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.

近距离放射疗法是一种放射疗法，其中将含有治疗性放射性同位素的钛胶囊植入肿瘤组织内，从而能够对种子周围的肿瘤组织进行大剂量放射线照射。尽管已经证明了显着的治疗效果，但是近距离放射治疗需要在全身麻醉下使用复杂的植入技术，并且种子可能会迁移到其他器官。这项研究的目的是建立一种使用⁹⁰ Y标记的生物相容性，可注射热响应性聚合物（polyoxazoline [POZ]）的新型近距离放射疗法，该聚合物可以在特定的转变温度（Tt）以上自聚集，从而长期保留肿瘤的放射性和治疗作用。因此，我们评估了放射性标记的POZ衍生物的肿瘤保留及其治疗效果。方法：使用具有乙基（Et），异丙基（Isp）和丙基（Pr）侧链的恶唑啉衍生物，我们合成了EtPOZ，IspPOZ，Isp-PrPOZ（杂聚物）和PrPOZ，并测量了它们的特征Tts。评估¹¹¹ In标记的P​​OZ在注射PC-7人前列腺癌的裸鼠中的肿瘤内保留时间，直到注射后7 d。通过放射自显影研究了^111种In-标记的POZ衍生物的肿瘤内定位。此外，进行了使用⁹⁰ Y标记的Isp-PrPOZ的治疗研究，并评估了肿瘤的生长和存活率。结果：EtPOZ，IspPOZ，Isp-PrPOZ和PrPOZ（〜20 kDa）的Tts分别高于70°C，34°C，25°C和19°C。在肿瘤内注射研究中，Tts低于肿瘤温度（麻醉下为33.5°C）的Isp-PrPOZ和PrPOZ（2,000μM）显示，注射后1 d的放射性保留率明显高于注射后1 d（分别为73.6％和73.9％）。 EtPOZ（5.6％）和IspPOZ（15.8％）。即使在低注射剂量（100μM）下，Isp-PrPOZ仍显示出高保留率（1 d时为68.3％）。注射后7 d，Isp-PrPOZ的高放射性保留在肿瘤中（69.5％）。放射自显影研究表明¹¹¹ In标记的Isp-PrPOZ和PrPOZ的放射性位于一个小区域。在治疗研究中使用⁹⁰与溶媒注射组和非放射性Isp-PrPOZ注射组相比，以Y标记的Isp-PrPOZ，显着抑制肿瘤生长和延长存活率的剂量依赖性。结论：可注射的⁹⁰ Y标记的Isp-PrPOZ通过自身聚集而在肿瘤组织中保留了较长时间，并显示出显着的治疗效果，表明其可用于近距离放射治疗。