Structural Investigations, Cellular Imaging, and Radiolabeling of Neutral, Polycationic, and Polyanionic Functional Metalloporphyrin Conjugates.
Structural Investigations, Cellular Imaging, and Radiolabeling of Neutral, Polycationic, and Polyanionic Functional Metalloporphyrin Conjugates.
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中性、多阳离子和多阴离子功能金属卟啉偶联物的结构研究、细胞成像和放射性标记。
DOI：
10.1021/acs.bioconjchem.0c00691
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发表时间：
2021-07-21
影响因子：
4.7
通讯作者：
Pascu SI
中科院分区：
文献类型：
--
作者：
Ciaffaglione V;Waghorn PA;Exner RM;Cortezon-Tamarit F;Godfrey SP;Sarpaki S;Quilter H;Dondi R;Ge H;Kociok-Kohn G;Botchway SW;Eggleston IM;Dilworth JR;Pascu SI
在过去的十年中，卟啉衍生物已成为宝贵的合成积木和治疗诊断试剂盒，用于细胞荧光成像和光动力治疗。四苯基卟啉（TPP），其金属配合物，和相关的衍生物已被研究，它们的用途作为染料在组织学和作为组件的多模态成像探针。具有放射性金属的卟啉-金属配合物的光物理性质一直是我们关注的焦点，用于实现具有放射性成像能力和具有“真正”治疗诊断前景的治疗潜力的荧光成像探针。我们在此报告的合成，放射化学，结构调查，并初步在体外和体内摄取的研究范围内的功能化卟啉衍生物。在追求开发新的卟啉为基础的探针的多模态成像应用，我们报告了新的功能化的中性，聚阳离子和聚阴离子卟啉纳入硝基咪唑和磺酰胺部分，这被用作靶向基团，以改善臭名昭著的穷人的卟啉标签的药代动力学。所得的功能性金属卟啉物种在血清挑战下是稳定的，硝基咪唑和磺酰胺衍生物保持荧光，允许在体外共聚焦研究和可视化的溶酶体摄取的镓（III）磺酰胺衍生物。选择卟啉衍生物的分子结构，确定了单晶X-射线衍射使用同步辐射。我们还研究了模型功能卟啉的发射/激发行为的性质，使用在硅片的方法，如TD DFT在简单的溶剂化模型。还实现了卟啉与蛙皮素的[7-13]和[7-14]片段的缀合，以提供对胃泌素释放肽受体（GRPR）的靶向。根据金属，已经设计并测试了与单光子发射计算机断层摄影术（SPECT）或正电子发射断层摄影术（PET）探针相关的探针缀合物，其中使用TPP和相关的功能性游离碱卟啉作为双功能螯合剂合成支架，并分别使用111 In [In]或68 Ga [Ga]作为中心金属离子。有趣的是，对于简单的卟啉共轭物，两种放射性金属都获得了良好的放射化学掺入，但肽的存在显着降低了放射性掺入产率。尽管蛙皮素缀合物的镓-68放射化学没有显示出适合于体内研究的放射化学掺入，可能是因为肽的存在改变了单独摄取的TPP-NH 2合成子的行为，但光学成像测定表明缀合的肽标签确实介导卟啉单元摄取到细胞中。
Over the past decade, porphyrin derivatives have emerged as invaluable synthetic building blocks and theranostic kits for the delivery of cellular fluorescence imaging and photodynamic therapy. Tetraphenylporphyrin (TPP), its metal complexes, and related derivatives have been investigated for their use as dyes in histology and as components of multimodal imaging probes. The photophysical properties of porphyrin–metal complexes featuring radiometals have been a focus of our attention for the realization of fluorescence imaging probes coupled with radioimaging capabilities and therapeutic potential having “true” theranostic promise. We report hereby on the synthesis, radiochemistry, structural investigations, and preliminary in vitro and in vivo uptake studies on a range of functionalized porphyrin-based derivatives. In pursuit of developing new porphyrin-based probes for multimodality imaging applications, we report new functionalized neutral, polycationic, and polyanionic porphyrins incorporating nitroimidazole and sulfonamide moieties, which were used as targeting groups to improve the notoriously poor pharmacokinetics of porphyrin tags. The resulting functional metalloporphyrin species were stable under serum challenges and the nitroimidazole and sulfonamide derivatives remained fluorescent, allowing in vitro confocal studies and visualization of the lysosomal uptake in a gallium(III) sulfonamide derivative. The molecular structures of selected porphyrin derivatives were determined by single crystal X-ray diffraction using synchrotron radiation. We also investigated the nature of the emission/excitation behavior of model functional porphyrins using in silico approaches such as TD DFT in simple solvation models. The conjugation of porphyrins with the [7-13] and [7-14] fragments of bombesin was also achieved, to provide targeting of the gastrin releasing peptide receptor (GRPR). Depending on the metal, probe conjugates of relevance for single photon emission computed tomography (SPECT) or positron emission tomography (PET) probes have been designed and tested hereby, using TPP and related functional free base porphyrins as the bifunctional chelator synthetic scaffold and 111In[In] or 68Ga[Ga], respectively, as the central metal ions. Interestingly, for simple porphyrin conjugates good radiochemical incorporation was obtained for both radiometals, but the presence of peptides significantly diminished the radio-incorporation yields. Although the gallium-68 radiochemistry of the bombesin conjugates did not show radiochemical incorporation suitable for in vivo studies, likely because the presence of the peptide changed the behavior of the TPP-NH2 synthon taken alone, the optical imaging assays indicated that the conjugated peptide tags do mediate uptake of the porphyrin units into cells.
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影响因子：
46.2
作者：
Jewett JC;Bertozzi CR
通讯作者：
Bertozzi CR
卟啉和邻苯烷在光动力疗法，成像和疗法学中的独特诊断和治疗作用。
影响因子：
12.4
作者：
Josefsen LB;Boyle RW
通讯作者：
Boyle RW
影响因子：
4.7
作者：
Le Guern, Florent;Sol, Vincent;Ouk, Tan-Sothea
通讯作者：
Ouk, Tan-Sothea
影响因子：
3.8
作者：
Dechan, Padma;Bajju, Gauri Devi
通讯作者：
Bajju, Gauri Devi
影响因子：
4.6
作者：
Enakieva, Yulia Yu.;Volostnykh, Marina V.;Guilard, Roger
通讯作者：
Guilard, Roger