第一作者：Linwei He, Xijian Chen, Zhuowei Zhang论文DOI: 10.1021/jacs.5c14889²¹¹At是靶向α治疗中极具前景的放射性核素，但其传统标记策略依赖不稳定的碳-砹（C-Ar-At）共价键，在体内易发生氧化裂解释放游离²¹¹At，导致脱靶辐射损伤。现有改进方法如侧基修饰或硼-砹键合成复杂或药代动力学欠佳。尽管利用氧化态砹阳离子（At(Ø)+）的配位化学可增强稳定性，但在皮摩尔级的示踪剂量下，其与离散配体结合的动力学限制难以克服。因此，本研究提出利用预组织配位环境的两性离子共价有机框架，通过多重非共价相互作用高效、快速捕获At(Ø)+，为解决²¹¹At体内脱砹这一关键难题提供了创新平台。砹-211（211At）是一种极具前景的靶向α治疗（TAT）α 发射体，其 α 发射率接近100%，且半衰期达7.21小时。然而，基于211At的放射性药物临床转化受到传统共价结构中不稳定的碳-砹键氧化裂解的阻碍，导致治疗过程中显著的脱靶效应和对正常组织的辐射危害。本文提出了一种突破性的放射性标记策略：在预组织的两性离子共价有机框架(ZVCOF ， ZV =两性离子乙烯基连接)中，通过协同多重非共价相互作用稳定固定阳离子211At物种（At(Ø)+）。该策略在ZVCOFs中实现了动态可逆的放射性标记路径，具有高标记效率(RCY ≥90%且标记动力学≤2分钟)和增强的体内抗去砹稳定性，超越了临床试验金标准N-琥珀酰亚胺基-3-[211At]砹苯甲酸酯等分子有机砹配合物。理论研究为At(Ø)+在 ZVCOF 中的配位化学与动态行为提供了基础性见解，而细胞及体内实验验证了该策略的实际应用潜力。本研究为下一代 α 治疗建立了稳健且抗去砹的平台，为释放211At在精准肿瘤学中的全部潜力提供了关键线索。
标记策略：利用预组织框架实现高效稳定捕获创新性地采用两性离子共价有机框架（ZVCOF）作为预组织平台，通过多重非共价相互作用（配位、静电、π‑阳离子及孔道限域）稳定捕获阳离子态²¹¹At(Ø)+，克服了传统C-Ar-At共价键易氧化断裂的瓶颈，实现了高标记效率（RCY ≥ 90%）与超快标记动力学（≤ 2分钟）。
卓越的体内稳定性与抗脱砹能力ZVCOF-²¹¹At(Ø)复合物在模拟生理氧化环境（如Fenton条件、肝微粒体酶）中表现出显著优于传统共价标记物的稳定性，体内实验证实其能有效阻止²¹¹At在甲状腺、胃等非靶器官的积累，大幅降低脱靶辐射风险。
高效肿瘤靶向治疗验证构建的纳米药物²¹¹At(Ø)-ZVCOF-PEG-FA在乳腺癌模型中显示出优异的肿瘤滞留（24小时仍保持87.9% ID/g）和强效抑瘤效果，显著延长小鼠生存期，且未引起明显全身毒性，为²¹¹At靶向α治疗提供了稳定、高效的递送平台。
a(a) Previously Reported Strategies for Radioastatination and the Corresponding Deastatination Mechanism for CAr−At Bond Cleavage in the Oxidative Approach3,15 (EDG = Electron-Donating Group. (b) Proposed astatine species from the Pourbaix diagram and equilibria reported recently.2,43 (c, d) Schematic comparison of pmol-level 211At(Ø)+ labeling in extremely dilute solution: discrete coordination centers (monomers) vs preorganized frameworks. Corresponding energy profiles for three subprocesses: (1) independent state; (2) kinetic process; and (3) thermodynamic process. (e) Schematic illustration of the mechanism for 211At radiolabeling from the 211At(Ø)+ precursor using ZVCOFs.
Figure 1. (a) Synthetic route of the ZVCOF. (b) PXRD profiles of the ZVCOF: experimentally observed results (black), Pawley refined (red), simulation (purple), Bragg position (green), and difference (cyan). (c) FTIR spectra of the ZVCOF (red), PSTMP (blue), and TFPT (cyan). (d) N2 adsorption (blue dots) and desorption (green dots) isotherms at 77 K and pore width distribution (red dots) for the ZVCOF. (e) Solvent-accessible surface model for the ZVCOF.
Figure 2. (a) RCY of the 211At/131I-ZVCOF under oxidation or reduction conditions. The radiolabeled product under oxidizing conditions is denoted as the 211At(Ø)/131I(+)-ZVCOF, while under reducing conditions, it is denoted as the 211At/131I-ZVCOF. (b) Comparison of the 211At radiolabeling efficiency between the PSTMP monomer and ZVCOF. (c) Radiolabeling kinetics of the ZVCOF with different species of 211At (or 131I). The RCY of 211At(Ø)-ZVCOFs (d) at different pH values and (e) in the presence oxidants with different redox potentials (NCS = N chlorosuccinimide, Ch-T = chloramine-T). (f) Radiochemical stability of the 211At(Ø)-ZVCOF, 211At-TM-TPT-COF, and 211At-ATE-NHS after incubation under Fenton conditions or in the presence of the liver microsomal enzyme. (g) Comparison of the radiolabeling kinetics between the coordination binding mediated radioastatination proposed in this work and those in the previously reported work.
