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Chelator-Free Radiolabeling of Nanographene: Breaking the Stereotype of Chelation.

ABSTRACT: Macrocyclic chelators have been widely employed in the realm of nanoparticle-based positron emission tomography (PET) imaging, whereas its accuracy remains questionable. Here, we found that ⁶⁴ Cu can be intrinsically labeled onto nanographene based on interactions between Cu and the π electrons of graphene without the need of chelator conjugation, providing a promising alternative radiolabeling approach that maintains the native in vivo pharmacokinetics of the nanoparticles. Due to abundant π bonds, reduced graphene oxide (RGO) exhibited significantly higher labeling efficiency in comparison with graphene oxide (GO) and exhibited excellent radiostability in vivo. More importantly, nonspecific attachment of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) on nanographene was observed, which revealed that chelator-mediated nanoparticle-based PET imaging has its inherent drawbacks and can possibly lead to erroneous imaging results in vivo.

SUBMITTER: Shi S

PROVIDER: S-EPMC5345346 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Chelator-Free Radiolabeling of Nanographene: Breaking the Stereotype of Chelation.

Shi Sixiang S Xu Cheng C Yang Kai K Goel Shreya S Valdovinos Hector F HF Luo Haiming H Ehlerding Emily B EB England Christopher G CG Cheng Liang L Chen Feng F Nickles Robert J RJ Liu Zhuang Z Cai Weibo W

Angewandte Chemie (International ed. in English) 20170207 11

Macrocyclic chelators have been widely employed in the realm of nanoparticle-based positron emission tomography (PET) imaging, whereas its accuracy remains questionable. Here, we found that <sup>64</sup> Cu can be intrinsically labeled onto nanographene based on interactions between Cu and the π electrons of graphene without the need of chelator conjugation, providing a promising alternative radiolabeling approach that maintains the native in vivo pharmacokinetics of the nanoparticles. Due to ab ...[more]

PMID: 28170126

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Project description:BackgroundCombining optical (fluorescence) imaging with nuclear imaging has the potential to offer a powerful tool in personal health care, where nuclear imaging offers in vivo functional whole-body visualization, and the fluorescence modality may be used for image-guided tumor resection. Varying chemical strategies have been exploited to fuse both modalities into one molecular entity. When radiometals are employed in nuclear imaging, a chelator is typically inserted into the molecule to facilitate radiolabeling; the availability of the chelator further expands the potential use of these platforms for targeted radionuclide therapy if a therapeutic radiometal is employed. Herein, a novel mixed modality scaffold which contains a tetrazine (Tz)--for biomolecule conjugation, fluorophore-for optical imaging, and chelator-for radiometal incorporation, in one construct is presented. The novel platform was characterized for its fluorescence properties, radiolabeled with single-photon emission computed tomography (SPECT) isotope indium-111 (111In3+) and therapeutic alpha emitter actinium-225 (225Ac3+). Both radiolabels were conjugated in vitro to trans-cyclooctene (TCO)-modified trastuzumab; biodistribution and immuno-SPECT imaging of the former conjugate was assessed.ResultsKey to the success of the platform synthesis was incorporation of a 4,4'-dicyano-BODIPY fluorophore. The route gives access to an advanced intermediate where final chelator-incorporated compounds can be easily accessed in one step prior to radiolabeling or biomolecule conjugation. The DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugate was prepared, displayed good fluorescence properties, and was successfully radiolabeled with 111In & 225Ac in high radiochemical yield. Both complexes were then separately conjugated in vitro to TCO modified trastuzumab through an inverse electron demand Diels-Alder (IEDDA) reaction with the Tz. Pilot small animal in vivo immuno-SPECT imaging with [111In]In-DO3A-BODIPY-Tz-TCO-trastuzumab was also conducted and exhibited high tumor uptake (21.2 ± 5.6%ID/g 6 days post-injection) with low uptake in non-target tissues.ConclusionsThe novel platform shows promise as a multi-modal probe for theranostic applications. In particular, access to an advanced synthetic intermediate where tailored chelators can be incorporated in the last step of synthesis expands the potential use of the scaffold to other radiometals. Future studies including validation of ex vivo fluorescence imaging and exploiting the pre-targeting approach available through the IEDDA reaction are warranted.

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Chelator-Free Radiolabeling of Nanographene: Breaking the Stereotype of Chelation.

Publications

Chelator-Free Radiolabeling of Nanographene: Breaking the Stereotype of Chelation.

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