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. Graphical abstractChelator-free radiolabeling based on interactions between Cu and the π electrons of nanographene was shown, which can potentially substitute chelator-assisted labeling. The reliability of in vivo positron emission tomography imaging is enhanced while bypassing the inherent drawbacks of conventional chelator-based labeling. Macrocyclic chelators, such as DOTA (1,4,7,10-tetraazacy-clododecane-1,4,7,10-tetraacetic acid) or NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), have been routinely employed for small molecule and antibody-based positron emission tomography (PET), offering sensitive, quantitative and non-invasive functional detection of diseases at cellular or molecular levels. [1] In the past decade, with the explosive advances in nanotheranostic research, chelator conjugation has been expanded to the realm of nanoparticle-based PET imaging, [2] which has assisted in the evaluation of new nanoparticles by better understanding their in vivo biodistribution. Owing to the numerous reports of successful nanoparticle-based PET imaging employing macrocyclics-aided radiometal chelation, [3] it is now considered as the gold standard in PET-based evaluation of nanoparticle kinetics. However, chelator-based radiolabeling and PET imaging have their inevitable challenges. The incorporation of chelators might alter the size, surface charge, and hydrophilicity of the tracers, which may eventually lead to completely different imaging consequences. [4] In addition, due to their macrocyclic structure and relatively hydrophobic nature, [5] chelators might also interact with nanoparticles, influencing the overall imaging results. Therefore, although chelators have been widely employed in PET imaging of nanomaterials in the past decade, it is still questionable whether such a practice is precise enough to depict their real biodistribution.To better understand the in vivo behavior of the nanoparticles and avoid the influence of the chelators, a novel chelator-free radiolabeling approach can be employed, whereby radiometals can directly label onto the nano...

Ultra-small iron-gallic acid coordination polymer nanoparticles for chelator-free labeling of 64Cu and multimodal imaging-guided photothermal therapy

“…Thus, chelator-free radiolabeling techniques as alternative methods to label nanoparticles would be quite attractive. 44 Motivated by the high affinity between iron and the phenolic hydroxyl groups of GA, we thus hypothesized that Fe-GA CPNs may be labeled with 64 Cu in a chelator-free manner (Fig. 3a).…”

Nanoparticles as a Tool in Neuro-Oncology Theranostics

“…Another study shared the mechanism of indocyanine green attachment for the imaging of 4T1 breast carcinoma, notably showing 2-fold greater enhancement with the SWCNT–indocyanine green combination than indocyanine green alone [ 88 ]. Other carbon-based nanoparticles useful for PA imaging include graphene oxide nanosheets, which served as PA contrast in two multimodal studies imaging 4T1 breast carcinoma [ 19 , 89 ], and hollow mesoporous carbon nanospheres, which did the same for two other theranostic xenograft studies [ 90 , 91 ]. Aside from carbon-based nanoparticles, our search yielded a mix of other agents that have been studied as PA contrast.…”

“…The study that differed used both 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and desferrioxamine B (DFO) as radiolabels attached to SWCNT for imaging colon adenocarcinoma (LS174T cell line) [ 98 ]. All of the following nanoparticles were transfected with [ 64 ] Cu for PET imaging: graphene oxide nanosheets in two studies viewing breast carcinoma [ 89 , 99 ], zinc oxide to image breast carcinoma [ 100 ], boron nitride nanoparticles in a therapeutic study of breast carcinoma [ 101 ], and molybdenum disulfide–iron oxide nanocomposite as previously mentioned to view breast carcinoma [ 34 ]. Iron oxide radiolabeled with [ 64 ] Cu has been shown to provide contrast on PET for imaging various brain tumors [ 54 ], while SWCNT have been used to view a glioblastoma model [ 96 ].…”