Actinium (Ac), element 89 on the periodic table, marks the beginning of the actinide series. Unlike its neighbors, its chemistry and chemical properties have scarcely been explored. This knowledge gap is mostly due to the lack of stable or long-lived isotopes of this element—the most abundant isotope of plutonium, 239Pu, for instance, has a half-life of over 24,000 years, whereas the longest-lived isotope of actinium, 227Ac, has a half-life of only 21.77 years. Therefore, capabilities to produce and handle macroscopic quantities of this highly radioactive element are correspondingly very limited. Most of our knowledge of the chemical properties of Ac arises from harrowing studies1 in the 1950s and 1960s, when researchers engaged in an operation to generate milligram quantities of this element for fundamental studies. Alas, due to the great hazards associated with this work and the scarce availability of Ac, those efforts were largely abandoned, and our understanding of this element has not substantially progressed in the last 50 years. In contrast, the chemistry of the other early actinide elements has been steadily developed throughout the last several decades, with thousands of research articles describing the chemistry of actinides such as plutonium and uranium. The motivations for these research efforts are fairly obvious—these actinides play crucial roles in the nuclear energy cycle and weapons. What uses and applications would suddenly prompt us to be concerned about the 50 year actinium chemistry hiatus?
In contrast to the other actinides, it has become clear within the last two decades that the most important application of Ac lies within the realm of medicine. Although seemingly contradictory to the known radiotoxicity of the actinides, the clinical use of 225Ac is a promising strategy for the treatment of cancer and other diseases, via targeted radionuclide therapy. 225Ac emits a total of four alpha particles throughout its decay chain with a short half-life (t1/2 = 9.92 days), which renders it compatible for biological use (see Fig. 1 in subsequent article by Stein and Kerlin, p7). By chemically attaching this isotope via a chelating ligand to an antibody (a large biomolecule that selectively and strongly binds to cell surface receptors of cancer cells), the otherwise damaging alpha particles can be strategically harnessed to destroy malignant tumors (Fig. 1). Preclinical trials of 225Ac-antibody constructs have demonstrated the therapeutic utility of this isotope and general strategy. Highly selective antibodies are well developed, and efforts for large-scale production of 225Ac are also underway. An open question remains, however, regarding the most effective way to chemically attach the Ac ion to the cancer cell-targeting antibody. Displacement of Ac prior to its arrival at the target site will lead to toxic side-effects arising from unselective damage of healthy tissue from its alpha particles. The lack of progress in Ac chemistry has hindered the development of an appropriate chelating agent. A better appreciation and understanding of this element’s chemical properties will facilitate new ligand design, enabling the development of safer Ac-based radiopharmaceuticals.
1 On a per mass basis, 227Ac is 2.2 × 1013 times more radioactive than 238U!
Ac3+ chemical properties
Several of the fundamental chemical properties of Ac are known. Only the +3 oxidation state, which has a closed-shell radon electron configuration, is stable in aqueous solution. As a result, the Ac3+ ion is diamagnetic with no valence electrons in the 6d or 5f orbitals, rendering this ion spectroscopically silent. A unique property of the Ac3+ ion is its large six-coordinate ionic radius of 1.13 Å; Ac3+ is the largest trivalent ion in the periodic table. The absolute chemical hardness of an ion, another fundamental property, is a measure of its polarizability. Metal-ligand interactions are dictated by the hard-soft acid-base (HSAB) principle, whereby “hard” ions interact most strongly with “hard” ligands and vice versa. This principle, therefore, dictates the choice of preferred donor atom for a given metal ion. Using density functional theory (DFT) calculations, we computed the chemical hardness of Ac3+ to be 14.5 eV. This value classifies Ac3+ as a moderately hard ion. Taken together, these data show that Ac3+ is the largest +3 ion in the periodic table with a stable noble gas electron configuration and indicate a preference for hard donor atoms.
With this knowledge in hand, we began our investigation into Ac chemistry by evaluating the relative binding affinity of this ion with the nitrogen-rich macrocycles shown in Fig. 2 (nitrogen being classified as a moderately hard donor atom). The nature of each pendant N-heterocycle varies slightly with regard to chemical hardness. We reasoned that differences in binding affinity might shed light on an optimal value of ligand chemical hardness for forming stable bonds with the Ac ion.
Attempts to radiolabel these ligands with short-lived 225Ac, however, led to an unexpected result. Under all conditions screened, Ac3+ did not coordinate to the macrocyclic ligands. Instead, the third daughter isotope of 225Ac, 213Bi, was incorporated rapidly and selectively (see Fig. 1 on p7). This result highlights the surprisingly low nitrogen atom affinity of the Ac3+ ion. Indeed, estimation of the binding constant (K) of Ac3+ for a quintessential nitrogen donor ligand, NH3, gives a relatively small value of logK = 0.8. The higher corresponding value for Bi3+ (logK = 5.1) explains the observed selectivity. Additionally, preliminary work utilizing the expanded porphyrin-like macrocycle, texaphyrin (Fig. 2), again demonstrated selective labeling of 213Bi over 225Ac. From these studies, it is clear that an ideal chelating agent for Ac3+ should bear some oxygen atom donors (which are less polarizable than nitrogen atoms), or other chemically hard donors, rather than nitrogen donors.
