Radiolabeled L-oligonucleotides with tunable pharmacokinetics — a suitable complementary system for pretargeting technologies

Complementary mirror-image L-oligonucleotides (L-ON) and tumorspecific antibodies appear as a suitable system for pretargeting technologies. However, optimization of the radiopharmacological characteristics of the LON is a prerequisite for high accumulation in the target. The objective was to decrease the kidney uptake, to increase the area under the blood curve (AUC), and to minimize the nonspecific accumulation in the body. Therefore the L-ON were conjugated with PEG units of increasing size (2, 5, 10, 20 kDa) and subsequently derivatized with NOTA and DOTA for radiolabeling with Ga-68, Cu-64, Y-86, Y-90, Lu-177.
We investigated the impact of size and structure of the radiolabeled (Ga-68, Cu-64) L-ON on biodistribution and positron emission tomography kinetics. The increasing PEG units, up to 20 kDa PEG, decreased the kidney uptake, increased the activity concentration in the blood, e.g., the AUC, but also increased the liver uptake. We can decisively influence the pharmacokinetics resulting in optimal L-ON kinetics and distribution. These results, combined with the option of different radionuclides and high specific activities of the radiolabeled L-ON, emphasizes the attractiveness of this complementary system for pretargeting approaches.