Enhanced Delivery of Radiolabeled Polyoxazoline into Tumors via Self-Aggregation under Hyperthermic Conditions

In order to develop a radiopharmaceutical for internal radiotherapy that had a high anticancer effect while exposing normal tissues to low radiation levels, we synthesized a radiolabeled polyoxazoline (POZ), a thermoresponsive polymer, and established a novel drug delivery system for targeting tumors by accelerating the accumulation of the radiolabeled POZ via self-aggregation under hyperthermic (42-43 °C) conditions. By living-cationic polymerization using 2-ethyl-2-oxazoline and 2-isopropyl-2-oxazoline, POZ derivatives (Et-IspPOZ) (10, 20, and 30 kDa) with lower critical solution temperatures (LCSTs) of 37-38 °C were synthesized; the POZ derivatives were soluble at the body temperature but self-aggregated upon heat treatment (42-43 °C). Next, the indium-111 (¹¹¹In)-labeled Et-IspPOZ was prepared, and the effect of molecular weight and injected POZ dose on the accumulation of radioactivity in the tumors was investigated upon intravenous injection of probes under hyperthermic conditions in colon 26-bearing mice. The uptake of radioactivity in tumors was increased when the molecular weight of POZ was greater than 20 kDa, while it was independent of the injected POZ dose (4-40 nmol). The amount of radioactivity retained in the tumor did not change for up to 3 h after exposure to heat treatment was stopped. Furthermore, the tumor uptake of the Et-IspPOZ derivative with an LCST greater than 42 °C was significantly lower than that of Et-IspPOZ, which had an LCST of 37-38 °C, suggesting the involvement of the self-aggregation of POZ on tumor uptake. Finally, the intratumoral localization of fluorescence-labeled Et-IspPOZ was evaluated using in vivo confocal laser microscopy. Many bright fluorescence spots were observed in the heat-treated tumors nearby and within blood vessels. In conclusion, the high tumor uptake of radiolabeled Et-IspPOZ was elucidated under hyperthermic conditions; thereby, the possibility of developing a novel internal radiotherapy using radiolabeled POZ derivatives was demonstrated.