Additional efforts to understand the chemical properties of Ac3+ employed the long-lived isotope, 227Ac (t1/2 = 21.77 years). For this research, we were able to utilize a supply of 10 mCi of 227Ac, which corresponds to only 0.61 μmol, or 140 μg, of Ac. The small quantities available, and the challenges associated with handling this highly radioactive element, necessitate a method of chemical analysis that is highly sensitive to low concentrations. We reasoned that fluorescence spectroscopy, a technique that can be commonly used for the detection of sub-micromolar concentrations of analyte, would be an effective method for probing Ac3+ chemistry. Because Ac3+ is spectroscopically silent, an organic fluorophore with a metal ion-binding unit is needed to relay information. Furthermore, to extract useful data regarding the Ac3+ ion, a fluorescent sensor that responds in a metal ion-dependent manner, rather than a simple “on-off” response, is necessary.
These efforts led to the design and synthesis of a new ligand, Ds-DOTAM (Fig. 3). This ligand bears a macrocyclic metal ion-binding unit and a fluorescent dansyl (Ds) group. The hard oxygen atom of the sulfone group of dansyl can interact favorably with similarly hard metal ions, perturbing its photophysical properties. Indeed, addition of the non-radioactive lanthanide 4f0 ion La3+ (six-coordinate ionic radius 1.03 Å vs. 1.13 Å for Ac3+) to Ds-DOTAM led to a red shift in the absorbance maximum of the ligand (i.e., an increase in wavelength and quenching of the dansyl emission; see Fig. 3). DFT calculations indicate that this red shift arises from a stabilization of the lowest-unoccupied molecular orbital (LUMO), primarily due to an electrostatic interaction of the M3+ ion with the dansyl sulfone group. The addition of Ac(NO3)3 showed similar spectroscopic changes. The UV-vis. absorbance spectrum is, however, partially obscured by the presence of a large excess of NO3 – ion, which absorbs at 290 nm and is carried over from radiochemical separation procedures. This data indicates that Ac3+ and La3+ interact with Ds-DOTAM in a similar manner. Nonetheless, strategies to purify the Ac3+ ion from excess NO3 –ions remain an important goal for obtaining high quality spectra.
X-ray absorption spectroscopy
Although the fluorescence spectroscopy results revealed that both La3+ and Ac3+ interact with Ds-DOTAM, the precise nature of that interaction will certainly be different for the two ions, which possess substantially different ionic radii. To ascertain structural aspects of Ac chemistry, we directed efforts toward X-ray absorption spectroscopy (i.e., X-ray absorption near edge structure, XANES, and extended X-ray absorption fine structure, EXAFS), using high intensity synchrotron sources coupled with fluorescence detection methods.
Analyzing a small quantity of 227Ac with these methods gave a significant edge-rise at 15.87 keV (Fig. 4). This energy corresponds to the LIII edge of Ac, and is therefore diagnostic of this element. Although the XANES region is not expected to yield a large amount of information about the non-redox-active Ac3+ ion, the EXAFS region can inform us about Ac-ligand interatomic distances. For this particular sample, Ac3+ was dissolved in 0.1 M ammonium acetate pH 5 buffer. These conditions mimic those used to create therapeutically relevant 225Ac-labeled antibodies, and can therefore shed light on the speciation and nature of Ac3+ prior to conjugation.
In conjunction with DFT and molecular dynamics calculations, EXAFS data analysis is underway. These data represent the first X-ray absorption spectra of Ac, and will enable the determination of Ac-ligand interatomic distances and coordination numbers in the solution phase for the first time (see article by Stein & Kerlin).
For the first time in over 50 years, the chemistry of actinium is under active exploration by researchers at Los Alamos National Laboratory (LANL). This effort is motivated by the great therapeutic potential of 225Ac, the clinical development of which is currently limited by a lack of knowledge of the fundamental coordination chemistry of this element. Our research has thus far demonstrated that Ac3+ is generally averse to interacting with nitrogen donor ligands. We have also shown that fluorescence spectroscopy can be used to interrogate Ac-ligand binding, and that 2 mCi quantities of 227Ac provide sufficient signal to obtain EXAFS spectra from which interatomic distances and coordination numbers can be obtained. These results provide a strong foundation for the continued exploration of Ac chemistry. The data obtained from these efforts will have direct application in the design of better ligands for Ac3+, leading to safer, more effective 225Ac-based radiopharmaceutical agents.
This work is a collaborative effort with several others researchers: Beau J. Barker, Enrique R. Batista, John M. Berg, Eva R. Birnbaum, Jonathan W. Engle, Michael E. Fassbender, Maryline G. Kerlin, Kevin D. John, Stosh A. Kozimor, Joel R. Maassen, Richard L. Martin, F. Meiring Nortier, Valery Radchenko, and Marianne P. Wilkerson all contributed and played vital roles in initiating and contributing to this ongoing project. Financial support was provided by the U.S. Department of Energy through the LANL/LDRD program and the Seaborg Institute for the postdoctoral fellowship to Dr. Wilson.
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