Brachytherapy with Intratumoral Injections of Radiometal-labeled Polymers that Thermo-responsively Self-aggregate in Tumor Tissues

Brachytherapy is a type of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radio-irradiation to tumor tissues around the seeds. Although marked therapeutic effects have been demonstrated, brachytherapy needs complicated implantation technique under general anesthesia and the seeds could migrate to other organs. The aim of this study is to establish a novel brachytherapy using biocompatible, injectable thermo-responsive polymers (polyoxazoline; POZ) labeled with yttrium-90 ((90)Y), which can self-aggregate above a specific transition temperature, 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, EtPOZ, IspPOZ, Isp-PrPOZ (heteropolymer), and PrPOZ were synthesized, and their characteristic transition temperature (Tt) was measured. The intratumoral retention of (111)In-labeled POZ was evaluated until 7 days post-injection in nude mice bearing PC-3 human prostate cancer. The intratumoral localization of (111)In-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using (90)Y-labeled Isp-PrPOZ was performed, and tumor growth and survival rate were evaluated. RESULTS: The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ (approximately 20 kDa) were >70°C, 34°C, 25°C, and 19°C, respectively. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2000 μM) with Tts lower than tumor temperature (33.5°C under anaesthesia) showed a significantly higher retention of radioactivity at 1 day post-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 day). The high level of radioactivity of Isp-PrPOZ was retained in the tumor 7 days post-injection (69.5%). The autoradiographic study demonstrated that the radioactivity of (111)In-labeled Isp-PrPOZ and PrPOZ was localized in a small area. In the therapeutic study using (90)Y-labeled Isp-PrPOZ, significant suppression of tumor growth and prolonged survival rate were achieved in an injection dose-dependent manner compared to that observed for the vehicle-injected group and non-radioactive Isp-PrPOZ-injected group. CONCLUSION: The injectable (90)Y-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.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017 Apr 13 [Epub ahead of print]

Kohei Sano, Yuko Kanada, Kengo Kanazaki, Ning Ding, Masahiro Ono, Hideo Saji

Kobe Pharmaceutical University, Japan., Graduate School of Pharmaceutical Sciences, Kyoto University, Japan., Canon Inc., Japan., Kyoto University, Japan.