Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes
Introduction
High-energy α-particles emitted by the decay of radioactive isotopes can be harnessed with an appropriate biological targeting vector to destroy malignant cells [1], [2], [3]. This therapeutic strategy, known as α-therapy, is the subject of intense current research, with its utility emphasized by the recent FDA-approval of the α-emitter 223RaCl2 for the treatment of bone metastases arising from castration-resistant prostate cancer [4]. The short range (several cell diameters) and high linear energy transfer (≈ 100 keV/μm) of emitted α-particles suggests their use in the treatment of micro-metastatic disease, where irradiation can be limited to the targeted cells. However, the limited availability of α-emitting nuclides with appropriate physical properties for therapy hinders their development for clinical application [5], [6].
Among the radionuclides proposed for targeted α-therapy (TAT), the decay chain of 213Bi (t1/2 = 45.6 m, 97.8% β-, 2.2% α), which entails an α emission from either of two possible branches thanks to its α-emitting daughter 213Po (t1/2 = 3.72 μs, 100% α), has shown significant promise. The short half-life of 213Bi is suitable for use with small-molecule and peptide-based targeting agents. Furthermore, its short half-life and small decay chain (Fig. 1) minimize toxic side effects that may arise from long-lived daughter nuclides, which can redistribute to non-target sites in vivo [7]. 213Bi can also be conveniently obtained from a generator system comprised of its longer-lived parent 225Ac (t1/2 = 9.9 d, 100% α), which is attractive for clinical use [8], [9], [10], [11]. Such generator systems are currently commercially available from Oak Ridge National Laboratory in the United States and the Institute for Transuranium Elements in Germany, with future commercial development underway at the Institute for Physics and Power Engineering in Russia [12]. Although the widespread availability of the 225Ac parent isotope is limited currently, impeding the further development of 213Bi pharmaceuticals [13], significant progress has been made toward the large-scale production of 225Ac [14], [15], [16], [17]. The great therapeutic utility of 213Bi is reflected by the several clinical trials that have employed this isotope for cancer treatment [18], [19], [20], [21], [22], [23]. The potential of 213Bi and other α-emitters for the treatment of infectious diseases is currently under intense investigation as well [24], [25], [26].
Despite the promise of 213Bi TAT, the element bismuth has complicated aqueous chemistry, rendering its complexation for biological delivery challenging. The high affinity of Bi3 + for OH- (logK = 12.9) [27] indicates the strong tendency of this ion to hydrolyze at even at slightly acidic pH values. Challenges associated with the aqueous chemistry of Bi3 + have largely hindered the development and rational design of chelating ligands. Ligands currently used for TAT with 213Bi are DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and CHX-A′′-DTPA (N-[(R)-2-amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N",N"-pentaacetic acid), shown in Fig. 2. Radiolabeling kinetics for DOTA are generally slow, and both CHX-A′′-DTPA and DOTA have high affinity for metal ions other than Bi3 +. The development of other bifunctional chelating agents for Bi3 +, which exhibit fast radiolabeling kinetics, high stability, and good metal ion selectivity, would be welcome additions to DOTA and CHX-A′′-DTPA for 213Bi TAT. A ligand that is highly selective for Bi3 + may minimize the effects of 225Ac breakthrough from the 225Ac/213Bi generator, which may occur after operator error.
Recently, we described a series of nitrogen-rich macrocyclic ligands and explored their coordination chemistry with La3 + [28]. These ligands (Fig. 2), Lpy (1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane), Lpyd (1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane), Lpyr (1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane), and Lpz (1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane), are structurally homologous, varying only in the nature of the pendant N-heterocyclic donors. The pendant donors vary in their relative basicity and chemical hardness values. In our previous work, we demonstrated how these subtle electronic modifications across this series of ligands have significant effects on the solution behavior of their La3 + complexes [28]. Here, we describe the utility of this class of ligands for the selective and stable chelation of radiobismuth. The fast radiolabeling kinetics, high stability, and good selectivity for Bi3 + over the generator parent Ac3 + indicate that these ligands may be useful for 213Bi TAT.
Section snippets
General
Aqueous buffers were prepared using 18 MΩ · cm Milli-Q water obtained from a Millipore filtration system. Trace metal-free Optima-grade acids and bases used for adjusting pH were obtained from Fisher Scientific. Other buffer components were obtained from commercial vendors and were of the highest purity available. The ligands DOTA and CHX-A′′-DTPA were purchased from Fluka Scientific and Macrocyclics, Inc (Dallas, TX, USA), respectively. The other ligands, Lpy, Lpyd, Lpyr, and Lpz, were
225Ac and 207Bi competition study
The ability of the nitrogen-rich macrocycles, DOTA, and CHX-A′′-DTPA to complex 225Ac and Bi was investigated. 225Ac was eluted from a 229Th generator and purified from 225Ra, as previously described [9], [30]. After reaching secular equilibrium with its daughters, a 9 kBq portion of 225Ac was spiked with 4 kBq of 207Bi. 207Bi (t1/2 = 32 a) was used as a longer-lived surrogate for the short-lived therapeutically relevant 225Ac daughter, 213Bi (t1/2 = 45.6 min). The resulting radioisotope mixture was
Discussion
The design of bifunctional chelating agents that form strong complexes with 213Bi has been the focus of many synthetic efforts. A number of multi-dentate polyamino carboxylate ligands for Bi3 + chelation have been synthesized and characterized [51], [52], [53], [54], [55], [56], [57], [58], [59], [60]. In particular, the polyamino carboxylate ligands known as DEPA and NETA exhibit fast Bi3 +-labeling kinetics and high stability, making them among the best known ligands for this unique ion [55],
Conclusions
The nitrogen-rich macrocylic ligands investigated in this work have a strong selectivity for Bi3 + over Ac3 +. This selectivity is important to minimize detrimental effects of 225Ac/213Bi generator breakthrough that can lead to inadvertent patient dosing with small quantities of long-lived 225Ac. DFT calculations indicate that coordination of these ligands to either La3 + or Ac3 + is strongly disfavored thermodynamically relative to Bi3 +. This thermodynamic preference most likely arises from the
Acknowledgements
JJW and MF acknowledge funding support via the LANL/LDRD program through a Seaborg Institute Postdoctoral and Graduate Student Summer Research Fellowship, respectively. JWE thanks the US DOE for a postdoctoral fellowship through the LANL/LDRD program. The research described in this paper was funded by the United States Department of Energy, Office of Science via funding from the Isotope Development and Production for Research and Applications subprogram in the Office of Nuclear Physics, and
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