Figure 3. ESP of (a) single-layered and (d) double-layered ZVCOF fragments. The gas-phase coordination structures of the model compounds (b, c) formed by At+/AtO+ interacting with the single-layered ZVCOF (labeled as COF-At+-H2O and COF-AtO+-H2O, respectively) and (e, f) formed by At+/AtO+ interacting with the double-layered ZVCOF (labeled as COF2-At+ and COF2-AtO+, respectively). (g) ΔEad corresponding to the energy change involved in the sorption of different 211At species onto the ZVCOF to form the corresponding model compounds (see Scheme S2 for reactions S1−S8). The up and down labels in parentheses refer to different adsorption sites of At−/I− and see Figure S8 for the detailed structures. (h) EDA results of different model compounds. The percentage contributions to the total attractive interactions (ΔEelstat + ΔEorb + ΔEdisp) are shown in columns with the specific values provided only for COF2-At+, COF2-AtO+, and Ph-At. (i) Major contributions in ETS-NOCV analysis for COF-At+-H2O, COF-AtO+-H2O, COF2-At+, and COF2-AtO+. The isovalues are 0.003 au. The pink and purple colors represent negative and positive, respectively. Cyan balls represent the ZVCOF skeleton. Color code: carbon, silver; nitrogen, blue; oxygen, red; sulfur, orange; hydrogen, white; and astatine, iceblue.
Figure 4. Statistical results of (a−c, g, h) {aqua-COF2-At+} and (d−f, i, j) {aqua-COF2-AtO+} model systems for the last 5 ps of AIMD simulations. (a, d) Potential energy plot. (b, e) Time evolution of the distances between At and the coordinated oxygen atoms (OS) from sulfonate groups, with the OS from the first and second layers of the ZVCOF denoted by OS1 and OS2, respectively. (c, f) At−O radial distribution functions (RDFs) and coordination numbers (CNs). The maximum positions of At−OS1/S2/S RDF peaks are indicated by purple, blue-green, and black numbers, respectively. The plateau positions in the CN curves (red dashed lines) are marked by blue dashed lines, with corresponding numbers indicated beside them. In (f), a shoulder peak to the right of the second At−O maximum corresponds to a coordinated water molecule. (g−j) Representative snapshots with the inner-sphere coordination structures of At(Ø)+ highlighted. Color code: carbon, silver; nitrogen, blue; oxygen, red; sulfur, orange; hydrogen, white; astatine, iceblue; and chlorine, green.
Figure 5. (a) DLS data and TEM images (inset) of the ZVCOF and ZVCOF-PEG-FA. (b) Radiolabeling stability of the 211At(Ø)-ZVCOF-PEG-FA after incubation with 50% fetal bovine serum (FBS) in phosphate-buffered saline (PBS) at RT and 37 °C. (c) Relative cell viability of 4T1 cells treated with 211At and the 211At(Ø)-ZVCOF-PEG-FA at various radioactive doses. (d) Micro-SPECT/CT images and (e) ex vivo biodistributions of 4T1-bearing mice after i.t. injection with free 211At, 211At -APA, and the 211At(Ø)-ZVCOF-PEG-FA taken at different time points post injection (n = 3). Biodistributions for the spleen, stomach, and thyroid are highlighted as insets. (f) Tumor growth index of mice with six group (n = 8) treatments. (g) Body weight change curves during treatment. (h) Survival curves for different groups of mice. Group I: PBS; Group II: ZVCOF-PEG-FA; Group III: 211At, 0.185 MBq; Group IV: 211At(Ø)-ZVCOF-PEG-FA, 0.185 MBq; Group V: 211At(Ø)-ZVCOF-PEG-FA, 0.555 MBq; and Group VI: 211At(Ø)-ZVCOF-PEG-FA, 0.925 MBq. The results are shown as an average value ± standard deviation, n = 4. ***p < 0.001.
本文提出了一种基于配位化学的211At放射性标记革命性策略，成功克服了传统碳原子-砹键固有的不稳定性。通过利用两性离子共价有机框架（ZVCOF）中预先构建的磺酸盐位点，我们开创性地实现了211At(Ø)+的快速高效固定化，其协同非共价作用机制在生理相关氧化还原条件下仍能保持优异的抗氧化裂解和去砹化稳定性。生物评估表明，工程化纳米药物211At(Ø)+- ZVCOF -PEG-FA展现出卓越的肿瘤滞留能力和理想细胞毒性，显著提升靶向α治疗效能。本策略确立了配位化学作为211At放射性药物设计的范式转换工具，为长期存在的砹不稳定难题提供了潜在解决方案。我们预计，这种稳健且模块化的标记平台将加速211At诊疗一体化技术的临床转化，推动精准靶向α治疗的发展。
https://pubs.acs.org/doi/10.1021/jacs.5c14889.
