Facile Method To Radiolabel Glycol Chitosan Nanoparticles
with <sup>64</sup>Cu via Copper-Free Click Chemistry for MicroPET
Imaging
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Abstract
An efficient and straightforward
method for radiolabeling nanoparticles
is urgently needed to understand the <i>in vivo</i> biodistribution
of nanoparticles. Herein, we investigated a facile and highly efficient
strategy to prepare radiolabeled glycol chitosan nanoparticles with <sup>64</sup>Cu via a strain-promoted azide–alkyne cycloaddition
strategy, which is often referred to as click chemistry. First, the
azide (N<sub>3</sub>) group, which allows for the preparation of radiolabeled
nanoparticles by copper-free click chemistry, was incorporated to
glycol chitosan nanoparticles (CNPs). Second, the strained cyclooctyne
derivative, dibenzyl cyclooctyne (DBCO) conjugated with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (DOTA) chelator, was synthesized for preparing the preradiolabeled
alkyne complex with <sup>64</sup>Cu radionuclide. Following incubation
with the <sup>64</sup>Cu-radiolabeled DBCO complex (DBCO-PEG<sub>4</sub>-Lys-DOTA-<sup>64</sup>Cu with high specific activity, 18.5 GBq/μmol),
the azide-functionalized CNPs were radiolabeled successfully with <sup>64</sup>Cu, with a high radiolabeling efficiency and a high radiolabeling
yield (>98%). Importantly, the radiolabeling of CNPs by copper-free
click chemistry was accomplished within 30 min, with great efficiency
in aqueous conditions. In addition, we found that the <sup>64</sup>Cu-radiolabeled CNPs (<sup>64</sup>Cu-CNPs) did not show any significant
effect on the physicochemical properties, such as size, zeta potential,
or spherical morphology. After <sup>64</sup>Cu-CNPs were intravenously
administered to tumor-bearing mice, the real-time, <i>in vivo</i> biodistribution and tumor-targeting ability of <sup>64</sup>Cu-CNPs
were quantitatively evaluated by microPET images of tumor-bearing
mice. These results demonstrate the benefit of copper-free click chemistry
as a facile, preradiolabeling approach to conveniently radiolabel
nanoparticles for evaluating the real-time <i>in vivo</i> biodistribution of nanoparticles