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Interventional nuclear medicine: 'click' chemistry as an in vivo targeting strategy for imaging microspheres and bacteria

机译：介入核医学：“点击”化学作为体内成像微球和细菌的体内靶向策略

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摘要

Aim: Pre-targeting is a proven strategy for in vivo delivery of a diagnostic or therapeutic payload. The pretargeting concept can be realized through various conjugation strategies, one of which is based on copperfree "click" chemistry. Copper-free click reactions have shown in vivo potential for imaging and radionuclide therapy, but this conjugation strategy has not yet been explored in combination with microspheres or unicellular organisms. This study aims to evaluate the in vivo efficacy of strain-promoted azide-alkyne cycloaddition (SPAAC) reactions to achieve imaging and targeting of azide-functionalized macro-aggregated albumin (MAA) microspheres and Staphylococcus aureus bacteria. Methods: MAA microspheres (diameter 10-90 μm) were functionalized with a biorthogonal Cy5 fluorophore, bearing an azide functionality (N_3), to generate MAA-Cy5-N_3. S. aureus (diameter ～1 μm) were functionalized with ~(99m)Tc-UBI_(29-41)-Cy5-N_3, generating S. aureus-~(99m)Tc-UBI_(29-41)-Cy5-N_3. In situ and in vitro click conjugation on the -N_3 moieties was studied for 20 h using a radioactivity-based assay and fluorescence microscopy. For in vivo validation, both primary entities, radiolabeled with ~(99m)Tc, were deposited into the microvasculature of the liver via intrasplenic injections. Secondary targeting was realized following the intravenous administration of indium-111-radiolabeled diethylenetriaminepentaacetic acid-dibenzocyclooctyne (~(111)In-DTPA-DBCO). To assess click reaction efficiency in vivo, ~(99m)Tc and ~(111)In-biodistributions were measured (SPECT and %ID g~(-1)). Use of ~(111)In-DTPA-DBCO in mice without MAA deposits or mice infected with non-functionalized S. aureus served as controls. Ex vivo confocal fluorescence imaging was carried out in excised tissues to confirm the presence of functionalized MAA and bacteria. Results: In vitro data confirmed effective click reactions on both the MAA particles and the bacterial membrane. SPECT imaging and biodistribution studies revealed significantly (p < 0.05) increased accumulation of ~(111)In-DTPA-DBCO at the sites where MAA-Cy5-N_3 (7.5 ± 1.5% ID g~(-1) vs. 3.5 ± 0.5%ID g~(-1) in control mice) and S. aureus-~(99m)Tc-UBI_(29-41)-Cy5-N_3 (9.3 ± 1.3%ID g~(-1) vs. 6.0 ± 0.5%ID g~(-1) in control mice) resided. Ex vivo fluorescence imaging confirmed the presence of either functionalized MAA or S. aureus in excised spleens and livers of mice. Conclusion: Copper-free click chemistry between a DBCO moiety and Cy5-N_3-functionalized microspheres or bacterial entities in the liver can be used to realize in vivo imaging and targeting.
机译：目的：预先定位是验证的策略，用于诊断或治疗有效载荷。可以通过各种共轭策略实现预靶向概念，其中一个是基于CopperFree“点击”化学。无铜咔哒反应显示了成像和放射性核素治疗的体内电位，但这种缀合策略尚未与微球或单细胞生物组合探索。本研究旨在评估应变促进的叠氮化物 - 炔环加油（SPAAC）反应的体内疗效，以实现叠氮化官能化宏观聚集白蛋白（MAA）微球和金黄色葡萄球菌的成像和靶向。方法：使用双正常Cy5荧光团，官能团官能化MAA微球（直径10-90μm），含有叠氮化物功能（N_3），以产生MAA-CY5-N_3。 S.UUREUS（直径约〜1μm）用〜（99m）TC-UBI_（29-41）-CY5-N_3官能化，产生的S.UUREUS-（99M）TC-UBI_（29-41）-CY5-N_3 。原位和体外单击“使用基于放射性的测定和荧光显微镜的测定”对-N_3部分的缀合20小时。对于体内验证，通过肾包血性注射液体沉积在肝脏〜（99米）Tc的微小实体中，沉积到肝脏的微血管系统中。在静脉内施用铟-111-放射性标记的二亚乙基四乙酰丙烯酸 - 二苯并苯并苯并辛酸酯（〜（111）IN-DTPA-DBCO）之后实现了二次靶向。为了评估体内的咔哒反应效率，测量〜（99米）Tc和〜（111）的生物分布（SPECT和％ID G〜（-1））。在没有Maa沉积物的小鼠中使用〜（111）in-dtpa-dbco或用非官能化的金黄色葡萄球菌感染的小鼠作为对照。在切除的组织中进行前体内共焦荧光成像以确认官能化MAA和细菌的存在。结果：体外数据确认有效点击MAA颗粒和细菌膜的反应。 SPECT成像和生物分布研究显着显着（P <0.05）在MAA-CY5-N_3（7.5±1.5％ID G〜（-1）与3.5±0.5对照小鼠的％ID G〜（-1））和S.UUREUS-〜（99M）TC-UBI_（29-41）-CY5-N_3（9.3±1.3％ID G〜（-1）与6.0±0.5对照小鼠的％ID G〜（-1））居住。前体内荧光成像证实了在切除的脾脏和小鼠中官能化的MAA或S.UUREUS存在。结论：在肝脏和肝脏中的DBCO部分和Cy5-N_3-官能化的微球或细菌实体之间无铜咔哒化学可用于实现体内成像和靶向。

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  • 来源
    《Biomaterials Science》 |2021年第5期|共8页
  • 作者

    M. M. Welling; N. Duszenko; D. M. van Willigen; A. W. Hensbergen; T. Buckle; D. D. D. Rietbergen; M. Roestenberg; F. W. B. van Leeuwen;

  • 作者单位

    Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Albinusdreef 2 2300 RC Leiden Netherlands;

    Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Albinusdreef 2 2300 RC Leiden Netherlands;

    Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Albinusdreef 2 2300 RC Leiden Netherlands;

    Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Albinusdreef 2 2300 RC Leiden Netherlands;

    Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Albinusdreef 2 2300 RC Leiden Netherlands;

    Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Albinusdreef 2 2300 RC Leiden Netherlands;

    Departments of Parasitology and Infectious Diseases Leiden University Medical Center Leiden Netherlands;

    Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Albinusdreef 2 2300 RC Leiden Netherlands;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 计量学;
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