission; Emax=0.334 MeV) is potentially more favorable than 212Bi alone for α-therapy. While this pairing provides a potential in vivo generator of 212Bi, the 212Pb-to-212Bi nuclear transition may compromise this therapeutic strategy [7], [8], [9], [10], [11].

One challenge associated with performing preclinical experiments with 212Pb is the execution of accurate biodistribution and targeting assays of a 212Pb-radiolabeled monoclonal antibody (mAb). One viable option is to employ 203Pb (t1/2=51.9 h) as a surrogate radionuclide [12], [13]. 203Pb emits an imageable γ-ray (279 keV) that is suitable for SPECT imaging and thus provides useful and important pharmacokinetics and dosimetry information. For radiolabeling mAbs, 203Pb should not only be carrier free, but should also be of high radiochemical and chemical purity. The presence of other metal ions such as iron could compromise labeling efficiency of, if not completely inhibit, mAb radiolabeling. Lastly, since 203Pb can be routinely and efficiently produced by cyclotron facilities, this radionuclide could be in routine use.

This study describes a simple and rapid method for purification of cyclotron-produced 203Pb employing a commercially available Pb(II) selective ion-exchange resin, simply marketed as Pb Resin by Eichrom Technologies, Inc. (Darien, IL, USA).1 The utility of the 203Pb generated and purified by this method was then demonstrated by radiolabeling Herceptin and execution of a tumor targeting study.

Section snippets

Materials

Natural Tl2O3 (99.99%) was obtained from Aldrich Chemical Co. (Milwaukee, WI, USA). Enriched Tl2O3 [203Tl (97.1%), 205Tl (2.9%), lot 233208] was obtained from the Oak Ridge National Laboratory (Oak Ridge, TN, USA). The synthesis, characterization and purification of the bifunctional macrocycle ligand 1,4,7,10-tetraazacyclododecane-N,N′,N′,N″-tetraacetic acid (C-DOTA) have been detailed elsewhere [14]. The mAb Herceptin was provided by Dr. R. Altemus (Radiation Oncology Branch, NCI). The Pb(II)

Results and discussion

The requirement of a suitable tracer and/or imaging component for targeted radiation therapies originated with the use of 212Pb to treat disseminated disease provided the impetus for the development of 203Pb production.

Cyclotron production of 203Pb from thallium provides a convenient source of this isotope for both tracer applications and SPECT imaging. The 203Tl(d,2n) 203Pb reaction provides an efficient route to this isotope. While creating an effective isolation and purification process

References (23)

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