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.

Feasibility of poly(ethylene glycol) derivatives as diagnostic drug carriers for tumor imaging.

Poly(ethylene glycol) (PEG) is an artificial but biocompatible hydrophilic polymer that has been widely used in clinical products. To evaluate the feasibility of using PEG derivative itself as a tumor imaging carrier via an enhanced permeability and retention (EPR) effect, we prepared indium-111-labeled PEG ((111)In-DTPA-PEG) and indocyanine green (ICG)-labeled PEG (ICG-PEG) with PEG molecular weights of 5-40kDa and investigated their in vivo biodistribution in colon26 tumor-bearing mice. Thereafter, single-photon emission computed tomography (SPECT) and photoacoustic (PA) imaging studies were performed. The in vivo biodistribution studies demonstrated increased tumor uptake and a prolongation of circulation half-life as the molecular weight of PEG increased. Although the observed differences in in vivo biodistribution were dependent on the labeling method ((111)In or ICG), the tumor-to-normal tissue ratios were comparable. Because PEG-based probes with a molecular weight of 20kDa (PEG20) showed a preferable biodistribution (highest accumulation among tissues excised and relatively high tumor-to-blood ratios), an imaging study using (111)In-DTPA-PEG20 and ICG-PEG20 was performed. Colon26 tumors inoculated in the right shoulder were clearly visualized by SPECT 24h after administration. Furthermore, PA imaging using ICG-PEG20 also detected tumor regions, and the detected PA signals increased in proportion with the injected dose. These results suggest that PEG derivatives (20kDa) serve as robust diagnostic drug carriers for tumor imaging.