Brachytherapy with intratumoral injections of radiometal-labeled polymers that thermoresponsively self-aggregate in tumor tissues

Abstract

Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radioirradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs a complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study was to establish a novel brachytherapy using biocompatible, injectable thermoresponsive polymers (polyoxazoline [POZ]) labeled with 90Y, which can self-aggregate above a specific transition temperature (Tt), resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Therefore, we evaluated the tumor retention of radiolabeled POZ derivatives and their therapeutic effects. Methods: Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, we synthesized EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ and measured their characteristic Tts. The intratumoral retention of 111In-labeled POZ was evaluated until 7 d after injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization of 111In-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using 90Y-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. Results: The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (;20 kDa) were greater than 70°C, 34°C, 25°C, and 19°C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2,000 μM) with Tts lower than tumor temperature (33.5°C under anesthesia) showed a significantly higher retention of radioactivity at 1 d after injection (73.6% and 73.9%, respectively) than EtPOZ (5.6%) and IspPOZ (15.8%). Even at low injected dose (100 μM), Isp-PrPOZ exhibited high retention (68.3% at 1 d). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 d after injection (69.5%). The autoradiographic study demonstrated that the radioactivity of 111In-labeled Isp-PrPOZ and PrPOZ was localized in a small area. In the therapeutic study using 90Y-labeled Isp-PrPOZ, significant suppression of tumor growth and prolonged survival rate were achieved in an injection dose-dependent manner compared with that observed for the vehicle-injected group and nonradioactive Isp- PrPOZ-injected group. Conclusion: The injectable 90Y-labeled Isp-PrPOZ was retained for a prolonged period within tumor tissues via self-aggregation and exhibited marked therapeutic effect, suggesting its usefulness for brachytherapy.