Nanogels from Metal-Chelating Crosslinkers as Versatile Platforms Applied to Copper-64 PET Imaging of Tumors and Metastases

Abstract

Metals are essential in medicine for both therapy and diagnosis. We recently created the first metal-chelating nanogel imaging agent, which employed versatile, reproducible chemistry that maximizes chelation stability. Here we demonstrate that our metal chelating crosslinked nanogel technology is a powerful platform by incorporating 64Cu to obtain PET radiotracers. Polyacrylamide-based nanogels were crosslinked with three different polydentate ligands (DTPA, DOTA, NOTA). NOTA-based nanogels stably retained 64Cu in mouse serum and accumulated in tumors in vivo as detected by PET/CT imaging. Measurement of radioactivity in major organs ex vivo confirmed this pattern, revealing a high accumulation (12.3% ID/g and 16.6% ID/g) in tumors at 24 and 48 h following administration, with lower accumulation in the liver (8.5% ID/g at 24 h) and spleen (5.5% ID/g). Nanogels accumulated even more efficiently in metastases (29.9% and 30.4% ID/g at 24 and 48 h). These metal-chelating nanogels hold great promise for future application as bimodal PET/MRI agents; chelation of β-emitting radionuclides could enable radiation therapy.

Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation

“…Polyacrylamide-based nanogel crosslinked with polydentate chelating ligands that were developed by Allmutairi and coworkers can be also used as a scaffold for metal radionuclides to obtain PET radiotracers [182]. Various crosslinkers based on DTPA, DOTA or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) were synthesized to optimize the chelation stability of nanogels.…”

Long-Lasting and Efficient Tumor Imaging Using a High Relaxivity Polysaccharide Nanogel Magnetic Resonance Imaging Contrast Agent

“…β-CD disrupts the interaction between cholesterol moieties and therefore unravels CHPOA nanogels. 32 The size distribution of Gd-CHPOA in the presence of β-CD remained the same for 24 h ( Figure 2B). In contrast, within 1 h after addition of β-CD, the size distribution of CHPOA without chemical cross-links broadened to include multiple peaks at larger sizes, indicating the formation of large aggregates ( Figure 2C).…”

Nanogels as imaging agents for modalities spanning the electromagnetic spectrum

“…4 ). 93 64 Cu was selected because of its advantageous long half-life (12.7 h). To enhance Cu-chelating stability, a 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) crosslinker was synthesized and used in the PAAm nanogel formulation, allowing retention of 94% of the copper in the nanogels after 48 h of incubation in serum.…”