RT Journal Article SR Electronic T1 Brachytherapy using 90Y-labeled thermo-responsive polymers thatself-aggregate in tumor tissues JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 473 OP 473 VO 57 IS supplement 2 A1 Kohei Sano A1 Yuko Kanada A1 Kengo Kanazaki A1 Ning Ding A1 Masahiro Ono A1 Hideo Saji YR 2016 UL http://jnm.snmjournals.org/content/57/supplement_2/473.abstract AB 473Objectives Brachytherapy is a form of radiotherapy wherein titanium capsules containing therapeutic radioisotopes are implanted within tumor tissues, enabling high-dose radio-irradiation to tumor tissues around the seeds. Owing to long-term antitumor effect and low damage to normal tissues, brachytherapy demonstrates marked therapeutic effects especially for prostate cancer. However, because brachytherapy needs complicated implantation technique under general anesthesia and the seeds could migrate to other organs, the development of therapeutic radiopharmaceuticals that self-aggregate and are rigidly retained upon intratumoral injection are desired. The aim of this study is to establish a novel brachytherapy using injectable thermo-responsive polymers labeled with yttrium-90 (90Y, therapeutic β--ray emitting radiometal), which can aggregate at body temperature, resulting in long-term intratumoral retention of radioactivity and therapeutic effect. Polyoxazoline (POZ) is a biocompatible, water-soluble polymer that can be chemically synthesized by living cationic polymerization. POZ self-aggregates above a characteristic transition temperature (Tt), which is dependent on oxazoline composition and the molecular weight of polymers. Therefore, in this study, we first evaluated the tumor retention of POZ labeled with indium-111 (111In,γ-ray emitting radiometal), followed by a therapeutic study using 90Y-labeled POZ derivatives.Methods Using oxazoline derivatives with ethyl (Et), isopropyl (Isp), and propyl (Pr) side chains, EtPOZ, IspPOZ, PrPOZ, and Isp-PrPOZ (heteropolymer) were synthesized using microwave irradiation, and their Tts were measured. The intratumoral retention of radiolabeled POZ (0.1-2.0 mM, 5 μL) was evaluated until 7 days post-injection in nude mice bearing PC-3 human prostate cancer in the right legs. The intratumoral localization of 111In-labeled POZ derivatives was investigated by an autoradiographic study. Furthermore, a therapeutic study using 90Y-labeled Isp-PrPOZ (2.0 mM, 0.74-3.7 MBq) was performed, and tumor growth and survival rate were evaluated.Results The molecular weight of all polymers was adjusted to approximately 20 kDa. The Tts of EtPOZ, IspPOZ, Isp-PrPOZ, and PrPOZ were >70°C, 34°C, 25°C, and 19°C, respectively. Isp-PrPOZ and PrPOZ were immediately (<1 sec) aggregated by heating at 36°C. The radiochemical purity of 111In- or 90Y-labeled POZ was more than 99% for all polymers. In the intratumoral injection study, Isp-PrPOZ and PrPOZ (2.0 mM) with Tts lower than body temperature (approximately 35°C) 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 (0.1 mM), 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 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 to that observed for the vehicle-injected group and non-radioactive Isp-PrPOZ-injected group.Conclusions These results demonstrated that 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.