Radiolabeling and <i>in vivo</i> evaluation of lanmodulin with biomedically relevant lanthanide isotopes

Martin, Kirsten; Mattocks, Joseph A.; Smilowicz, Dariusz; Aluicio‐Sarduy, Eduardo; Whetter, Jennifer N; Engle, Jonathan W.; Boros, Eszter

doi:10.1039/d3cb00020f

Cited by 4 publications

(4 citation statements)

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“…37 LanM is also able to outcompete high concentrations of phosphate and other chelators in vitro, 38 although its affinity is insufficient in studies of radiolabeled LanM in a mouse tumor model. 10,39 Our investigation into the interaction of EF 2−3 with lanthanides has yielded several observations that shed light on how the structure of the full-length LanM relates to achieving this high affinity, underpinned by a combination of techniques: ITC, CD, 2D IR, and MD simulations. The measurements point to a primary 1:1 metal:peptide binding stoichiometry with micromolar affinity for the three examined ions.…”

Section: Discussionmentioning

confidence: 99%

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Lanmodulin’s EF 2–3 Domain: Insights from Infrared Spectroscopy and Simulations

Alasadi,

Choi,

Chen

et al. 2024

ACS Chem. Biol.

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Lanmodulins are small, ∼110-residue proteins with four EF-hand motifs that demonstrate a picomolar affinity for lanthanide ions, making them efficient in the recovery and separation of these technologically important metals. In this study, we examine the thermodynamic and structural complexities of lanthanide ion binding to a 41-residue domain, EF 2−3, that constitutes the two highest-affinity metal-binding sites in the lanmodulin protein from Methylorubrum extorquens. Using a combination of circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC), two-dimensional infrared (2D IR) spectroscopy, and molecular dynamics (MD) simulations, we characterize the metal binding capabilities of EF 2−3. ITC demonstrates that binding occurs between peptide and lanthanides with conditional dissociation constants (K d ) in the range 20−30 μM, with no significant differences in the K d values for La 3+ , Eu 3+ , and Tb 3+ at pH 7.4. In addition, CD spectroscopy suggests that only one binding site of EF 2−3 undergoes a significant conformational change in the presence of lanthanides. 2D IR spectroscopy demonstrates the presence of both mono-and bidentate binding configurations in EF 2−3 with all three lanthanides. MD simulations, supported by Eu 3+ luminescence measurements, explore these results, suggesting a competition between water−lanthanide and carboxylate− lanthanide interactions in the EF 2−3 domain. These results underscore the role of the core helical bundle of the protein architecture in influencing binding affinities and communication between the metal-binding sites in the full-length protein.

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Section: Discussionmentioning

confidence: 99%

“…extorquens . LanM is also able to outcompete high concentrations of phosphate and other chelators in vitro, although its affinity is insufficient in studies of radiolabeled LanM in a mouse tumor model. , …”

Section: Discussionmentioning

confidence: 99%

Lanmodulin’s EF 2–3 Domain: Insights from Infrared Spectroscopy and Simulations

Alasadi,

Choi,

Chen

et al. 2024

ACS Chem. Biol.

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“…To date, clinical radiopharmaceuticals are exclusively synthesized in solution, relying on high radioisotopic purity and concentration of the radionuclide, typically achieved by the preceding isotope separation and concentration process. , This poses time constraints on the radiosynthesis and limits achievable radiochemical yields by competing, coordinating impurities. , Conclusively, we considered this an area of potential for significant innovation.…”

Section: Selective Radiochelation On a Solid Supportmentioning

confidence: 99%

“…76,77 This poses time constraints on the radiosynthesis and limits achievable radiochemical yields by competing, coordinating impurities. 78,79 Conclusively, we considered this an area of potential for significant innovation. Most chelator systems employed in nuclear medicine, such as the small aza-macrocycle 2,2′,2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), exhibit selectivity for trivalent over divalent ions.…”

Section: Radiosynthesis On a Solid Support: Photolysismentioning

confidence: 99%

Exploring Aqueous Coordination Chemistry of Highly Lewis Acidic Metals with Emerging Isotopes for Nuclear Medicine

Whetter,

Śmiłowicz,

Boros

2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Nuclear medicine harnesses radioisotopes for the diagnosis and treatment of disease. While the isotopes 99m Tc and 111 In have enabled the clinical diagnosis of millions of patients over the past 3 decades, more recent clinical translation of numerous 68 Ga/ 177 Lu-based radiopharmaceuticals for diagnostic imaging and therapy underscores the clinical utility of metal-based radiopharmaceuticals in mainstream cancer treatment. In addition to such established radionuclides, advancements in radioisotope production have enabled the production of radionuclides with a broad range of half-lives and emission properties of interest for nuclear medicine. Chemical means to form kinetically inert, in vivo-compatible species that can be modified with disease-targeting vectors is imperative. This presents a challenge for radiosiotopes of elements where the aqueous chemistry is still underdeveloped and poorly understood. Here, we discuss our efforts to date in exploring the aqueous, radioactive coordination chemistry of highly Lewis acidic metal ions and how our discoveries apply to the diagnosis and treatment of cancer in preclinical models of disease. The scope of this Account includes approaches to aqueous coordination of to-date understudied highly Lewis acidic metal ions with radioisotopes of emerging interest and the modulation of well-understood coordination environments of radio-coordination complexes to induce metal-catalyzed reactivity for separation and pro-drug applications. First, we discuss the development of seven-coordinate, small-cavity macrocyclic chelator platform mpatcn/picaga as an exemplary case study, which forms robust complexes with 44 Sc/ 47 Sc isotopes. Due to the high chemical hardness and pronounced Lewis acidity of the Sc 3+ ion, the displacement of ternary ligand H 2 O by 18/nat F − can be achieved to form an inert Sc− 18/nat F bond. Corresponding coordination complex nat Sc− 18 F is in vivo compatible and forms a theranostic tetrad with corresponding 44 Sc/ 47 Sc, 177 Lu complexes all exhibiting homologous biodistribution profiles. Another exceptionally hard, highly Lewis acidic ion with underdeveloped aqueous chemistry and emerging interest in nuclear medicine is 45 Ti 4+ . To develop de novo approaches to the mononuclear chelation of this ion under aqueous conditions, we employed a fragment-based bidentate ligand screening approach which identified two leads. The screen successfully predicted the formation of [ 45 Ti][Ti(TREN-CAM)], a Ti-triscatechol complex that exhibits remarkable in vivo stability. Furthermore, the fragment-based screen also identified approaches that enabled solid-phase separation of Ti 4+ and Sc 3+ of interest in streamlining the isotope production of 45 Ti and accessing new ways to separate 44 Ti/ 44 Sc for the development of a longlived generator system. In addition to establishing the inert chelation of Ti 4+ and Sc 3+ , we introduce controlled, metal-induced reactivity of corresponding coordination complexes on macrosc...

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Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement

Jiang,

Li,

2024

Drug Resistance Updates

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Radiolabeling and in vivo evaluation of lanmodulin with biomedically relevant lanthanide isotopes

Abstract: Short-lived, radioactive lanthanides comprise an emerging class of radioisotopes attractive for biomedical imaging and therapy applications. To deliver such isotopes to target tissues, they must be appended to entities that...

Cited by 4 publications

References 38 publications

Lanmodulin’s EF 2–3 Domain: Insights from Infrared Spectroscopy and Simulations

Lanmodulin’s EF 2–3 Domain: Insights from Infrared Spectroscopy and Simulations

Exploring Aqueous Coordination Chemistry of Highly Lewis Acidic Metals with Emerging Isotopes for Nuclear Medicine

Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement

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