PET and MR imaging with 64Cu/68Ga-labeled AGuIX ultra-small nanoparticles in tumor-bearing mice

Objectives To determine tumor targeting by MRI and PET imaging with ultra-small gadolinium-based nanoparticles, AGuIX, AGuIX-⁶⁸Ga and AGuIX-NODA-⁶⁴Cu, in a 4T1 murine breast cancer model. These particles have capabilities to radiosensitive tumors prior to external beam irradiation, and therefore imaging will assist in guiding radiation therapy.

Methods Radiolabeling conditions for ultra-small nanoparticles with either ⁶⁸Ga or ⁶⁴Cu were optimized for small animal PET imaging. Ten female BALB/c mice were injected subcutaneously above the right shoulder with 1 x 10⁵ 4T1 cells and allowed to grow to ~100-500 mm³. Two mice were imaged by MRI immediately after tail vein injection of unlabeled AGuIX nanoparticles. Four mice were imaged by PET/CT at 1, 2, 4, 24 h after injection with AGuIX-NODA-⁶⁴Cu. And four mice were imaged by PET/CT at 1, 2, 4 h after injection with AGuIX-⁶⁸Ga. Biodistribution studies were done at the 24 h and 4 h time point for mice injected with AGuIX-NODA-⁶⁴Cu and AGuIX-⁶⁸Ga, respectively.

Results The radiolabeling yields of these ultra-small nanoparticles were 81-85%. T1-weighted MRI of tumors following i.v. injection showed fast accumulation (within 10 min p.i.) and slow diffusion out of the tumor (over 30 min p.i.). The PET images showed significant accumulation in the tumor, 3.00 ± 0.53% ID/g for AGuIX-NODA-⁶⁴Cu 24 h p.i. and for 4.59 ± 1.02% ID/g AGuIX-⁶⁸Ga 4 h p.i. Measurement of radioactivity in major organs ex vivo of AGuIX-NODA-⁶⁴Cu 24h p.i. gave tumor:muscle ratios of 10.42, and the SUV_max was 2.56. For AGuIX-NODA-⁶⁴Cu, the kidney had the highest non-target tissue uptake (55.9%ID/g_max at 24 h), with relatively low liver and muscle uptake (4.17 and 0.71%ID/g_max at 24 h, respectively).

Conclusions Radiolabeling conditions are being optimized to increase radiochemical yield. The MR images with AGuIX and PET with AGuIX-NODA-⁶⁴Cu and AGuIX-⁶⁸Ga nanoparticles showed accumulation in tumors with renal clearance. Optimal nanoparticle uptake into the tumors was from 1 to 4 h post injection as determined by PET/CT imaging. SUPPORT: DOE DE SC0008833, NCI P30CA047904, and S10 RR025098.