To create a platform applicable to the many uses of metals in medicine, we recently synthesized the first metal-chelating nanogel imaging agent, which employs versatile, reproducible chemistry for maximal chelation stability. Combining positron emission tomography (PET) and magnetic resonance imaging (MRI) brings together high sensitivity and high resolution, so our overall goal is a multimodal imaging agent. Here we demonstrate that our metal-chelating crosslinked nanogel technology is a versatile platform by incorporating either Gd3+ to obtain MRI contrast agents or 64Cu to obtain PET radiotracers. The nanogel structure slows the chelator's tumbling frequency and allows fast exchange with water, both of which enhance relaxivity. Polyacrylamide-based nanogels (diameter 50 to 85 nm) incorporating these crosslinkers and chelating Gd3+ display higher relaxivity than clinically used contrast agents, up to 6-fold greater than Dotarem®. Importantly, these nanogels also stabilize Gd3+ within the chelate against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. After radiolabeling, nanogels stably retained 64Cu in mouse serum and accumulated in tumors and metastases in vivo as detected by PET/CT imaging. Biodistribution studies revealed high accumulation in tumors (12.3% ID/g and 16.6% ID/g) and metastases (29.9% and 30.4% ID/g) at 24 and 48 h following administration, and low accumulation in the liver (8.5% ID/g at 24 h) and spleen (5.5% ID/g). We are now incorporating our crosslinkers into nanogels composed of a biodegradable polymer to allow breakdown into biocompatible small molecules to facilitate clearance. We also plan to chelate our crosslinkers with 177Lu to obtain theranostic nanogels for bimodal imaging MRI/PET and radiation therapy.

Nanogels from metal-chelating crosslinkers applied to copper-64 PET imaging of tumors and metastases

249th National Meeting (2015)

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